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de Sousa DP, de Assis Oliveira F, Arcanjo DDR, da Fonsêca DV, Duarte ABS, de Oliveira Barbosa C, Ong TP, Brocksom TJ. Essential Oils: Chemistry and Pharmacological Activities-Part II. Biomedicines 2024; 12:1185. [PMID: 38927394 PMCID: PMC11200837 DOI: 10.3390/biomedicines12061185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 05/17/2024] [Accepted: 05/20/2024] [Indexed: 06/28/2024] Open
Abstract
The importance of essential oils and their components in the industrial sector is attributed to their chemical characteristics and their application in the development of products in the areas of cosmetology, food, and pharmaceuticals. However, the pharmacological properties of this class of natural products have been extensively investigated and indicate their applicability for obtaining new drugs. Therefore, this review discusses the use of these oils as starting materials to synthesize more complex molecules and products with greater commercial value and clinic potential. Furthermore, the antiulcer, cardiovascular, and antidiabetic mechanisms of action are discussed. The main mechanistic aspects of the chemopreventive properties of oils against cancer are also presented. The data highlight essential oils and their derivatives as a strategic chemical group in the search for effective therapeutic agents against various diseases.
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Affiliation(s)
| | | | - Daniel Dias Rufino Arcanjo
- LAFMOL—Laboratory of Functional and Molecular Studies in Physiopharmacology, Department of Biophysics and Physiology, Federal University of Piaui, Teresina 64049-550, Brazil; (D.D.R.A.); (C.d.O.B.)
| | - Diogo Vilar da Fonsêca
- Collegiate of Medicine, Federal University of São Francisco Valley, Bahia 48607-190, Brazil;
| | - Allana Brunna S. Duarte
- Laboratory of Pharmaceutical Chemistry, Federal University of Paraíba, João Pessoa 58051-900, Brazil;
| | - Celma de Oliveira Barbosa
- LAFMOL—Laboratory of Functional and Molecular Studies in Physiopharmacology, Department of Biophysics and Physiology, Federal University of Piaui, Teresina 64049-550, Brazil; (D.D.R.A.); (C.d.O.B.)
| | - Thomas Prates Ong
- Department of Food Science and Nutrition, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo 05508-000, Brazil;
- Food Research Center (FoRC), University of São Paulo, São Paulo 05508-000, Brazil
| | - Timothy John Brocksom
- Department of Chemistry, Federal University of São Carlos, São Carlos 13565-905, Brazil;
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Su Y, Zhang X, Liang Y, Sun J, Lu C, Huang Z. Integrated analysis of single-cell RNA-seq and bulk RNA-seq to unravel the molecular mechanisms underlying the immune microenvironment in the development of intestinal-type gastric cancer. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166849. [PMID: 37591405 DOI: 10.1016/j.bbadis.2023.166849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 08/02/2023] [Accepted: 08/12/2023] [Indexed: 08/19/2023]
Abstract
Intestinal-type gastric cancer (IGC) is the most frequent type of gastric cancer in high-incidence populations. The early stages of IGC growth successively include nonatrophic gastritis (NAG), chronic atrophic gastritis (CAG) and intestinal metaplasia (IM). However, the mechanisms of IGC development through these stages remain unclear. For this study, single-cell RNA-seq data related to IGC were downloaded from the GEO database, and immune cells of the tumor microenvironment (TME) were annotated using R software. Changes in the proportion of immune cells and altered cell-to-cell interactions were explored at different disease stages using R software, with a focus on plasma cells. Additionally, IGC samples from the TCGA database were used for immune cell infiltration analysis, and a Cox proportional risk regression model was constructed to identify possible prognostic genes. The results indicated that for precancerous lesions, interactions between immune cells were mainly dominated by chemokines to stimulate the infiltration and activation of immune cells. In tumors, intercellular movement of upregulated molecules and amplified signals were associated with the tumor necrosis factor family and immunosuppression to escape immune surveillance and promote tumor growth. Regarding prognostic analysis, IGLC3, IGLV1-44, IGKV1-16, IGHV3-21, IGLV1-51, and IGLV3-19 were found to be novel biomarkers for IGC. Our analysis of the IGC single-cell atlas together with bulk transcriptome data contributes to understanding TME heterogeneity at the molecular level during IGC development and provides insights for elucidating the mechanism of IGC and discovering novel targets for precise therapy.
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Affiliation(s)
- Yongjian Su
- Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China; Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan, China
| | - Xiaoqing Zhang
- School of Basic Medicine, Guangdong Medical University, Dongguan, China
| | - Youcheng Liang
- Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China; Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan, China
| | - Jianbo Sun
- Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
| | - Chengyu Lu
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan, China.
| | - Zunnan Huang
- Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China; Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan, China.
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Yoon K. Gastric Cancer: H. pylori and Macrophage Migration Inhibitory Factor. HELICOBACTER PYLORI 2023:321-326. [DOI: 10.1007/978-981-97-0013-4_25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Macrophage Migration Inhibitory Factor (MIF) as a Stress Molecule in Renal Inflammation. Int J Mol Sci 2022; 23:ijms23094908. [PMID: 35563296 PMCID: PMC9102975 DOI: 10.3390/ijms23094908] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 04/26/2022] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
Renal inflammation is an initial pathological process during progressive renal injury regardless of the initial cause. Macrophage migration inhibitory factor (MIF) is a truly proinflammatory stress mediator that is highly expressed in a variety of both inflammatory cells and intrinsic kidney cells. MIF is released from the diseased kidney immediately upon stimulation to trigger renal inflammation by activating macrophages and T cells, and promoting the production of proinflammatory cytokines, chemokines, and stress molecules via signaling pathways involving the CD74/CD44 and chemokine receptors CXCR2, CXCR4, and CXCR7 signaling. In addition, MIF can function as a stress molecule to counter-regulate the immunosuppressive effect of glucocorticoid in renal inflammation. Given the critical position of MIF in the upstream inflammatory cascade, this review focuses on the regulatory role and molecular mechanisms of MIF in kidney diseases. The therapeutic potential of targeting MIF signaling to treat kidney diseases is also discussed.
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Ren S, Wei Y, Niu M, Li R, Wang R, Wei S, Wen J, Wang D, Yang T, Chen X, Wu S, Tong Y, Jing M, Li H, Wang M, Zhao Y. Mechanism of rutaecarpine on ethanol-induced acute gastric ulcer using integrated metabolomics and network pharmacology. Biomed Pharmacother 2021; 138:111490. [PMID: 33773465 DOI: 10.1016/j.biopha.2021.111490] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/22/2021] [Accepted: 03/09/2021] [Indexed: 11/15/2022] Open
Abstract
This study was aimed to explore the mechanism of rutaecarpine (RUT) on ethanol-induced gastric ulcer (GU) in mice by integrated approaches. At first, the efficacy was determined through the macroscopic and microscopic state of stomach tissue and the expression levels of GU-related factors. Then, the serum metabolomics method based on UPLC-Q-TOF/MS was used to explore the specific metabolites and metabolic pathways. Finally, the upstream key protein targets of these specific metabolites were analyzed by network pharmacology and verified by PCR to explore the potential mechanism. RUT alleviated the histological and pathological damage of gastric tissue caused by ethanol, and could remarkably ameliorate the level of GU-related factors. Subsequently, a total of 7 potential metabolites involved in 9 metabolic pathways were identified by metabolomics analysis. Then, a 'component-targets-metabolites' interaction network was constructed, and therefore 4 key target proteins (PLA2G1B, PDE5A, MIF and SRC) that may regulate the specific metabolites were obtained. This case was further verified by the results of PCR. ALL the above results strongly demonstrated that RUT exerted a gastroprotective effect against GU. And it is the first time to combine metabolomics combined with network pharmacology to elucidate the mechanism of RUT on GU, which may be related to the regulation of energy metabolism, oxidative stress, and inflammation, and these pathways may be regulated through the upstream protein PLA2G1B, PDE5A, MIF and SRC.
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Affiliation(s)
- Sichen Ren
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacy, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Ying Wei
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacy, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Ming Niu
- Department of China Military Institute of Chinese Materia, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Ruisheng Li
- Research Center for Clinical and Translational Medicine, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Ruilin Wang
- Integrative Medical Center, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Shizhang Wei
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacy, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Jianxia Wen
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacy, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Dan Wang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacy, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Tao Yang
- Department of Pharmacy, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China; College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Xing Chen
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacy, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Shihua Wu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacy, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Yuling Tong
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacy, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Manyi Jing
- Department of Pharmacy, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Haotian Li
- Department of Pharmacy, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Min Wang
- Department of Pharmacy, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Yanling Zhao
- Department of Pharmacy, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China.
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Asgharzadeh F, Hashemzadeh A, Yaghoubi A, Avan A, Nazari SE, Soleimanpour S, Hassanian SM, Ferns GA, Rahmani F, Khazaei M. Therapeutic effects of silver nanoparticle containing sulfasalazine on DSS-induced colitis model. J Drug Deliv Sci Technol 2021. [DOI: 10.1016/j.jddst.2020.102133] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Hisert KB, Birkland TP, Schoenfelt KQ, Long ME, Grogan B, Carter S, Liles WC, McKone EF, Becker L, Manicone AM, Gharib SA. CFTR Modulator Therapy Enhances Peripheral Blood Monocyte Contributions to Immune Responses in People With Cystic Fibrosis. Front Pharmacol 2020; 11:1219. [PMID: 33013356 PMCID: PMC7461946 DOI: 10.3389/fphar.2020.01219] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 07/27/2020] [Indexed: 12/12/2022] Open
Abstract
Background CFTR modulators decrease some etiologies of CF airway inflammation; however, data indicate that non-resolving airway infection and inflammation persist in individuals with CF and chronic bacterial infections. Thus, identification of therapies that diminish airway inflammation without allowing unrestrained bacterial growth remains a critical research goal. Novel strategies for combatting deleterious airway inflammation in the CFTR modulator era require better understanding of cellular contributions to chronic CF airway disease, and how inflammatory cells change after initiation of CFTR modulator therapy. Peripheral blood monocytes, which traffic to the CF airway, can develop both pro-inflammatory and inflammation-resolving phenotypes, represent intriguing cellular targets for focused therapies. This therapeutic approach, however, requires a more detailed knowledge of CF monocyte cellular programming and phenotypes. Material and Methods In order to characterize the inflammatory phenotype of CF monocytes, and how these cells change after initiation of CFTR modulator therapy, we studied adults (n=10) with CF, chronic airway infections, and the CFTR-R117H mutations before and 7 days after initiation of ivacaftor. Transcriptomes of freshly isolated blood monocytes were interrogated by RNA-sequencing (RNA-seq) followed by pathway-based analyses. Plasma concentrations of cytokines and chemokines were evaluated by multiplex ELISA. Results RNAseq identified approximately 50 monocyte genes for which basal expression was significantly changed in all 10 subjects after 7 days of ivacaftor. Of these, the majority were increased in expression post ivacaftor, including many genes traditionally associated with enhanced inflammation and immune responses. Pathway analyses confirmed that transcriptional programs were overwhelmingly up-regulated in monocytes after 7 days of ivacaftor, including biological modules associated with immunity, cell cycle, oxidative phosphorylation, and the unfolded protein response. Ivacaftor increased plasma concentrations of CXCL2, a neutrophil chemokine secreted by monocytes and macrophages, and CCL2, a monocyte chemokine. Conclusions Our results demonstrate that ivacaftor causes acute changes in blood monocyte transcriptional profiles and plasma chemokines, and suggest that increased monocyte inflammatory signals and changes in myeloid cell trafficking may contribute to changes in airway inflammation in people taking CFTR modulators. To our knowledge, this is the first report investigating the transcriptomic response of circulating blood monocytes in CF subjects treated with a CFTR modulator.
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Affiliation(s)
- Katherine B Hisert
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, CO, United States.,Center for Lung Biology, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, United States
| | - Timothy P Birkland
- Center for Lung Biology, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, United States
| | - Kelly Q Schoenfelt
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, United States
| | - Matthew E Long
- Center for Lung Biology, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, United States
| | - Brenda Grogan
- Department of Medicine, St. Vincent's University Hospital, Dublin, Ireland
| | - Suzanne Carter
- Department of Medicine, St. Vincent's University Hospital, Dublin, Ireland
| | - W Conrad Liles
- Center for Lung Biology, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, United States
| | - Edward F McKone
- Department of Medicine, St. Vincent's University Hospital, Dublin, Ireland
| | - Lev Becker
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, United States
| | - Anne M Manicone
- Center for Lung Biology, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, United States
| | - Sina A Gharib
- Center for Lung Biology, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, United States
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Guo H, Chen B, Yan Z, Gao J, Tang J, Zhou C. Metabolites profiling and pharmacokinetics of troxipide and its pharmacodynamics in rats with gastric ulcer. Sci Rep 2020; 10:13619. [PMID: 32788674 PMCID: PMC7423950 DOI: 10.1038/s41598-020-70312-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 07/24/2020] [Indexed: 12/17/2022] Open
Abstract
Troxipide is widely used to treat gastric ulcer (GU) in the clinic. However, a lack of systematic metabolic, pharmacokinetic and pharmacological studies limits its clinical use. This study aimed to firstly explore the metabolic, pharmacokinetic and pharmacological mechanisms of troxipide in rats with GU compared to normal control (NC) rats. First, metabolic study was perormed by a highly selective, high-resolution mass spectrometry method. A total of 45 metabolites, including 9 phase I metabolites and 36 phase II metabolites, were identified based on MS/MS spectra. Subsequently, the pharmacokinetics results suggested that the Cmax, Ka, t1/2, AUC(0-t) and AUC(0-∞) of troxipide were significantly increased in rats with GU compared with NC rats. The Vz, K10 and absolute bioavailability of troxipide were obviously decreased in rats with GU compared with NC rats, and its tissue distribution (in the liver, lung and kidney) was significantly different between the two groups of rats. Additionally, the pharmacodynamic results suggested that the levels of biochemical factors (IL-17, IL-6, TNF-α, IFN-γ, AP-1, MTL, GAS, and PG-II) were significantly increased, the PG-Ӏ level was obviously decreased, and the protein expression levels of HSP-90, C-Cas-3 and C-PARP-1 were markedly increased in rats with GU compared with NC rats. The above results suggested that the therapeutic mechanisms underlying the metabolic, pharmacokinetic and pharmacological properties of troxipide in vivo in rats deserve further attention based on the importance of troxipide in the treatment of GU in this study, and these mechanisms could be targets for future studies.
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Affiliation(s)
- Hongbin Guo
- College of Pharmaceutical Sciences, Institute of Life Science and Green Development, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, 180 WuSi Road, Lianchi District, Baoding, 071002, China
| | - Baohua Chen
- College of Pharmaceutical Sciences, Institute of Life Science and Green Development, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, 180 WuSi Road, Lianchi District, Baoding, 071002, China
| | - Zihan Yan
- College of Pharmaceutical Sciences, Institute of Life Science and Green Development, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, 180 WuSi Road, Lianchi District, Baoding, 071002, China
| | - Jian Gao
- College of Pharmaceutical Sciences, Institute of Life Science and Green Development, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, 180 WuSi Road, Lianchi District, Baoding, 071002, China
| | - Jiamei Tang
- College of Pharmaceutical Sciences, Institute of Life Science and Green Development, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, 180 WuSi Road, Lianchi District, Baoding, 071002, China
| | - Chengyan Zhou
- College of Pharmaceutical Sciences, Institute of Life Science and Green Development, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, 180 WuSi Road, Lianchi District, Baoding, 071002, China.
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Yoon K, Kim N, Park Y, Kim BK, Park JH, Shin CM, Lee DH, Surh YJ. Correlation between macrophage migration inhibitory factor and autophagy in Helicobacter pylori-associated gastric carcinogenesis. PLoS One 2019; 14:e0211736. [PMID: 30742638 PMCID: PMC6370197 DOI: 10.1371/journal.pone.0211736] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 01/18/2019] [Indexed: 02/06/2023] Open
Abstract
The role of macrophage migration inhibitory factor (MIF) and autophagy in gastric cancer is not clear. We determined H. pylori infection status of the subjects and investigated the expression of MIF and autophagy markers (Atg5, LC3A and LC3B) in human gastric tissue at baseline. Then H. pylori eradication was done for H. pylori positive patients and MIF and Atg5 levels were investigated on each follow-up for both H. pylori-eradicated and H. pylori negative patients. Baseline tissue mRNA expression of MIF, Atg5, LC3A and LC3B was measured by real-time PCR in 453 patients (control 165, gastric dysplasia 82, and gastric cancer 206). Three hundred three patients (66.9%) had H. pylori infection at the time of enrollment. Only within H. pylori-positive group, MIF level was significantly elevated in patients with cancer than in control or dysplasia groups (P<0.05). LC3A and LC3B levels also showed significant differences within H. pylori-positive subgroups. H. pylori-positive dysplasia subgroup showed significantly lower (LC3A) (P<0.05) and higher (LC3B) mRNA levels (P<0.05) than in other subgroups. On follow-up, within H. pylori-eradicated group, Atg5 expression increased sequentially from control to dysplasia and cancer subgroups. Multiple linear regression showed autophagy markers (LC3A, LC3B, and Atg5) directly predicted MIF level (adjusted R2 = 0.492, P<0.001). Serial follow-up showed longitudinal increase in Atg5 level in general, with constantly higher levels in H. pylori-eradicated group than in -negative group. Intestinal metaplasia (IM) group initially showed higher Atg5 expression than the IM-negative group. However, it was reversed between the groups eventually because of the lower rate of increase in IM group. These results suggest a role of MIF and autophagy markers and their interaction in H. pylori-associated gastric carcinogenesis.
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Affiliation(s)
- Kichul Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- * E-mail:
| | - Youngmi Park
- Medical Research Collaborating Center, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Bo Kyung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Ji Hyun Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Young-Joon Surh
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea
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In vivo cellular and molecular gastroprotective mechanisms of chrysin; Emphasis on oxidative stress, inflammation and angiogenesis. Eur J Pharmacol 2017; 818:486-498. [PMID: 29126792 DOI: 10.1016/j.ejphar.2017.11.008] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 10/28/2017] [Accepted: 11/06/2017] [Indexed: 12/18/2022]
Abstract
Gastric ulcer is one of the major gastrointestinal disorders affecting people worldwide. Despite medical advances, management of gastric ulcer and its complications remains a challenge facing medicine nowadays. In addition, currently available medicines exhibit limited efficacy and several side effects. In the current study, the potential protective effects of chrysin -naturally occurring flavonoid - were tested against indomethacin-induced gastric ulcer model in rats. It was found that chrysin in both doses; 50 and 100mg/kg were effective in promoting mucus secretion and preventing the rise in ulcer and lesion indices, acid production and histologic changes induced by indomethacin. During investigation of the possible underlying mechanisms, chrysin significantly attenuated indomethacin-induced oxidative injury and inflammatory response. Also, chrysin activated peroxisome proliferator activated receptor-ɣ (PPAR-ɣ) leading to a phenotypic switch from pro-inflammatory M1 macrophages to the anti-inflammatory M2 macrophages that evidenced by the upregulated mRNA expression levels of PPAR-ɣ and M2 marker genes (Arg-1 and CD206) and down regulation of M1 marker genes (IL-6 and CCL3). Furthermore, chrysin promoted angiogenesis via increasing expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and cluster of differentiation-31 (CD31). Collectively, these findings indicate that chrysin possesses a potential protective effect against indomethacin-induced gastric ulcer.
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Heidari Z, Mahmoudzadeh-Sagheb H, Hashemi M, Ansarimoghaddam S, Moudi B, Sheibak N. Association of macrophage migration inhibitory factor gene polymorphisms with chronic periodontitis in a South Eastern Iranian population. Dent Res J (Isfahan) 2017; 14:395-402. [PMID: 29238378 PMCID: PMC5713063 DOI: 10.4103/1735-3327.218563] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Background: Macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator. It plays a vital role in immune response against the oral disease. MIF is a regulator of innate immunity, and bacterial antigens can stimulate serum level of this protein. In experimental gingivitis, the expression level of MIF increases and this increment positively correlates with oral plaque index. The single nucleotide polymorphisms in the gene encoding the MIF protein can control the function of MIF. The aim of the present study was a clarification of the associations between MIF-173 G/C, MIF 95 bp, and 189 bp insertion/deletion (I/D) polymorphisms and chronic periodontitis (CP) compared with healthy controls. Materials and Methods: This case–control study was carried out on 210 CP patients and 100 normal subjects. MIF-173 G/C and MIF 95 bp and 189 bp I/D polymorphisms were genotyped, using polymerase chain reaction–restriction fragment-length polymorphism (PCR-RFLP) and PCR, respectively. Allele and genotype frequencies of the variants were compared between patients and controls using Chi-square. test. The value of P < 0.05 was considered statistically significant. Results: The study findings showed that MIF-173 G/C polymorphism, especially the C allele increased the risk of CP. The 95-bp I/D polymorphism was not associated with CP and the 185-bp I/D variant was not polymorphic in our population. Conclusion: Therefore, MIF-137 G/C variant increased the risk of CP in the South East of the Iranian population. In other words, polymorphisms in MIF gene influence clinical outcome of CP infection and influence the susceptibility to disease. Further studies with larger sample sizes and different ethnicities are required to validate our findings.
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Affiliation(s)
- Zahra Heidari
- Infectious Diseases and Tropical Medicine Research Center, Zahedan University of Medical Sciences, Zahedan, Iran.,Department of Histology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Hamidreza Mahmoudzadeh-Sagheb
- Infectious Diseases and Tropical Medicine Research Center, Zahedan University of Medical Sciences, Zahedan, Iran.,Department of Histology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Mohammad Hashemi
- Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan, Iran.,Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences and Health Services, Zahedan, Iran
| | - Somayeh Ansarimoghaddam
- Department of Periodontology, School of Dentistry, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Bita Moudi
- Infectious Diseases and Tropical Medicine Research Center, Zahedan University of Medical Sciences, Zahedan, Iran.,Department of Histology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Nadia Sheibak
- Department of Histology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
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Delbrouck C, Gabius HJ, Vandenhoven G, Kiss R, Hassid S. Budesonide-Dependent Modulation of Expression of Macrophage Migration Inhibitory Factor in a Polyposis Model: Evidence for Differential Regulation in Surface and Glandular Epithelia. Ann Otol Rhinol Laryngol 2016; 113:544-51. [PMID: 15274414 DOI: 10.1177/000348940411300706] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Macrophage migration inhibitory factor (MIF) is a counterregulatory lymphokine for glucocorticoid action within the immune system. To provide further insights into the way expression of pleiotropically acting MIF is modulated by glucocorticoids, we investigated the influence of the glucocorticoid budesonide on the level of expression of MIF in a model of human nasal polyposis by quantitative immunohistochemical analysis. Ten nasal polyps obtained from surgical resection were maintained for 24 hours in the presence of 3 budesonide concentrations: 10, 50, and 250 ng/mL. As quantitatively demonstrated by computer-assisted microscopy, 50 ng/mL induced an increase in MIF expression in the surface epithelium and a decrease in MIF expression in the glandular epithelium. At the 250 ng/mL dose, the inverse effect was induced. Evidently, surface and glandular epithelia react nonuniformly to the glucocorticoid regarding MIF presence, adding dependence on the cell type to the regulatory network.
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Affiliation(s)
- Carine Delbrouck
- Department of Otolaryngology-Head and Neck Surgery, Erasmus University Hospital, Brussels, Belgium
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13
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Xie J, Yang L, Tian L, Li W, Yang L, Li L. Macrophage Migration Inhibitor Factor Upregulates MCP-1 Expression in an Autocrine Manner in Hepatocytes during Acute Mouse Liver Injury. Sci Rep 2016; 6:27665. [PMID: 27273604 PMCID: PMC4897699 DOI: 10.1038/srep27665] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 05/24/2016] [Indexed: 02/07/2023] Open
Abstract
Macrophage migration inhibitor factor (MIF), a multipotent innate immune mediator, is an upstream component of the inflammatory cascade in diseases such as liver disease. Monocyte chemoattractant protein-1 (MCP-1), a highly representative chemokine, is critical in liver disease pathogenesis. We investigated the role of MIF in regulating hepatocytic MCP-1 expression. MIF and MCP-1 expression were characterized by immunochemistry, RT-PCR, ELISA, and immunoblotting in CCl4-treated mouse liver and isolated hepatocytes. MIF was primarily distributed in hepatocytes, and its expression increased upon acute liver injury. Its expression was also increased in injured hepatocytes, induced by LPS or CCl4, which mimic liver injury in vitro. MIF was expressed earlier than MCP-1, strongly inducing hepatocytic MCP-1 expression. Moreover, the increase in MCP-1 expression induced by MIF was inhibited by CD74- or CD44-specific siRNAs and SB203580, a p38 MAPK inhibitor. Further, CD74 or CD44 deficiency effectively inhibited MIF-induced p38 activation. MIF inhibitor ISO-1 reduced MCP-1 expression and p38 phosphorylation in CCl4-treated mouse liver. Our results showed that MIF regulates MCP-1 expression in hepatocytes of injured liver via CD74, CD44, and p38 MAPK in an autocrine manner, providing compelling information on the role of MIF in liver injury, and implying a new regulatory mechanism for liver inflammation.
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Affiliation(s)
- Jieshi Xie
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China
| | - Le Yang
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China
| | - Lei Tian
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China
| | - Weiyang Li
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China
| | - Lin Yang
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China
| | - Liying Li
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China
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14
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Yoon K. Gastric Cancer: H. pylori and Macrophage Migration Inhibitory Factor. HELICOBACTER PYLORI 2016:269-274. [DOI: 10.1007/978-981-287-706-2_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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15
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He LJ, Xie D, Hu PJ, Liao YJ, Deng HX, Kung HF, Zhu SL. Macrophage migration inhibitory factor as a potential prognostic factor in gastric cancer. World J Gastroenterol 2015; 21:9916-9926. [PMID: 26379396 PMCID: PMC4566384 DOI: 10.3748/wjg.v21.i34.9916] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 04/13/2015] [Accepted: 07/15/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate macrophage migration inhibitory factor (MIF) expression and its clinical relevance in gastric cancer, and effects of MIF knockdown on proliferation of gastric cancer cells.
METHODS: Tissue microarray containing 117 samples of gastric cancer and adjacent non-cancer normal tissues was studied for MIF expression by immunohistochemistry (IHC) semiquantitatively, and the association of MIF expression with clinical parameters was analyzed. MIF expression in gastric cancer cell lines was detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Two pairs of siRNA targeting the MIF gene (MIF si-1 and MIF si-2) and one pair of scrambled siRNA as a negative control (NC) were designed and chemically synthesized. All siRNAs were transiently transfected in AGS cells with OligofectamineTM to knock down the MIF expression, with the NC group and mock group (OligofectamineTM alone) as controls. At 24, 48, and 72 h after transfection, MIF mRNA was analyzed by RT-PCR, and MIF and proliferating cell nuclear antigen (PCNA) proteins were detected by Western blot. The proliferative rate of AGS cells was assessed by methylthiazolyl tetrazolium (MTT) assay and colony forming assay.
RESULTS: The tissue microarray was informative for IHC staining, in which the MIF expression in gastric cancer tissues was higher than that in adjacent non-cancer normal tissues (P < 0.001), and high level of MIF was related to poor tumor differentiation, advanced T stage, advanced tumor stage, lymph node metastasis, and poor patient survival (P < 0.05 for all). After siRNA transfection, MIF mRNA was measured by real-time PCR, and MIF protein and PCNA were assessed by Western blot analysis. We found that compared to the NC group and mock group, MIF expression was knocked down successfully in gastric cancer cells, and PCNA expression was downregulated with MIF knockdown as well. The cell counts and the doubling times were assayed by MTT 4 d after transfection, and colonies formed were assayed by colony forming assay 10 d after transfection; all these showed significant changes in gastric cancer cells transfected with specific siRNA compared with the control siRNA and mock groups (P < 0.001 for all).
CONCLUSION: MIF could be of prognostic value in gastric cancer and might be a potential target for small-molecule therapy.
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Oliveira FDA, Andrade LN, de Sousa EBV, de Sousa DP. Anti-ulcer activity of essential oil constituents. Molecules 2014; 19:5717-47. [PMID: 24802985 PMCID: PMC6290561 DOI: 10.3390/molecules19055717] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Revised: 04/18/2014] [Accepted: 04/25/2014] [Indexed: 12/14/2022] Open
Abstract
Essential oils have attracted considerable worldwide attention over the last few decades. These natural products have wide-ranging pharmacological activities and biotechnological applications. Faced with the need to find new anti-ulcer agents and the great effort on the development of drugs for the treatment of ulcers, in this review, the anti-ulcer activities of 21 bioactive compounds found in essential oils are discussed.
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Affiliation(s)
| | - Luciana Nalone Andrade
- Universidade Federal de Sergipe, Departamento de Farmácia, São Cristóvão, SE 49100-000, Brazil
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17
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Prencipe G, Auriti C, Inglese R, Gallusi G, Dotta A, De Benedetti F. The macrophage migration inhibitory factor -173G/C polymorphism is not significantly associated with necrotizing enterocolitis in preterm infants. J Pediatr Surg 2013; 48:1499-502. [PMID: 23895962 DOI: 10.1016/j.jpedsurg.2013.01.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2012] [Revised: 12/28/2012] [Accepted: 01/04/2013] [Indexed: 02/01/2023]
Abstract
BACKGROUND AND PURPOSE Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality among premature infants. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that has been implicated in the pathophysiology of inflammatory bowel diseases. The MIF promoter contains a functionally relevant single nucleotide polymorphism (SNP) G→C at position -173, with the MIF -173*C allele being associated with higher MIF expression in vitro and with higher MIF levels in vivo. The aim of this study was to investigate whether the G/C polymorphism at -173 of the MIF promoter is associated with the development of NEC. METHODS In this retrospective cohort study, 107 preterm infants (GA ≤ 32 weeks), of whom 41 had NEC (NEC Stage I n = 20, Stage II n = 3, Stage III n = 18) and 66 were not affected, were genotyped for the MIF -173 SNP. MIF genotyping was carried out by PCR and DHPLC. RESULTS We did not find significant differences in the prevalence of the -173G/C polymorphism and in the distribution of the -173 MIF genotype in infants with NEC compared to controls. Moreover, we did not observe an association between the polymorphism and mortality. CONCLUSIONS The polymorphism -173G/C of the MIF promoter does not appear to be of major importance in the pathophysiology of NEC in preterm infants.
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Affiliation(s)
- Giusi Prencipe
- Laboratory of Rheumatology, Bambino Gesù Children's Hospital, Roma, Italy
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18
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Li X, Lan HY, Huang XR, Zhang C, Jin LJ. Expression profile of macrophage migration-inhibitory factor in human gingiva and reconstituted human gingival epithelia stimulated by Porphyromonas gingivalis lipopolysaccharide. J Periodontal Res 2013; 48:527-32. [PMID: 23298274 DOI: 10.1111/jre.12035] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/30/2012] [Indexed: 11/29/2022]
Abstract
BACKGROUND AND OBJECTIVE Macrophage migration-inhibitory factor (MIF) plays crucial roles in the recruitment and activation of macrophages as well as in helping to kill bacteria. This study investigated the expression profile of MIF in human gingiva under different periodontal conditions and its expression patterns induced by Porphyromonas gingivalis lipopolysaccharide (LPS) in gingival epithelia. MATERIAL AND METHODS Gingival tissue samples were collected from deep pockets and clinically healthy sites of 22 nonsmoking subjects with chronic periodontitis. The expression of MIF mRNA and protein was evaluated using real-time PCR and immunohistochemistry, respectively. The in vitro study analyzed the effects of P. gingivalis LPS on the expression of MIF in a reconstituted human gingival epithelia (RHGE) model. RESULTS In gingival epithelia, MIF protein was diffusely expressed from the basal layer to the granular and spinous layers; whereas, in the underlying connective tissues, MIF was observed around the dilated blood vessels in the deep-pocket tissues. A significantly lower level of expression of MIF mRNA and an increased level of expression of MIF protein were found in deep-pocket tissues compared with clinically healthy tissues. Expression of MIF mRNA in the RHGE model was significantly down-regulated by P. gingivalis LPS. CONCLUSION The present study suggests that MIF expression may be related to periodontal conditions and that its expression profile could be modulated by P. gingivalis LPS. MIF may play a role in periodontal pathogenesis.
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Affiliation(s)
- X Li
- Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China
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19
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Fehlings M, Drobbe L, Moos V, Renner Viveros P, Hagen J, Beigier-Bompadre M, Pang E, Belogolova E, Churin Y, Schneider T, Meyer TF, Aebischer T, Ignatius R. Comparative analysis of the interaction of Helicobacter pylori with human dendritic cells, macrophages, and monocytes. Infect Immun 2012; 80:2724-34. [PMID: 22615251 PMCID: PMC3434561 DOI: 10.1128/iai.00381-12] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2012] [Accepted: 05/14/2012] [Indexed: 12/15/2022] Open
Abstract
Helicobacter pylori may cause chronic gastritis, gastric cancer, or lymphoma. Myeloid antigen-presenting cells (APCs) are most likely involved in the induction and expression of the underlying inflammatory responses. To study the interaction of human APC subsets with H. pylori, we infected monocytes, monocyte-derived dendritic cells (DCs), and monocyte-derived (classically activated; M1) macrophages with H. pylori and analyzed phenotypic alterations, cytokine secretion, phagocytosis, and immunostimulation. Since we detected CD163(+) (alternatively activated; M2) macrophages in gastric biopsy specimens from H. pylori-positive patients, we also included monocyte-derived M2 macrophages in the study. Upon H. pylori infection, monocytes secreted interleukin-1β (IL-1β), IL-6, IL-10, and IL-12p40 (partially secreted as IL-23) but not IL-12p70. Infected DCs became activated, as shown by the enhanced expression of CD25, CD80, CD83, PDL-1, and CCR7, and secreted IL-1β, IL-6, IL-10, IL-12p40, IL-12p70, and IL-23. However, infection led to significantly downregulated CD209 and suppressed the constitutive secretion of macrophage migration inhibitory factor (MIF). H. pylori-infected M1 macrophages upregulated CD14 and CD32, downregulated CD11b and HLA-DR, and secreted mainly IL-1β, IL-6, IL-10, IL-12p40, and IL-23. Activation of DCs and M1 macrophages correlated with increased capacity to induce T-cell proliferation and decreased phagocytosis of dextran. M2 macrophages upregulated CD14 and CD206 and secreted IL-10 but produced less of the proinflammatory cytokines than M1 macrophages. Thus, H. pylori affects the functions of human APC subsets differently, which may influence the course and the outcome of H. pylori infection. The suppression of MIF in DCs constitutes a novel immune evasion mechanism exploited by H. pylori.
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Affiliation(s)
- Michael Fehlings
- Institute of Tropical Medicine and International Health, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Lea Drobbe
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Verena Moos
- Medical Clinic I, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Pablo Renner Viveros
- Institute of Tropical Medicine and International Health, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Jana Hagen
- Institute of Tropical Medicine and International Health, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | | | - Ervinna Pang
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Elena Belogolova
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Yuri Churin
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Thomas Schneider
- Medical Clinic I, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Thomas F. Meyer
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Toni Aebischer
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
- Robert Koch Institute, Berlin, Germany
| | - Ralf Ignatius
- Institute of Tropical Medicine and International Health, Charité-Universitätsmedizin Berlin, Berlin, Germany
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20
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Alam A, Haldar S, Thulasiram HV, Kumar R, Goyal M, Iqbal MS, Pal C, Dey S, Bindu S, Sarkar S, Pal U, Maiti NC, Bandyopadhyay U. Novel anti-inflammatory activity of epoxyazadiradione against macrophage migration inhibitory factor: inhibition of tautomerase and proinflammatory activities of macrophage migration inhibitory factor. J Biol Chem 2012; 287:24844-61. [PMID: 22645149 DOI: 10.1074/jbc.m112.341321] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Macrophage migration inhibitory factor (MIF) is responsible for proinflammatory reactions in various infectious and non-infectious diseases. We have investigated the mechanism of anti-inflammatory activity of epoxyazadiradione, a limonoid purified from neem (Azadirachta indica) fruits, against MIF. Epoxyazadiradione inhibited the tautomerase activity of MIF of both human (huMIF) and malaria parasites (Plasmodium falciparum (PfMIF) and Plasmodium yoelii (PyMIF)) non-competitively in a reversible fashion (K(i), 2.11-5.23 μm). Epoxyazadiradione also significantly inhibited MIF (huMIF, PyMIF, and PfMIF)-mediated proinflammatory activities in RAW 264.7 cells. It prevented MIF-induced macrophage chemotactic migration, NF-κB translocation to the nucleus, up-regulation of inducible nitric-oxide synthase, and nitric oxide production in RAW 264.7 cells. Epoxyazadiradione not only exhibited anti-inflammatory activity in vitro but also in vivo. We tested the anti-inflammatory activity of epoxyazadiradione in vivo after co-administering LPS and MIF in mice to mimic the disease state of sepsis or bacterial infection. Epoxyazadiradione prevented the release of proinflammatory cytokines such as IL-1α, IL-1β, IL-6, and TNF-α when LPS and PyMIF were co-administered to BALB/c mice. The molecular basis of interaction of epoxyazadiradione with MIFs was explored with the help of computational chemistry tools and a biological knowledgebase. Docking simulation indicated that the binding was highly specific and allosteric in nature. The well known MIF inhibitor (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) inhibited huMIF but not MIF of parasitic origin. In contrast, epoxyazadiradione inhibited both huMIF and plasmodial MIF, thus bearing an immense therapeutic potential against proinflammatory reactions induced by MIF of both malaria parasites and human.
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Affiliation(s)
- Athar Alam
- Division of Infectious Diseases and Immunology, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India
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21
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de Dios Rosado J, Rodriguez-Sosa M. Macrophage migration inhibitory factor (MIF): a key player in protozoan infections. Int J Biol Sci 2011; 7:1239-56. [PMID: 22110378 PMCID: PMC3221362 DOI: 10.7150/ijbs.7.1239] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Accepted: 10/01/2011] [Indexed: 12/27/2022] Open
Abstract
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine produced by the pituitary gland and multiple cell types, including macrophages (Mø), dendritic cells (DC) and T-cells. Upon releases MIF modulates the expression of several inflammatory molecules, such as TNF-α, nitric oxide and cyclooxygenase 2 (COX-2). These important MIF characteristics have prompted investigators to study its role in parasite infections. Several reports have demonstrated that MIF plays either a protective or deleterious role in the immune response to different pathogens. Here, we review the role of MIF in the host defense response to some important protozoan infections.
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Affiliation(s)
| | - Miriam Rodriguez-Sosa
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), 54090 Tlalnepantla, Estado de México, México
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22
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Vera PL, Meyer-Siegler KL. Association between macrophage migration inhibitory factor promoter region polymorphism (-173 G/C) and cancer: a meta-analysis. BMC Res Notes 2011; 4:395. [PMID: 22168770 PMCID: PMC3238298 DOI: 10.1186/1756-0500-4-395] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2011] [Accepted: 10/11/2011] [Indexed: 12/21/2022] Open
Abstract
Background Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine upstream of many inflammatory cytokines. MIF is implicated in several acute and chronic inflammatory conditions. MIF's promoter region has functional single nucleotide polymorphisms that controls MIF expression and protein levels. Since increased plasma MIF levels are associated with cancer, studies have examined the association between Mif promoter polymorphisms and cancer. This study is a meta-analysis of the available studies on such an association. Results A total of 5 studies were included in this meta-analysis to include 1116 cases (cancer patients) and 1728 controls (no cancer). Carrying any C allele in the Mif -173 G/C promoter polymorphism resulted in a significantly greater risk for developing cancer [OR = 1.89 (1.15-3.11), p = 0.012)] when compared to the (G/G) genotype. Subgroup analysis revealed that this association was significant only for "solid" tumors (including gastric and prostate cancers) [OR = 2.67 (1.26-5.65), p = 0.010] but not for "non-solid" tumors (leukemia) [OR = 1.21 (0.95-1.55), p = 0.122]. Furthermore, when only prostate tumor studies were included in the analysis, the association became even stronger [OR = 3.72 (2.55-5.41), p < 0.0001]. Conclusions Meta-analysis suggests there is an association between any C allele in the Mif -173 G/C promoter polymorphism and an increased risk of cancer, particularly for solid tumors. The association appeared stronger for prostate cancer, specifically. Future studies that include different types of cancers are needed to support and extend these observations.
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Affiliation(s)
- Pedro L Vera
- The Bay Pines VA Healthcare System, Research & Development, Bay Pines, Florida, USA.
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Clinicopathological significance of macrophage migration inhibitory factor and its relation with p53 in gastric cancer. J Gastrointest Cancer 2011; 42:5-10. [PMID: 20922580 DOI: 10.1007/s12029-010-9215-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
AIM Based on previous investigations, the progress of gastritis may lead to gastric carcinomas. In some epithelial tumors, macrophage migration inhibitory factor (MIF), which is an inflammatory cytokine may inactivate p53 and play a role in tumorigenesis process. We decided to evaluate clinicopathological significance of MIF expression and the relation between p53 and MIF expressions in gastric adenocarcinomas. METHODS Seventy-three consecutive cases of gastric adenocarcinomas, the tissue samples of which were available, were included in this study. Tissue sections were stained for MIF and p53 expression by immunohistochemistry and the expression was defined as positive (for more than 10%) and negative (for less than 10%) groups. Location of the tumor, histological subtypes, and grade of the tumor were determined by using routine H&E staining. Distant metastasis, lymph node involvement, and consequently the stage of tumor were specified. The patients' age and gender were obtained from their medical records. The relationship between expression of MIF and these variables was determined. RESULTS Overexpression of MIF was observed in the cytoplasm of cancer cells in 46.6% (34/73) of cases and nuclear immunostaining of p53 was observed in 37% (27/73) of cases. Expression of MIF was significantly correlated with the location of tumor, but this expression has no statistically significant correlation with variables including: age, gender histological subtypes, distant metastasis, and lymph node involvement, stage and grade of the tumor, and p53 tumor suppressor gene expression. CONCLUSIONS Our study suggests that MIF in gastric adenocarcinomas versus many other epithelial tumors cannot have a prominent role in tumor progress and inactivation of p53 tumor suppressor gene.
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Al-Sayyad AJ, El-Morshedy SM, Al Hamid EAA, Karam NA, Imam ABA, Karam RA. Evaluation of Biomarkers to Differentiate Upper From Lower Urinary Tract Infections in Children. UROTODAY INTERNATIONAL JOURNAL 2011; 04. [DOI: 10.3834/uij.1944-5784.2011.08.05] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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Ohkawara T, Takeda H, Ohnishi S, Kato M, Nishihira J, Asaka M. Macrophage migration inhibitory factor contributes to development of nonsteroidal anti-inflammatory drugs-induced gastric injury in mice. Int Immunopharmacol 2010; 11:418-23. [PMID: 21185918 DOI: 10.1016/j.intimp.2010.12.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2010] [Revised: 12/09/2010] [Accepted: 12/10/2010] [Indexed: 01/06/2023]
Abstract
Macrophage migration inhibitory factor (MIF) plays an important role in the development of inflammation. In this study, we evaluated the role of MIF in gastric injury induced by non-steroidal anti-inflammatory drugs (NSAIDs) in mice. To induce gastric injury, mice were intraperitnoneally injected with 35 mg/kg of indomethacin. The level of MIF protein was up-regulated and severe gastric injury with inflammatory infiltrate was observed in the stomach of wild-type (WT) mice treated with indomethacin. The severity of gastric injury in MIF-deficient mice was less than that in WT mice. Increase in TNF-α in gastric tissue of mice treated with indomethacin was suppressed in MIF-deficient mice. The expression of HSP70, which has a cytoprotective role, was remarkably up-regulated in the stomach of MIF-deficient mice compared with WT mice after indomethacin treatment. Our results suggest that MIF is essential for the development of gastric injury-induced by NSAIDs.
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Affiliation(s)
- Tatsuya Ohkawara
- Department of Gastroenterology and Hematology, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Sapporo 060-8638, Japan.
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Chen PF, Luo YL, Wang W, Wang JX, Lai WY, Hu SM, Cheng KF, Al-Abed Y. ISO-1, a macrophage migration inhibitory factor antagonist, inhibits airway remodeling in a murine model of chronic asthma. Mol Med 2010; 16:400-8. [PMID: 20485865 DOI: 10.2119/molmed.2009.00128] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2009] [Accepted: 04/13/2010] [Indexed: 11/06/2022] Open
Abstract
Airway remodeling is the process of airway structural change that occurs in patients with asthma in response to persistent inflammation and leads to increasing disease severity. Drugs that decrease this persistent inflammation play a crucial role in managing asthma episodes. Mice sensitized (by intraperitoneal administration) and then challenged (by inhalation) with ovalbumin (OVA) develop an extensive eosinophilic inflammatory response, goblet cell hyperplasia, collagen deposition, airway smooth muscle thickening, and airway wall area increase, similar to pathologies observed in human asthma. We used OVA-sensitized/challenged mice as a murine model of chronic allergic airway inflammation with subepithelial fibrosis (i.e., asthma). In this OVA mouse model, mRNA and protein of macrophage migration inhibitory factor (MIF) are upregulated, a response similar to what has been observed in the pathogenesis of acute inflammation in human asthma. We hypothesized that MIF induces transforming growth factor-β1 (TGF-β1) synthesis, which has been shown to play an important role in asthma and airway remodeling. To explore the role of MIF in the development of airway remodeling, we evaluated the effects of an MIF small-molecule antagonist, (S,R)3-(4-hy-droxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), on pathologies associated with the airway-remodeling process in the OVA mouse model. We found that administration of ISO-1 significantly mitigated all symptoms caused by OVA treatment. In addition, the treatment of OVA-sensitized mice with the MIF antagonist ISO-1 significantly reduced TGF-β1 mRNA levels in pulmonary tissue and its protein level in bronchial alveolar lavage fluid supernatants. We believe the repression of MIF in the ISO-1 treatment group led to the significant suppression observed in the inflammatory responses associated with the allergen-induced lung inflammation and fibrosis in our murine asthma (OVA) model. Our results implicate a possible function of MIF in the pathogenesis of chronic asthma and suggest that MIF might be an important therapeutic target for airway remodeling.
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Affiliation(s)
- Pei-Fen Chen
- Departments of Respiratory Diseases and ShenZhen Third People Hospital, Guangdong, China
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Mao Y, Xu B, Su Y, Zhang Z, Ding S, Wang D, Wang J. Cloning and mRNA expression of macrophage migration inhibitory factor (MIF) gene of large yellow croaker (Pseudosciaena crocea). ACTA OCEANOLOGICA SINICA 2010; 29:63-73. [DOI: 10.1007/s13131-010-0037-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Gregory JL, Hall P, Leech M, Morand EF, Hickey MJ. Independent roles of macrophage migration inhibitory factor and endogenous, but not exogenous glucocorticoids in regulating leukocyte trafficking. Microcirculation 2010; 16:735-48. [PMID: 19905972 DOI: 10.3109/10739680903210421] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVES Macrophage migration inhibitory factor (MIF) promotes leukocyte recruitment and antagonizes the anti-inflammatory effects of glucocorticoids (GC). The aim of this study was to examine whether interaction between MIF and GC underlies the ability of MIF to promote leukocyte-endothelial cell (EC) interactions. METHODS Intravital microscopy was used to assess leukocyte-EC interactions in wild-type and MIF(-/-) mice following treatment with lipopolysaccharide (LPS), the GC dexamethasone, and inhibition of endogenous GC, using the GC-receptor antagonist, RU486. RESULTS Dexamethasone reduced LPS-induced leukocyte interactions in wild-type mice to levels similar to those observed in MIF(-/-) mice not treated with dexamethasone, whereas in MIF(-/-) mice, leukocyte interactions were not further inhibited by dexamethasone. RU486 increased LPS-induced leukocyte adhesion and emigration to a similar extent in both wild-type and MIF(-/-) mice, indicating that endogenous GC exert a similar inhibitory effect on leukocyte trafficking in wild-type and MIF(-/-) mice. Both MIF deficiency and RU486 treatment reduced VCAM-1 expression, while neither treatment modulated expression of ICAM-1 or chemokines CCL2, KC, and MIP-2. CONCLUSIONS These results suggest that endogenous MIF and GC regulate leukocyte-EC interactions in vivo reciprocally but through predominantly independent mechanisms, and that the anti-inflammatory effect of MIF deficiency is comparable to that of exogenous GC.
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Affiliation(s)
- Julia L Gregory
- Monash University Department of Medicine, Monash Medical Center, Clayton, Victoria, Australia
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Xia HHX, Yang Y, Chu KM, Gu Q, Zhang YY, He H, Wong WM, Leung SY, Yuen ST, Yuen MF, Chan AOO, Wong BCY. Serum macrophage migration-inhibitory factor as a diagnostic and prognostic biomarker for gastric cancer. Cancer 2009; 115:5441-9. [PMID: 19685530 DOI: 10.1002/cncr.24609] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND This study aimed to determine the potential diagnostic value of migration-inhibitory factor (MIF) for gastric cancer in patients presenting with dyspepsia and its prognostic value for gastric cancer. METHODS A cohort of 97 patients with histologically confirmed gastric adenocarcinoma and 222 patients with dyspepsia were recruited. Enzyme-linked immunosorbent assay was used to measure serum MIF and carcinoembryonic antigen (CEA). RESULTS The serum MIF concentrations were 6554.0 +/- 204.1 pg/mL and 1453.7 +/- 79.9 pg/mL, respectively, in gastric cancer patients and dyspeptic patients (P < .001). Serum MIF levels increased with the advancing gastric pathologies (P < .001). With the cutoff value of 3230 pg/mL, serum MIF had sensitivity, specificity, and accuracy of 83.5%, 92.3%, and 89.7%, respectively, in diagnosing gastric cancer, whereas the rates were 60.8%, 83.3%, and 76.5%, respectively, for serum CEA. Gastric cancer patients with serum MIF levels above 6600 pg/mL had a lower 5-year survival rate than those with serum MIF level below that level (P = .012). Higher serum CEA levels were also associated with poor survival. The prediction for 5-year survival was even better (P = .0001), using a combination of serum MIF and CEA. CONCLUSIONS Serum MIF level, which correlates with gastric MIF expression, is a better molecular marker than CEA in diagnosing gastric cancer in patients presenting with dyspepsia. A combination of serum MIF and CEA predicts 5-year survival better than the individual test.
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Wong BLW, Zhu SL, Huang XR, Ma J, Xia HHX, Bucala R, Wong BCY, Lan HY. Essential role for macrophage migration inhibitory factor in gastritis induced by Helicobacter pylori. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 174:1319-28. [PMID: 19286569 PMCID: PMC2671363 DOI: 10.2353/ajpath.2009.080708] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Macrophage migration inhibitory factor (MIF) is an upstream regulator of immune and inflammatory responses; however, its role in Helicobacter pylori (HP)-associated gastritis remains unknown. We infected MIF knockout (KO) and wild-type mice with SS1 HP and found that 2 weeks after infection, MIF and its receptor CD74 were markedly up-regulated in wild-type mice. This up-regulation preceded the up-regulation of both tumor necrosis factor-alpha and intercellular adhesion molecule-1, as well as the development of moderate gastritis at 8 weeks, as determined by a significant infiltration of neutrophils, T cells, and macrophages. In contrast, KO mice were protected against HP-induced gastritis by preventing the up-regulation of CD74 and Th1-mediated immune injury, including a reduction in the Th1 transcriptional factor T-bet and the expression of interferon-gamma. Additionally, inhibition of skin delayed type hypersensitivity reactions to HP antigens in KO mice also suggested a critical role for MIF in cell-mediated injury. A regulatory role for MIF in Th1-immune responses was further demonstrated by the finding that antigen-primed CD4(+) T cells lacking MIF failed to differentiate into the Th1 phenotype; these cells were instead promoted to Th2 differentiation after challenge with HP antigen in vitro. Results from this study indicated that inhibition of HP-induced innate immune responses and Th1-mediated immune injury may be the key mechanisms by which KO mice failed to develop gastritis after HP infection.
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Affiliation(s)
- Benny L W Wong
- Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
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Urine macrophage migration inhibitory factor (MIF) in children with urinary tract infection: a possible predictor of acute pyelonephritis. Pediatr Nephrol 2009; 24:105-11. [PMID: 18800229 DOI: 10.1007/s00467-008-0969-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2008] [Revised: 06/13/2008] [Accepted: 06/16/2008] [Indexed: 12/21/2022]
Abstract
Macrophage migration inhibitory factor (MIF) is an important pro-inflammatory cytokine expressed at sites of inflammation. We have assessed this factor (MIF) in urinary tract infections with the aim of determining a non-invasive and sensitive method to differentiate upper and lower renal involvement. Thirty-three pediatric patients with urinary track infection (25 with acute pyelonephritis, eight with acute cystitis) and 40 healthy subjects were recruited for this prospective case-control study. Pyelonephritis was differentiated from cystitis by dimercaptosuccinic acid (DMSA) scan. Urinary MIF concentration was determined using an enzyme-linked immunosorbent assay method. The urine MIF/creatinine (Cr) ratio was significantly higher in pyelonephritis patients than in those with acute cystitis and the control group (P < 0.001). The optimal cut-point of 4.90 pg/micromol Cr for the urine MIF/Cr ratio has the potential to be a biomarker for distinguishing patients with acute pyelonephritis from those with acute cystitis. Determination of the urinary MIF was also useful in selecting the patients at risk of permanent renal damage. Of those patients with pyelonephritis, based on the DMSA scan at the time of infection, scarring on follow-up DMSA scan 9-12 months later occurred in patients with the highest urinary MIF/Cr ratios. We conclude that the urine MIF/Cr ratio is a sensitive test for differentiating acute pyelonephritis from acute cystitis and also for detecting children with acute pyelonephritis who are at a higher risk for permanent renal scars in the future.
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Houdeau E, Moriez R, Leveque M, Salvador-Cartier C, Waget A, Leng L, Bueno L, Bucala R, Fioramonti J. Sex steroid regulation of macrophage migration inhibitory factor in normal and inflamed colon in the female rat. Gastroenterology 2007; 132:982-93. [PMID: 17324399 DOI: 10.1053/j.gastro.2006.12.028] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2006] [Accepted: 11/27/2006] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Sex steroids influence IBD symptoms. Macrophage migration inhibitory factor (MIF), a target of sex steroids in other inflammatory models, promotes interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha release in colitis. We investigated whether estradiol and progesterone influence MIF, IL-1beta, and TNF-alpha production in experimental colitis. METHODS Colonic MIF, IL-1beta, and TNF-alpha levels were measured in cyclic and ovariectomized rats, with or without estradiol benzoate (EB) or progesterone (P) replacement. MIF distribution was assessed by immunohistochemistry. Cytokines, myeloperoxidase activity, macroscopic damage, and plasma corticosterone were assessed 24 hours after intrarectal trinitrobenzene sulfonic acid (TNBS), with and without neutralizing anti-MIF antibody. Effects of EB and P on myeloperoxidase activity and MIF concentration were also assessed at 7 days in dextran sulfate sodium-induced colitis. RESULTS Basal IL-1beta and TNF-alpha contents did not fluctuate during the estrous cycle, while MIF concentrations increased from estrus (estrogen dominance) to metestrus (P dominance; P < .05). EB and P treatment mimicked these effects in ovariectomized rats, and similarly altered MIF immunostaining. Progesterone dominance aggravated TNBS colitis in comparison with estrogen. Progesterone enhanced TNBS-induced MIF (P < .001) and TNF-alpha (P < .01) production, while EB decreased MIF (P < .01) and IL-beta levels (P < .01). Anti-MIF antibody prevented P-mediated up-regulation of TNF-alpha, improved TNBS colitis, and enhanced plasma corticosterone. At 7 days after dextran sulfate sodium, EB decreased myeloperoxidase activity and MIF concentration, while P had no effect. CONCLUSIONS Estrogen decreases while progesterone increases MIF production in the female rat colon. Changes in basal MIF contents may affect colon susceptibility to inflammation, by modulating TNF-alpha and IL-1beta production during early stages of colitis.
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Affiliation(s)
- Eric Houdeau
- Neuro-Gastroenterology and Nutrition Unit, Institut National de la Recherche Agronomique, Toulouse, France.
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de Mendonça-Filho HTF, Pereira KC, Fontes M, Vieira DADSA, de Mendonça MLAF, Campos LADA, Castro-Faria-Neto HC. Circulating inflammatory mediators and organ dysfunction after cardiovascular surgery with cardiopulmonary bypass: a prospective observational study. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2006; 10:R46. [PMID: 16542504 PMCID: PMC1550915 DOI: 10.1186/cc4857] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/12/2005] [Revised: 01/24/2006] [Accepted: 02/17/2006] [Indexed: 11/25/2022]
Abstract
Introduction Cardiovascular surgery with cardiopulmonary bypass (CPB) has improved in past decades, but inflammatory activation in this setting is still unpredictable and is associated with several postoperative complications. Perioperative levels of macrophage migration inhibitory factor (MIF) and other inflammatory mediators could be implicated in adverse outcomes in cardiac surgery. Methods Serum levels of MIF, monocyte chemoattractant protein (MCP)-1, soluble CD40 ligand, IL-6 and IL-10 from 93 patients subjected to CPB were measured by enzyme-linked immunosorbent assay and compared with specific and global postoperative organ dysfunctions through multiple organ dysfunction score (MODS) and sequential organ failure assessment (SOFA). Results Most of the cytokines measured had a peak of production between 3 and 6 hours after CPB, but maximum levels of MIF occurred earlier, at the cessation of CPB. Among specific organ dysfunctions, the most frequent was hematological, occurring in 82% of the patients. Circulatory impairment was observed in 73.1% of the patients, and 51% of these needed inotropics or vasopressors within the first 24 hours after surgery. The third most frequent dysfunction was pulmonary, occurring in 48.4% of the patients. Preoperative levels of MIF showed a relevant direct correlation with the intensity of global organ dysfunction measured by SOFA (ρ = 0.46, p < 0.001) and MODS (ρ = 0.50, p < 0.001) on the third day after surgery. MCP-1 production was associated with postoperative thrombocytopenia, and MIF was related to the use of a high dose of vasopressors in patients with cardiovascular impairment and also to lower values of the ratio of partial arterial oxygen tension (PaO2) to fraction of inspired oxygen (FiO2) registered in the first 24 hours after CPB. Conclusion Despite the multifactorial nature of specific or multiple organ dysfunctions, MIF should be explored as a predicting factor of organ dysfunction, or even as a potential therapeutic target in decreasing postoperative complications.
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Affiliation(s)
- Hugo Tannus Furtado de Mendonça-Filho
- Núcleo de Pesquisa Translacional, Hospital Pró Cardíaco, Rua General Polidoro 192, Botafogo, Rio de Janeiro, RJ, 22280-000 Brazil
- Laboratório de Imunofarmacologia, Departamento de Farmacodinamica, Instituto Oswaldo Cruz, Rio de Janeiro, RJ, 21045-900 Brazil
| | - Kelly Cristina Pereira
- Núcleo de Pesquisa Translacional, Hospital Pró Cardíaco, Rua General Polidoro 192, Botafogo, Rio de Janeiro, RJ, 22280-000 Brazil
| | - Mariane Fontes
- Núcleo de Pesquisa Translacional, Hospital Pró Cardíaco, Rua General Polidoro 192, Botafogo, Rio de Janeiro, RJ, 22280-000 Brazil
| | | | | | - Luiz Antonio de Almeida Campos
- Núcleo de Pesquisa Translacional, Hospital Pró Cardíaco, Rua General Polidoro 192, Botafogo, Rio de Janeiro, RJ, 22280-000 Brazil
| | - Hugo Caire Castro-Faria-Neto
- Laboratório de Imunofarmacologia, Departamento de Farmacodinamica, Instituto Oswaldo Cruz, Rio de Janeiro, RJ, 21045-900 Brazil
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Lebiedz P, Heidemann J, Lugering A, Riedel S, Herbst H, Domschke W, Kucharzik T, Maaser C. Gastric epithelial expression of macrophage migration inhibitory factor is not altered by Helicobacter pylori infection in humans. Helicobacter 2006; 11:258-65. [PMID: 16882329 DOI: 10.1111/j.1523-5378.2006.00411.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Recent reports have shown an upregulation of macrophage migration inhibitory factor (MIF) during gastric ulcer development in a rat model and elevated counts of MIF-positive cells in biopsies from Helicobacter pylori-infected patients. H. pylori infection is a proven cofactor in humans causing gastritis and gastric ulcers. The aim of this study was to characterize MIF expression in human gastric epithelial cells in response to H. pylori. METHODS MIF mRNA and MIF protein expression was detected in human gastric epithelial cell lines after stimulation with proinflammatory cytokines or infection with H. pylori (cagA+/vacA+) using real-time reverse transcriptase-polymerase and enzyme-linked immunosorbent assay. Interleukin-8 secretion was measured as positive control. MIF mRNA and MIF protein expression was assessed in H. pylori-positive and -negative human gastric biopsy samples. RESULTS While interleukin-8 mRNA expression and interleukin-8 secretion were upregulated in gastric epithelial cells in vitro after H. pylori infection, no changes in MIF mRNA expression and MIF secretion could be detected. We found no significant differences in MIF expression in total RNA extracted from gastric biopsy tissue when comparing H. pylori-positive to control patients. Likewise, MIF protein expression in gastric epithelium was unaffected by H. pylori infection as compared to uninfected tissue. CONCLUSIONS While an increased MIF expression and positive effects of MIF blockade in ulcer healing have been shown in a rodent model and elevated numbers of MIF-positive cells have been found in H. pylori-infected human tissue, we herein could not confirm any differences in human gastric epithelial MIF expression and secretion after H. pylori infection in vitro and in vivo.
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Affiliation(s)
- Pia Lebiedz
- Department of Medicine B, University of Muenster, Albert-Schweitzer-Strasse 33, D-48129 Muenster, Germany.
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Amin MA, Haas CS, Zhu K, Mansfield PJ, Kim MJ, Lackowski NP, Koch AE. Migration inhibitory factor up-regulates vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 via Src, PI3 kinase, and NFkappaB. Blood 2006; 107:2252-61. [PMID: 16317091 PMCID: PMC1472703 DOI: 10.1182/blood-2005-05-2011] [Citation(s) in RCA: 120] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2005] [Accepted: 11/07/2005] [Indexed: 01/16/2023] Open
Abstract
Cell adhesion molecules are critical in monocyte (MN) recruitment in immune-mediated and hematologic diseases. We investigated the novel role of recombinant human migration inhibitory factor (rhMIF) in up-regulating vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) and their signaling pathways in human MNs. rhMIF-induced expression of VCAM-1 and ICAM-1 was significantly higher compared with nonstimulated MNs. rhMIF induced MN VCAM-1 and ICAM-1 expression in a concentration-dependent manner (P < .05). Antisense oligodeoxynucleotides (ODNs) and inhibitors of Src, PI3K, p38, and NFkappaB significantly reduced rhMIF-induced MN VCAM-1 and ICAM-1 expression (P < .05). However, Erk1/2 and Jak2 were not involved. Silencing RNA directed against MIF, and inhibitors of Src, PI3K, NFkappaB, anti-VCAM-1, and anti-ICAM-1 significantly inhibited rhMIF-induced adhesion of HL-60 cells to human dermal microvascular endothelial cells (HMVECs) or an endothelial cell line, HMEC-1, in cell adhesion assays, suggesting the functional significance of MIF-induced adhesion molecules (P < .05). rhMIF also activated MN phospho-Src, -Akt, and -NFkappaB in a time-dependent manner. rhMIF induced VCAM-1 and ICAM-1 up-regulation in 12 hours via Src, PI3K, and NFkappaB as shown by Western blotting and immunofluorescence. MIF and MIF-dependent signaling pathways may be a potential target for treating diseases characterized by up-regulation of cell adhesion molecules.
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Affiliation(s)
- M Asif Amin
- Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
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Ohkawara T, Takeda H, Miyashita K, Nishiwaki M, Nakayama T, Taniguchi M, Yoshiki T, Tanaka J, Takana J, Imamura M, Sugiyama T, Asaka M, Nishihira J. Regulation of Toll-like receptor 4 expression in mouse colon by macrophage migration inhibitory factor. Histochem Cell Biol 2005; 125:575-82. [PMID: 16283355 DOI: 10.1007/s00418-005-0092-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/27/2005] [Indexed: 01/09/2023]
Abstract
Recent studies have indicated that macrophage migration inhibitory factor (MIF) and Toll-like receptor (TLR) play an important role in the regulation of innate immune responses. In this study, we investigated the effect of MIF on the expression of TLR4, a receptor that recognizes lipopolysaccharide, in colon using MIF-deficient mice. TLR4 mRNA expression in the colon tissues was determined by northern blot analysis. Western blot analysis and immunohistochemistry in the colon tissues were performed to evaluate the expression of TLR4 protein. The expressions of TLR4 mRNA and protein were remarkably down-regulated in colon tissues of MIF-deficient mice compared with wild-type mice and up-regulated by treatment with recombinant MIF. Immunohistochemical study revealed the presence of TLR4-positive staining in mononuclear cells in the lamina propria and intraepithelial mononuclear cells as well as weak staining in epithelial cells and crypts in colon tissues of wild-type mice. In contrast, MIF-deficient mice did not show TLR4-positive staining in the colonic mucosa. In MIF-deficient mice injected with recombinant mouse MIF (rMIF), TLR4-positive staining cells were observed in colon tissues similar to the findings in wild-type mice. Administration of dextran sulfate sodium (DSS) up-regulated the expression of TLR4 in the colons of WT mice but not in those of MIF-deficient mice. Furthermore, pretreatment with rMIF up-regulated the expression of TLR4 in response to DSS in MIF-deficient mice. Our results suggest that MIF affects the expression of TLR4 in mouse colon under both normal and colitic conditions.
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Affiliation(s)
- Tatsuya Ohkawara
- Department of Gastroenterology and Hematology, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, 060-8638, Sapporo, Japan.
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Nakamaru Y, Oridate N, Nishihira J, Takagi D, Furuta Y, Fukuda S. Macrophage migration inhibitory factor (MIF) contributes to the development of allergic rhinitis. Cytokine 2005; 31:103-8. [PMID: 15922619 DOI: 10.1016/j.cyto.2005.04.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2004] [Revised: 03/15/2005] [Accepted: 04/01/2005] [Indexed: 11/16/2022]
Abstract
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine whose expression has been found to be critical to the generation of antigen-specific immune responses. Recent studies suggested that MIF played a role in the initiation and maintenance of allergic diseases. To elucidate MIF's role in the pathogenesis of allergic rhinitis (AR), we sensitized MIF-deficient gene knockout (KO) mice and wild-type (WT) mice intraperitoneally with ovalbumin (OVA) and compared their clinical symptoms and allergic responses after intranasal challenge. Antigen-induced nasal symptoms were significantly reduced in MIF KO mice compared to WT mice. Histological examination of nasal mucosa showed that the number of infiltrating eosinophils in MIF KO mice was significantly lower than that in WT mice (P < 0.05). The concentration of TNF-alpha in nasal mucosa was also significantly lower in MIF KO mice than in WT mice (P < 0.05). We have demonstrated that the absence of MIF affects several aspects of experimental AR. One mechanism by which these effects might be mediated is by down regulating TNF-alpha. The block of allergic inflammation in MIF KO mice suggests that MIF may play a role in the allergic response.
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Affiliation(s)
- Yuji Nakamaru
- Department of Otolaryngology and Head and Neck Surgery, Hokkaido University Graduate School of Medicine, West 7 North 15, Sapporo 060-8638, Japan.
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Ohkawara T, Takeda H, Nishihira J, Miyashita K, Nihiwaki M, Ishiguro Y, Takeda K, Akira S, Iwanaga T, Sugiyama T, Asaka M. Macrophage migration inhibitory factor contributes to the development of acute dextran sulphate sodium-induced colitis in Toll-like receptor 4 knockout mice. Clin Exp Immunol 2005; 141:412-21. [PMID: 16045730 PMCID: PMC1809451 DOI: 10.1111/j.1365-2249.2005.02877.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Toll-like receptor 4 (TLR4), which recognizes lipopolysaccharides, plays an important role in the innate immune response. In this study, we investigated the role of TLR4 in the development of experimental colitis with regard to the biological actions of macrophage migration inhibitory factor (MIF) using TLR4 null ((-/-)) mice. TLR4(-/-) mice were given 2% dextran sulphate sodium (DSS) in drinking water to induce colitis, which was clinically and histologically as severe as that seen in wild-type (WT) mice. The level of tumour necrosis factor (TNF)-alpha in colon tissues was increased in WT mice but unchanged in TLR4(-/-) mice. The level of myeloperoxidase (MPO) activity in colon tissues was increased by DSS administration in both TLR4(-/-) and WT mice. The expression of MIF was up-regulated in the colons of TLR4(-/-) mice with acute DSS-induced colitis. An anti-MIF antibody significantly suppressed colitis and elevation of matrix metalloproteinase-13 in TLR4(-/-) mice. The current results obtained from TLR4(-/-) mice provide evidence that MIF plays a critical role in the development of acute DSS-induced colitis.
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Affiliation(s)
- T Ohkawara
- Department of Gastroenterology and Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
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Wang F, Gao F, Jing L. Is macrophage migration inhibitory factor (MIF) the "control point" of vascular hypo-responsiveness in septic shock? Med Hypotheses 2005; 65:1082-7. [PMID: 16125329 DOI: 10.1016/j.mehy.2005.05.047] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2005] [Accepted: 05/19/2005] [Indexed: 10/25/2022]
Abstract
Macrophage migration inhibitory factor (MIF), a member of the cytokine family, is beginning to be recognized as a pleiotropic proinflammatory molecule. MIF exerts function via antagonistic regulation of glucocorticoids, inhibition to apoptosis-mediated p53, influence on vasodilator gas NO and inducible nitric oxide synthase (iNOS), feedback counter-regulation of complement C5a controlling MIF release, and interaction with major cations as well. Interestingly, aforementioned glucocorticoids, apoptosis, NO, iNOS, C5a, Ca2+, Mg2+, Na+, K+, and H+ that are greatly associated with vascular tone or vasomotion. Nevertheless, the elevated serum and cytosolic concentrations of MIF exactly affect all above facets in septic shock models and patients, during which vasodilation of the peripheral resistance vessels occurs, and accompanied with decreased responsiveness to vascular pressors. Thus MIF may bring into play as one of point-controlling proteins in the onset of sustained vascular hypo-reactivity during the process of septic shock.
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Affiliation(s)
- Fuzhou Wang
- Department of Anaesthesiology, Research Institute of Intensive Care Medicine, ZhongDa Hospital, Southeast University, Nanjing 210009, China.
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Shun CT, Lin JT, Huang SP, Lin MT, Wu MS. Expression of macrophage migration inhibitory factor is associated with enhanced angiogenesis and advanced stage in gastric carcinomas. World J Gastroenterol 2005; 11:3767-71. [PMID: 15968736 PMCID: PMC4316032 DOI: 10.3748/wjg.v11.i24.3767] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Macrophage migration inhibitory factor (MIF) was reported to inactivate p53 and play an essential role in the growth and angiogenesis of tumors that arise at sites of chronic inflammation. Gastric inflammation is a prerequisite for the development of gastric carcinoma (GC), which has recently been linked to Helicobacter pylori (H pylori) infection. This study aimed to investigate clinicopathological significance of MIF expression in GCs.
METHODS: We selected 90 consecutive patients with GCs for investigation of the relation among MIF status, clinicopathological parameters, p53 expression and angiogenesis. MIF and p53 expression was assessed by immunohistochemistry as positive and negative groups. Tumor vascularity was evaluated by counting microvessel density on anti-CD34 stained sections. Expression status of MIF was correlated with determined clinicopathological data, p53 immunoreactivity and microvessel counts.
RESULTS: Strong immunostainings of MIF were observed in the cytoplasm of cancerous cells in 40% (36/90) of cases but not in normal or metaplastic epithelia. There was no statistically significant correlation between MIF expression and age, gender, H pylori infection, tumor location, histological subtypes, lymph node metastasis or p53 expression. Early GC less frequently overexpressed MIF as compared to advanced GCs (4/20 vs 32/70, P = 0.04). A remarkably increased microvessel count was noted in GCs with MIF expression than those without MIF expression (55.1±30.1 vs 31.3±28.8, P = 0.0001).
CONCLUSION: Our results suggest that expression of MIF may contribute to the progression and enhanced angiogenesis in a substantial portion of GCs.
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Affiliation(s)
- Chia-Tung Shun
- Department of Forensic Medicne and Pathology, National Taiwan University, Taipei, Taiwan, China
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Ren Y, Lin CL, Li Z, Chen XY, Huang X, Lui V, Nicholls J, Lan HY, Tam PKH. Up-regulation of macrophage migration inhibitory factor in infants with acute neonatal necrotizing enterocolitis. Histopathology 2005; 46:659-67. [PMID: 15910597 DOI: 10.1111/j.1365-2559.2005.02159.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
AIMS To investigate the role of macrophage migration inhibitory factor (MIF) and its downstream cytokine cascade in necrotizing enterocolitis (NEC). METHODS AND RESULTS The expression of MIF mRNA and protein in NEC guts was assayed by in situ hybridization and immunohistochemistry, respectively. Concentrations of MIF, interleukin (IL)-6 and IL-8 in the serum and in the supernatant of macrophage cultures were examined by ELISA. Increased expression of MIF mRNA and protein was observed in the NEC guts, mainly in the infiltrating macrophages in the mucosa and submucosal layers. Up-regulation of MIF was associated with the accumulation of macrophages and T cells. In addition, serum levels of MIF, IL-6 and IL-8 in NEC patients during the acute stage of the disease were significantly increased. The expression of MIF decreased both locally and systemically after the disease was resolved. MIF was also found to increase the secretion of IL-6 and IL-8 by macrophages isolated from healthy individuals in vitro in NEC. CONCLUSIONS MIF acts by stimulating macrophage production of IL-6 and IL-8. This further aggravates the inflammatory process by increasing the infiltration of neutrophils and activating inflammatory cells. The results of this study suggest that MIF plays an important role in the pathogenesis of NEC and may serve as a target for therapeutic intervention in NEC.
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Affiliation(s)
- Y Ren
- Department orf Surgery, University of Hong Kong, Hong Kong SAR, China.
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42
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Xia HHX, Lam SK, Chan AOO, Lin MCM, Kung HF, Ogura K, Berg DE, Wong BCY. Macrophage migration inhibitory factor stimulated by Helicobacter pylori increases proliferation of gastric epithelial cells. World J Gastroenterol 2005; 11:1946-50. [PMID: 15800984 PMCID: PMC4305715 DOI: 10.3748/wjg.v11.i13.1946] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM Helicobacter pylori (H pylori) is associated with increased gastric inflammatory and epithelial expression of macrophage migration inhibitory factor (MIF) and gastric epithelial cell proliferation. This study aimed at determining whether H pylori directly stimulates release of MIF in monocytes, whether the cag pathogenicity island (PAI) is involved for this function, and whether MIF stimulated by H pylori increases gastric epithelial cell proliferation in vitro. METHODS A cytotoxic wild-type H pylori strain (TN2), its three isogenic mutants (TN2Deltacag, TN2DeltacagA and TN2DeltacagE) were co-cultured with cells of a human monocyte cell line, THP-1, for 24 h at different organism/cell ratios. MIF in the supernatants was measured by an ELISA. Cells of a human gastric cancer cell line, MKN45, were then co-cultured with the supernatants, with and without monoclonal anti-MIF antibody for 24 h. The cells were further incubated for 12 h after addition of 3H-thymidine, and the levels of incorporation of 3H-thymidine were measured with a liquid scintillation counter. RESULTS The wild-type strain and the isogenic mutants, TN2DeltacagA and TN2 DeltacagE, increased MIF release at organism/cell ratios of 200/1 and 400/1, but not at the ratios of 50/1 and 100/1. However, the mutant TN2delta cag did not increase the release of MIF at any of the four ratios. 3H-thymidine readings for MKN-45 cells were significantly increased with supernatants derived from the wild-type strain and the mutants TN2DeltacagA and TN2DeltacagE, but not from the mutant TN2Deltacag. Moreover, in the presence of monoclonal anti-MIF antibody, the stimulatory effects of the wild-type strain on cell proliferation disappeared. CONCLUSION H pylori stimulates MIF release in monocytes, likely through its cag PAI, but not related to cagA or cagE. H pylori-stimulated monocyte culture supernatant increases gastric cell proliferation, which is blocked by anti-MIF antibody, suggesting that MIF plays an important role in H pylori-induced gastric epithelial cell proliferation.
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Affiliation(s)
- Harry Hua-Xiang Xia
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
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Abstract
Previous studies have shown a definite role of mitogen activated protein kinase (MAPK) and epidermal growth factors (EGF) in the maintenance and repair of gastric mucosa. The aim of this study is to investigate the effect of menadione, an activator of MAPK pathway, on gastric acid secretion and experimentally induced gastric ulcer in rats. Acid secretion studies were undertaken using pylorus-ligated rats pretreated with menadione (5 - 45 mg/kg, i.p.). The effect of orally administered menadione on ethanol-induced gastric ulcers was also examined. The level of gastric wall mucus, non-protein sulfhydryls (NP-SH) and myeloperoxidase (MPO) was measured in the glandular stomach of rats following ethanol-induced gastric lesions. There was a significant inhibition of gastric acid secretion in the menadione treated rats. Pretreatment of rats with menadione significantly protected gastric mucosa against ethanol-induced gastric lesion. A significant attenuation of ethanol-induced reduction of gastric wall mucus, depletion of NP-SH and increase in gastric MPO activity was also observed in menadione treated rats. In conclusion, this study clearly showed acid antisecretory and antiulcer activity of menadione. Further studies are warranted to determine the mechanism of antiacid and gastroprotective effect of menadione.
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Affiliation(s)
- Mohammad Tariq
- Research Center and Department of Pathology, Armed Forces Hospital, P. O. Box 7897, (W-912) Riyadh 11159, Saudi Arabia.
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44
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Morand EF, Leech M, Iskander MN. Therapeutic opportunities for antagonism of macrophage migration inhibitory factor. Expert Opin Ther Pat 2005. [DOI: 10.1517/13543776.13.8.1189] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Gregory JL, Leech MT, David JR, Yang YH, Dacumos A, Hickey MJ. Reduced leukocyte-endothelial cell interactions in the inflamed microcirculation of macrophage migration inhibitory factor-deficient mice. ACTA ACUST UNITED AC 2004; 50:3023-34. [PMID: 15457472 DOI: 10.1002/art.20470] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
OBJECTIVE Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with established roles in a range of inflammatory conditions. However, it is not known whether MIF influences inflammation via the direct promotion of leukocyte-endothelial cell interactions. Therefore, the aim of these experiments was to investigate the ability of MIF to regulate leukocyte-endothelial cell interactions in the inflamed microvasculature. METHODS Intravital microscopy was used to examine postcapillary venules in the cremaster muscle and synovium of wild-type and MIF(-/-) mice. Leukocyte-endothelial cell interactions (rolling, adhesion, emigration) were compared under a range of inflammatory conditions. RESULTS In cremasteric postcapillary venules of MIF(-/-) mice, lipopolysaccharide (LPS)-induced leukocyte rolling, adhesion, and emigration were significantly reduced relative to that in wild-type mice. Similar responses were observed in response to tumor necrosis factor alpha and histamine. Examination of the synovial microvasculature following exposure to carrageenan revealed that leukocyte rolling and adhesion in synovial postcapillary venules and leukocyte entry into the joint space were also reduced significantly in MIF(-/-) mice. In each of these models, the level of P-selectin-dependent rolling was reduced in MIF(-/-) mice. Despite this, no difference in P-selectin expression was observed following LPS treatment. However, microvascular shear forces were elevated in MIF(-/-) mice, raising a possible mechanism to explain the reduced interactions in these animals. CONCLUSION MIF(-/-) mice consistently displayed a reduction in P-selectin-dependent rolling, suggesting that MIF exerts proinflammatory effects, in part, via the promotion of P-selectin-mediated rolling. Together, these data indicate that MIF promotes interactions between leukocytes and endothelial cells, thereby enhancing the entry of leukocytes into sites of inflammation.
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Affiliation(s)
- Julia L Gregory
- Centre for Inflammatory Diseases, Monash University, Victoria, Australia
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46
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Riedemann NC, Guo RF, Gao H, Sun L, Hoesel M, Hollmann TJ, Wetsel RA, Zetoune FS, Ward PA. Regulatory role of C5a on macrophage migration inhibitory factor release from neutrophils. THE JOURNAL OF IMMUNOLOGY 2004; 173:1355-9. [PMID: 15240730 DOI: 10.4049/jimmunol.173.2.1355] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
There is evidence that C5a and macrophage migration inhibitory factor (MIF) both play important roles in experimental sepsis. Humans with sepsis also show elevated levels of both mediators in the blood. Regulation of MIF during sepsis is poorly understood. We now demonstrate that neutrophil depletion greatly reduced serum MIF levels in rats and mice during the onset of sepsis after cecal ligation and puncture. In vitro, C5a induced MIF release from rat and mouse neutrophils. In vivo blockade of C5aR or absence of C5aR led to significantly reduced MIF generation during the onset of sepsis. C5a-induced release in vitro of MIF from neutrophils appeared to be due to up-regulation of MIF in cytoplasmic granules of neutrophils via activation of the protein kinase B signaling pathway together with involvement of PI3K. Our data suggest that C5a plays a role in enhancing MIF release from neutrophils in vitro and during sepsis. These findings represent a previously unrecognized function of C5a and neutrophils in the appearance of MIF in sepsis.
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Affiliation(s)
- Niels C Riedemann
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
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Leung SY, Yuen ST, Chu KM, Mathy JA, Li R, Chan ASY, Law S, Wong J, Chen X, So S. Expression profiling identifies chemokine (C-C motif) ligand 18 as an independent prognostic indicator in gastric cancer. Gastroenterology 2004; 127:457-69. [PMID: 15300578 DOI: 10.1053/j.gastro.2004.05.031] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Gastric cancer is one of the major cancers worldwide. Expression profiling has proven useful in delineating novel prognostic markers in various cancer types. We previously analyzed gene-expression patterns in 90 gastric adenocarcinomas by using complementary DNA microarrays and prioritized a list of genes whose expression levels predict patient outcome. METHODS We identified a specific gene of interest, chemokine (C-C motif) ligand 18 (CCL18), on the basis of a high absolute standardized log Cox hazard ratio, a high variance in expression among all tumor samples, and putative biologic function. Detailed analysis of CCL18 expression with clinicopathologic and survival data was performed (n = 89). Quantitative reverse-transcription polymerase chain reaction was used to verify the microarray expression data and was further applied to analyze an independent cohort of tumor samples (n = 59). The cellular source of CCL18 was determined with immunohistochemistry and in situ hybridization. RESULTS High CCL18 expression levels were associated with prolonged overall (P = 0.001; hazard ratio, 0.586) and disease-free (P = 0.002; hazard ratio, 0.416) patient survival in the array-based data set by univariate analysis. The observations were confirmed in an independent set of 59 patients by using quantitative reverse-transcription polymerase chain reaction. In multivariate analysis, tumor stage and CCL18 levels were independent prognostic factors for predicting both overall and disease-free survival. We found that CCL18 was expressed by a subpopulation of tumor-associated macrophages that were preferentially located at the tumor invasion front. CONCLUSIONS Macrophage-derived CCL18 may function as a local antitumor immunomodulator that affects patient outcome. Our study suggests CCL18 as a novel candidate for antitumor therapeutics and risk stratification in gastric cancer patients.
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Affiliation(s)
- Suet Yi Leung
- Department of Pathology, The University of Hong Kong, Queen Mary Hospital, China.
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Shimizu T, Nishihira J, Watanabe H, Abe R, Ishibashi T, Shimizu H. Cetirizine, an H1-receptor antagonist, suppresses the expression of macrophage migration inhibitory factor: its potential anti-inflammatory action. Clin Exp Allergy 2004; 34:103-9. [PMID: 14720269 DOI: 10.1111/j.1365-2222.2004.01836.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND H1-receptor antagonists are often effective in the treatment of allergic disorders such as atopic dermatitis. Cetirizine, a putative H1-receptor antagonist, has recently been shown to have anti-inflammatory properties through the inhibition of leucocyte recruitment and activation, and by the reduction of ICAM-1 expression on keratinocytes. OBJECTIVE To further elucidate the anti-inflammatory properties of cetirizine, we first examined its effects on antigen-induced eosinophilia and neutrophila in vivo. We then examined the anti-inflammatory effects of cetirizine on a human keratinocyte A431cell line. METHODS Mice were sensitized subcutaneously with ragweed pollen and were challenged intraperitoneally with the allergen. Cetirizine diluted in sterile water (0-20 mg/kg) or only sterile water was administered orally. Peritoneal cells were obtained at 8 and 24 h after challenge. The eosinophilia and neutrophilia induced by ragweed pollen extract were quantitated. Macrophage migration inhibitory factor (MIF), macrophage inflammatory protein 2 (MIP-2) and eotaxin contents of peritoneal fluid were also measured by mouse ELISA. The effects of cetirizine on MIF-induced IL-8 production in A431 cells were examined by ELISA. The effects of cetirizine on MIF expression and production in A431 cells were examined by human MIF ELISA and Northern blot analysis. RESULTS Eosinophilia and neutrophilia induced by ragweed pollen extract were found to be significantly reduced in cetirizine-treated mice (20 mg/kg). MIF, a pleuripotent cytokine, was significantly decreased at 8 and 24 h in the peritoneal fluid by cetirizine treatment. MIP-2 and eotaxin were also decreased 8 and 24 h, respectively, after challenge in the peritoneal fluid with cetirizine treatment. MIF stimulates IL-8 production in A431 cells. We found that MIF production in A431 cells was inhibited by 10 microm cetirizine. Consistent with this, cetirizine significantly inhibited MIF-induced IL-8 production. CONCLUSION These results suggest that cetirizine exerts its anti-inflammatory effects by inhibiting MIF as well as IL-8 production, such as those involved in inflammatory allergic skin disease, suggesting a broad spectrum of action beyond its mere H1-receptor-antagonistic function.
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Affiliation(s)
- T Shimizu
- Departments of Dermatology Molecular Biochemistry, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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Abstract
Cytokines are essential effector molecules of innate immunity that initiate and coordinate the cellular and humoral responses aimed, for example, at the eradication of microbial pathogens. Discovered in the late 1960s as a product of activated T cells, the cytokine macrophage migration inhibitory factor (MIF) has been discovered recently to carry out important functions as a mediator of the innate immune system. Constitutively expressed by a broad spectrum of cells and tissues, including monocytes and macrophages, MIF is rapidly released after exposure to microbial products and pro-inflammatory mediators, and in response to stress. After it is released, MIF induces pro-inflammatory biological responses that act as a regulator of immune responses. MIF activates the extracellular signal-regulated kinase 1 (ERK1)/ERK2–mitogen-activated protein kinase pathway, inhibits the activity of JUN activation domain-binding protein 1 (JAB1) — a co-activator of the activator protein 1 (AP1) — upregulates the expression of Toll-like receptor 4 to promote the recognition of endotoxin-expressing bacterial pathogens, sustains pro-inflammatory function by inhibiting p53-dependent apoptosis of macrophages and counter-regulates the immunosuppressive effects of glucocorticoids on immune cells. As a pro-inflammatory mediator, MIF has been shown to be implicated in the pathogenesis of severe sepsis and septic shock, acute respiratory distress syndrome, and several other inflammatory and autoimmune diseases, including rheumatoid arthritis, glomerulonephritis and inflammatory bowel diseases. Given its crucial role as a regulator of innate and acquired immunity, pharmacological or immunological modulation of MIF activity might offer new treatment opportunities for the management of acute and chronic inflammatory diseases. For more than a quarter of a century, macrophage migration inhibitory factor (MIF) has been a mysterious cytokine. In recent years, MIF has assumed an important role as a pivotal regulator of innate immunity. MIF is an integral component of the host antimicrobial alarm system and stress response that promotes the pro-inflammatory functions of immune cells. A rapidly increasing amount of literature indicates that MIF is implicated in the pathogenesis of sepsis, and inflammatory and autoimmune diseases, suggesting that MIF-directed therapies might offer new treatment opportunities for human diseases in the future.
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Affiliation(s)
- Thierry Calandra
- Division of Infectious Diseases, Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland.
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50
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Ren Y, Tsui HT, Poon RTP, Ng IOL, Li Z, Chen Y, Jiang G, Lau C, Yu WC, Bacher M, Fan ST. Macrophage migration inhibitory factor: roles in regulating tumor cell migration and expression of angiogenic factors in hepatocellular carcinoma. Int J Cancer 2003; 107:22-9. [PMID: 12925952 DOI: 10.1002/ijc.11287] [Citation(s) in RCA: 101] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Macrophage migration inhibitory factor (MIF) may contribute to multiple aspects of tumor progression, including control of cell proliferation, differentiation, cell survival and angiogenesis. However, the potential roles of MIF in regulating hepatocellular carcinoma (HCC) tumor cell migration and the expression of angiogenic factors by HCC tumor cells have not been studied yet. In our study, we reported that intracellular MIF mRNA and protein were overexpressed in HCC tissues compared to nontumor tissues by using in situ hybridization and immunohistochemic staining. HCC tumor cell lines also secreted large amounts of MIF into the supernatants of tumor cell culture. To assess the role of MIF in HCC, we employed the transwell invasion chamber to study the effect of MIF on tumor cell migration. Our results showed that recombinant MIF and the supernatants of tumor cell line culture could enhance the invasion and migration of HCC cells. This effect can be inhibited by the addition of a neutralizing anti-MIF antibody. We observed that increased MIF serum levels correlated with higher levels of interleukin-8 (IL-8) in the sera of patients with HCC than in normal volunteers. We therefore hypothesized that MIF may regulate the production of angiogenic factors by HCC cells. To test this hypothesis, we examined the effect of MIF treatment on vascular endothelial growth factor (VEGF) and IL-8 expression by HCC cell lines. MIF induced a significant dose-dependent increase in IL-8 and VEGF production. Taken together, our results indicated that MIF may act as an autocrine-acting factor that stimulates angiogenesis and metastasis in HCC by promoting expression of angiogenic factors and migration of tumor cells. A more detailed understanding of the MIF regulatory mechanisms involved may provide insight into new direction in the treatment of HCC.
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Affiliation(s)
- Yi Ren
- Centre for the Study of Liver Disease and Department of Surgery, University of Hong Kong Medical Centre, Hong Kong SAR, China.
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