|
1
|
Elsabbagh RA, Abdelhady G, Urlaub D, Sandusky M, Khorshid O, Gad MZ, Abou-Aisha K, Watzl C, Rady M. N 6-methyladenosine RNA base modification regulates NKG2D-dependent and cytotoxic genes expression in natural killer cells. BMC Med Genomics 2025; 18:91. [PMID: 40389988 PMCID: PMC12090489 DOI: 10.1186/s12920-025-02147-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 04/17/2025] [Indexed: 05/21/2025] Open
Abstract
BACKGROUND Breast cancer (BC) is the most commonly diagnosed cancer in women. N6-methyladenosine (m6A) is the most prevalent internal modification in mammalian mRNAs and plays a crucial role in various biological processes. However, its function in Natural killer (NK) cells in BC remains unclear. NK cells are essential for cancer immunosurveillance. This study aims to assess m6A levels in transcripts involved in the NKG2D cytotoxicity signaling pathway in NK cells of BC patients compared to controls and find out its impact on mRNA levels. Additionally, it evaluates how deliberately altering m6A levels in NK cells affects mRNA and protein expression of NKG2D pathway genes and NK cell functionality. METHODS m6A methylation in transcripts of NKG2D-pathway-related genes in BC patients and controls was determined using methylated RNA immunoprecipitation-reverse transcription-PCR (MERIP-RT-PCR). To deliberately alter m6A levels in primary cultured human NK cells, the m6A demethylases, FTO and ALKBH5, were knocked out using the CRISPR-CAS9 system, and FTO was inhibited using Meclofenamic acid (MA). The impact of m6A alteration on corresponding mRNA and protein levels was assessed using RT-qPCR and Western blot analysis or flow cytometry, respectively. Additionally, NK cell functionality was evaluated through degranulation and 51Cr release cytotoxicity assays. RESULTS Transcripts of NKG2D, an activating receptor that detects stressed non-self tumour cells, had significantly higher m6A levels in the 3' untranslated region (3'UTR) accompanied by a marked reduction in their corresponding mRNA levels in BC patients compared to controls. Conversely, transcripts of ERK2 and PRF1 exhibited significantly lower m6A levels escorted with higher mRNA expression in BC patients relative to controls. The mRNA levels of PI3K, PAK1 and GZMH were also significantly elevated in BC patients. Furthermore, artificially increasing transcripts' m6A levels via MA in cultured primary NK cells reduced mRNA levels of NKG2D pathway genes and death receptor ligands but did not affect protein expression or NK cell functionality. CONCLUSION Transcripts with higher m6A levels in the 3'UTR region were less abundant, and vice versa. However, changes in mRNA levels of the target genes didn't impact their corresponding protein levels or NK cell functionality.
Collapse
Affiliation(s)
- Raghda A Elsabbagh
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, the German University in Cairo, Cairo, Egypt
| | - Ghada Abdelhady
- Microbiology, Immunology and Biotechnology Department, Faculty of Pharmacy and Biotechnology, the German University in Cairo, Cairo, Egypt
| | - Doris Urlaub
- Leibniz Research Centre for Working Environment and Human Factors (IfADo), TU Dortmund, Dortmund, Germany
| | - Mina Sandusky
- Leibniz Research Centre for Working Environment and Human Factors (IfADo), TU Dortmund, Dortmund, Germany
| | - Ola Khorshid
- Medical Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Mohamed Z Gad
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, the German University in Cairo, Cairo, Egypt
| | - Khaled Abou-Aisha
- Microbiology, Immunology and Biotechnology Department, Faculty of Pharmacy and Biotechnology, the German University in Cairo, Cairo, Egypt
| | - Carsten Watzl
- Leibniz Research Centre for Working Environment and Human Factors (IfADo), TU Dortmund, Dortmund, Germany.
| | - Mona Rady
- Microbiology, Immunology and Biotechnology Department, Faculty of Pharmacy and Biotechnology, the German University in Cairo, Cairo, Egypt.
- Faculty of Biotechnology, German International University, New Administrative Capital, Egypt.
| |
Collapse
|
|
2
|
Ismail NI. Relative expression of receptors in uterine natural killer cells compared to peripheral blood natural killer cells. Front Immunol 2023; 14:1166451. [PMID: 37051244 PMCID: PMC10083503 DOI: 10.3389/fimmu.2023.1166451] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 03/13/2023] [Indexed: 03/29/2023] Open
Abstract
One would expect maternal immune cells to attack the invading trophoblast as the placenta is semi-allogenic. However, they appear to cooperate with the trophoblast in disrupting the arterial wall which has been determined in several studies. uNK cells are a particular type of immune cell that appears to play a role in pregnancy. As in pregnancy, the key contributors to trophoblast invasion appear to be a unique combination of genes, which appear to regulate multiple components of the interactions between placental and maternal cells, called HLA class 1b genes. The HLA class 1b genes have few alleles, which makes them unlikely to be recognized as foreign by the maternal cells. The low polymorphic properties of these particular HLAs may aid trophoblasts in actively avoiding immune attacks. This review gives a complete description of the mechanisms of interaction between HLAs and maternal uNK cells in humans.
Collapse
|
|
3
|
Alrumaihi F. The Multi-Functional Roles of CCR7 in Human Immunology and as a Promising Therapeutic Target for Cancer Therapeutics. Front Mol Biosci 2022; 9:834149. [PMID: 35874608 PMCID: PMC9298655 DOI: 10.3389/fmolb.2022.834149] [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: 12/13/2021] [Accepted: 05/26/2022] [Indexed: 11/13/2022] Open
Abstract
An important hallmark of the human immune system is to provide adaptive immunity against pathogens but tolerance toward self-antigens. The CC-chemokine receptor 7 (CCR7) provides a significant contribution in guiding cells to and within lymphoid organs and is important for acquiring immunity and tolerance. The CCR7 holds great importance in establishing thymic architecture and function and naïve and regulatory T-cell homing in the lymph nodes. Similarly, the receptor is a key regulator in cancer cell migration and the movement of dendritic cells. This makes the CCR7 an important receptor as a drug and prognostic marker. In this review, we discussed several biological roles of the CCR7 and its importance as a drug and prognostic marker.
Collapse
Affiliation(s)
- Faris Alrumaihi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| |
Collapse
|
|
4
|
Manzoor S, Muhammad JS, Maghazachi AA, Hamid Q. Autophagy: A Versatile Player in the Progression of Colorectal Cancer and Drug Resistance. Front Oncol 2022; 12:924290. [PMID: 35912261 PMCID: PMC9329589 DOI: 10.3389/fonc.2022.924290] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/06/2022] [Indexed: 11/13/2022] Open
Abstract
Colorectal cancer (CRC) is among the topmost malignancies for both genders. Despite the high incidence rate and advances in diagnostic tools, treatment in many cases is still ineffective. Most cancerous lesions in CRC begin as benign, followed by the development of invasive forms and metastases. The development of CRC has been linked to defects in autophagy, which plays both a pro-and anti-tumor role and is mainly context-dependent. Autophagy suppression could enhance apoptosis via p53 activation, or autophagy also promotes tumor progression by maintaining tumor growth and increasing resistance to chemotherapy. Autophagy promotes the invasion and metastasis of CRC cells via increased epithelial-mesenchymal transition (EMT). Moreover, dysbiosis of gut microbiota upregulated autophagy and metastasis markers. Autophagy responses may also modulate the tumor microenvironment (TME) via regulating the differentiation process of several innate immune cells. Treatments that promote tumor cell death by stimulating or inhibiting autophagy could be beneficial if used as an adjunct treatment, but the precise role of various autophagy-modulating drugs in CRC patients is needed to be explored. In this article, we present an overview of the autophagy process and its role in the pathogenesis and therapeutic resistance of CRC. Also, we focused on the current understanding of the role of the EMT and TME, including its relation to gut microbiota and immune cells, in autophagic manipulation of CRC. We believe that there is a potential link between autophagy, TME, EMT, and drug resistance, suggesting that further studies are needed to explore this aspect.
Collapse
Affiliation(s)
- Shaista Manzoor
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Jibran Sualeh Muhammad
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Azzam A. Maghazachi
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Qutayba Hamid
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Meakins-Christie Laboratories, Research Institute of the McGill University Health Center, Montreal, QC, Canada
- *Correspondence: Qutayba Hamid,
| |
Collapse
|
|
5
|
Leopold AV, Thankachan S, Yang C, Gerashchenko D, Verkhusha VV. A general approach for engineering RTKs optically controlled with far-red light. Nat Methods 2022; 19:871-880. [PMID: 35681062 DOI: 10.1038/s41592-022-01517-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 05/06/2022] [Indexed: 11/09/2022]
Abstract
Regulation of receptor tyrosine kinase (RTK) activity is necessary for studying cell signaling pathways in health and disease. We developed a generalized approach for engineering RTKs optically controlled with far-red light. We targeted the bacterial phytochrome DrBphP to the cell surface and allowed its light-induced conformational changes to be transmitted across the plasma membrane via transmembrane helices to intracellular RTK domains. Systematic optimization of these constructs has resulted in optically regulated epidermal growth factor receptor, HER2, TrkA, TrkB, FGFR1, IR1, cKIT and cMet, named eDrRTKs. eDrRTKs induced downstream signaling in mammalian cells in tens of seconds. The ability to activate eDrRTKs with far-red light enabled spectral multiplexing with fluorescent probes operating in a shorter spectral range, allowing for all-optical assays. We validated eDrTrkB performance in mice and found that minimally invasive stimulation in the neocortex with penetrating via skull far-red light-induced neural activity, early immediate gene expression and affected sleep patterns.
Collapse
Affiliation(s)
- Anna V Leopold
- Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | | | - Chun Yang
- Department of Psychiatry, Harvard Medical School, West Roxbury, MA, USA
| | | | - Vladislav V Verkhusha
- Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland. .,Department of Genetics and Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, USA.
| |
Collapse
|
|
6
|
Rowaiye AB, Asala T, Oli AN, Uzochukwu IC, Akpa A, Esimone CO. The Activating Receptors of Natural Killer Cells and Their Inter-Switching Potentials. Curr Drug Targets 2021; 21:1733-1751. [PMID: 32914713 DOI: 10.2174/1389450121666200910160929] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 07/14/2020] [Accepted: 07/24/2020] [Indexed: 12/18/2022]
Abstract
The global incidence of cancer is on the increase and researchers are prospecting for specific and non-selective therapies derived from the immune system. The killer activating receptors of NK cells are known to be involved in immunosurveillance against tumor and virally-infected cells. These receptors belong to two main categories, namely the immunoglobulin like and C-lectin like families. Though they have different signal pathways, all the killer activating receptors have similar effector functions which include direct cytotoxicity and the release of inflammatory cytokines such as IFN-gamma and TNF-alpha. To transduce signals that exceed the activation threshold for cytotoxicity, most of these receptors require synergistic effort. This review profiles 21 receptors: 13 immunoglobulin-like, 5 lectin-like, and 3 others. It critically explores their structural uniqueness, role in disease, respective transduction signal pathways and their status as current and prospective targets for cancer immunotherapy. While the native ligands of most of these receptors are known, much work is required to prospect for specific antibodies, peptides and multi-target small molecules with high binding affinities.
Collapse
Affiliation(s)
| | - Titilayo Asala
- Department of Medical Biotechnology, National Biotechnology Development Agency, Abuja, Nigeria
| | - Angus Nnamdi Oli
- Department of Pharmaceutical Microbiology and Biotechnology, Faculty of Pharmaceutical Sciences, Nnamdi Azikiwe University, Agulu, Anambra state, Nigeria
| | - Ikemefuna Chijioke Uzochukwu
- Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmaceutical sciences, Nnamdi Azikiwe University, Agulu, Anambra state, Nigeria
| | - Alex Akpa
- Department of Medical Biotechnology, National Biotechnology Development Agency, Abuja, Nigeria
| | - Charles Okechukwu Esimone
- Department of Pharmaceutical Microbiology and Biotechnology, Faculty of Pharmaceutical Sciences, Nnamdi Azikiwe University, Agulu, Anambra state, Nigeria
| |
Collapse
|
|
7
|
Al-Ani M, Elemam NM, Hundt JE, Maghazachi AA. Drugs for Multiple Sclerosis Activate Natural Killer Cells: Do They Protect Against COVID-19 Infection? Infect Drug Resist 2020; 13:3243-3254. [PMID: 33061471 PMCID: PMC7519863 DOI: 10.2147/idr.s269797] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Accepted: 09/07/2020] [Indexed: 12/15/2022] Open
Abstract
COVID-19 infection caused by the newly discovered coronavirus severe acute respiratory distress syndrome virus-19 (SARS-CoV-2) has become a pandemic issue across the globe. There are currently many investigations taking place to look for specific, safe and potent anti-viral agents. Upon transmission and entry into the human body, SARS-CoV-2 triggers multiple immune players to be involved in the fight against the viral infection. Amongst these immune cells are NK cells that possess robust antiviral activity, and which do not require prior sensitization. However, NK cell count and activity were found to be impaired in COVID-19 patients and hence, could become a potential therapeutic target for COVID-19. Several drugs, including glatiramer acetate (GA), vitamin D3, dimethyl fumarate (DMF), monomethyl fumarate (MMF), natalizumab, ocrelizumab, and IFN-β, among others have been previously described to increase the biological activities of NK cells especially their cytolytic potential as reported by upregulation of CD107a, and the release of perforin and granzymes. In this review, we propose that such drugs could potentially restore NK cell activity allowing individuals to be more protective against COVID-19 infection and its complications.
Collapse
Affiliation(s)
- Mena Al-Ani
- Department of Clinical Sciences, College of Medicine and the Immuno-Oncology Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Noha Mousaad Elemam
- Department of Clinical Sciences, College of Medicine and the Immuno-Oncology Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
| | | | - Azzam A Maghazachi
- Department of Clinical Sciences, College of Medicine and the Immuno-Oncology Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
| |
Collapse
|
|
8
|
Shihab I, Khalil BA, Elemam NM, Hachim IY, Hachim MY, Hamoudi RA, Maghazachi AA. Understanding the Role of Innate Immune Cells and Identifying Genes in Breast Cancer Microenvironment. Cancers (Basel) 2020; 12:2226. [PMID: 32784928 PMCID: PMC7464944 DOI: 10.3390/cancers12082226] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/28/2020] [Accepted: 08/07/2020] [Indexed: 01/08/2023] Open
Abstract
The innate immune system is the first line of defense against invading pathogens and has a major role in clearing transformed cells, besides its essential role in activating the adaptive immune system. Macrophages, dendritic cells, NK cells, and granulocytes are part of the innate immune system that accumulate in the tumor microenvironment such as breast cancer. These cells induce inflammation in situ by secreting cytokines and chemokines that promote tumor growth and progression, in addition to orchestrating the activities of other immune cells. In breast cancer microenvironment, innate immune cells are skewed towards immunosuppression that may lead to tumor evasion. However, the mechanisms by which immune cells could interact with breast cancer cells are complex and not fully understood. Therefore, the importance of the mammary tumor microenvironment in the development, growth, and progression of cancer is widely recognized. With the advances of using bioinformatics and analyzing data from gene banks, several genes involved in NK cells of breast cancer individuals have been identified. In this review, we discuss the activities of certain genes involved in the cross-talk among NK cells and breast cancer. Consequently, altering tumor immune microenvironment can make breast tumors more responsive to immunotherapy.
Collapse
Affiliation(s)
- Israa Shihab
- Department of Clinical Sciences and the Immuno-Oncology Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, UAE; (I.S.); (B.A.K.); (N.M.E.); (I.Y.H.); (R.A.H.)
| | - Bariaa A. Khalil
- Department of Clinical Sciences and the Immuno-Oncology Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, UAE; (I.S.); (B.A.K.); (N.M.E.); (I.Y.H.); (R.A.H.)
| | - Noha Mousaad Elemam
- Department of Clinical Sciences and the Immuno-Oncology Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, UAE; (I.S.); (B.A.K.); (N.M.E.); (I.Y.H.); (R.A.H.)
| | - Ibrahim Y. Hachim
- Department of Clinical Sciences and the Immuno-Oncology Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, UAE; (I.S.); (B.A.K.); (N.M.E.); (I.Y.H.); (R.A.H.)
| | - Mahmood Yaseen Hachim
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai 505055, UAE;
| | - Rifat A. Hamoudi
- Department of Clinical Sciences and the Immuno-Oncology Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, UAE; (I.S.); (B.A.K.); (N.M.E.); (I.Y.H.); (R.A.H.)
| | - Azzam A. Maghazachi
- Department of Clinical Sciences and the Immuno-Oncology Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, UAE; (I.S.); (B.A.K.); (N.M.E.); (I.Y.H.); (R.A.H.)
| |
Collapse
|
|
9
|
Wu Y, Li J, Jabbarzadeh Kaboli P, Shen J, Wu X, Zhao Y, Ji H, Du F, Zhou Y, Wang Y, Zhang H, Yin J, Wen Q, Cho CH, Li M, Xiao Z. Natural killer cells as a double-edged sword in cancer immunotherapy: A comprehensive review from cytokine therapy to adoptive cell immunotherapy. Pharmacol Res 2020; 155:104691. [DOI: 10.1016/j.phrs.2020.104691] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 02/06/2020] [Accepted: 02/10/2020] [Indexed: 02/08/2023]
|
|
10
|
Identifying Dysregulated lncRNA-Associated ceRNA Network Biomarkers in CML Based on Dynamical Network Biomarkers. BIOMED RESEARCH INTERNATIONAL 2020; 2020:5189549. [PMID: 32149112 PMCID: PMC7049421 DOI: 10.1155/2020/5189549] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 01/04/2020] [Indexed: 11/17/2022]
Abstract
The incidence of chronic myeloid leukemia (CML) is increasing year by year, which is a serious threat to human health. Early diagnosis can reduce mortality and improve prognosis. LncRNAs have been shown to be effective biomarkers for a variety of diseases and can act as competitive endogenous RNA (ceRNA). In this study, the dysregulated lncRNA-associated ceRNA networks (DLCN) of the chronic phase (CP), accelerated phase (AP), and blastic crisis (BC) for CML are constructed. Then, based on dynamic network biomarkers (DNB), some dysregulated lncRNA-associated ceRNA network biomarkers of CP, AP, and BC for CML are identified according to DNB criteria. Thus, a lncRNA (SNHG5) is identified from DLCN_CP, a lncRNA (DLEU2) is identified from DLCN_AP, and two lncRNAs (SNHG3, SNHG5) are identified from DLCN_BC. In addition, the critical index (CI) used to detect disease outbreaks shows that CML occurs in CP, which is consistent with clinical medicine. By analyzing the functions of the identified ceRNA network biomarkers, it has been found that they are effective lncRNA biomarkers directly or indirectly related to CML. The result of this study will help deepen the understanding of CML pathology from the perspective of ceRNA and help discover the effective biomarkers of CP, AP, and BC for CML in the future, so as to help patients get timely treatment and reduce the mortality of CML.
Collapse
|
|
11
|
Maghazachi AA, Sand KL, Al-Jaderi Z. Glatiramer Acetate, Dimethyl Fumarate, and Monomethyl Fumarate Upregulate the Expression of CCR10 on the Surface of Natural Killer Cells and Enhance Their Chemotaxis and Cytotoxicity. Front Immunol 2016; 7:437. [PMID: 27807435 PMCID: PMC5069502 DOI: 10.3389/fimmu.2016.00437] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Accepted: 10/04/2016] [Indexed: 02/06/2023] Open
Abstract
In vitro harnessing of immune cells is the most important advance in the field of cancer immunotherapy. Results shown in the current paper may be used to harness natural killer (NK) cells in vitro. It is observed that drugs used to treat multiple sclerosis such as glatiramer acetate, dimethyl fumarate, and monomethyl fumarate upregulate the expression of chemokines receptor 10 (CCR10) on the surface of human IL-2-activated NK cells. This is corroborated with increased chemotaxis of these cells toward the concentration gradients of the ligands for CCR10, namely CCL27 and CCL28. It is also demonstrated that these three drugs enhance NK cell cytotoxicity against tumor target cells, an activity that is abrogated by prior incubation of the cells with anti-CCR10 antibody. Because CCL27 and CCL28 are secreted by selective tumor types such as malignant melanoma, squamous cell carcinomas, and colorectal cancer, respectively, it is hypothesized that activated NK cells may be harnessed in vitro with any of these drugs before utilizing them as a therapeutic modality for cancer.
Collapse
Affiliation(s)
- Azzam A. Maghazachi
- Department of Clinical Sciences, College of Medicine, and the Sharjah Institute for Medical Research (SIMR), University of Sharjah, Sharjah, United Arab Emirates
| | | | - Zaidoon Al-Jaderi
- Department of Clinical Sciences, College of Medicine, and the Sharjah Institute for Medical Research (SIMR), University of Sharjah, Sharjah, United Arab Emirates
- University of Oslo, Oslo, Norway
| |
Collapse
|
|
12
|
Lv W, Wang Q, Chen H, Jiang Y, Zheng J, Shi M, Xu Y, Han J, Li C, Zhang R. Prioritization of rheumatoid arthritis risk subpathways based on global immune subpathway interaction network and random walk strategy. MOLECULAR BIOSYSTEMS 2016; 11:2986-97. [PMID: 26289534 DOI: 10.1039/c5mb00247h] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The initiation and development of rheumatoid arthritis (RA) is closely related to mutual dysfunction of multiple pathways. Furthermore, some similar molecular mechanisms are shared between RA and other immune diseases. Therefore it is vital to reveal the molecular mechanism of RA through searching for subpathways of immune diseases and investigating the crosstalk effect among subpathways. Here we exploited an integrated approach combining both construction of a subpathway-subpathway interaction network and a random walk strategy to prioritize RA risk subpathways. Our research can be divided into three parts: (1) acquisition of risk genes and identification of risk subpathways of 85 immune diseases by using subpathway-lenient distance similarity (subpathway-LDS) method; (2) construction of a global immune subpathway interaction (GISI) network with subpathways identified by subpathway-LDS; (3) optimization of RA risk subpathways by random walk strategy based on GISI network. The results showed that our method could effectively identify RA risk subpathways, such as MAPK signaling pathway, prostate cancer pathway and chemokine signaling pathway. The integrated strategy considering crosstalk between immune subpathways significantly improved the effect of risk subpathway identification. With the development of GWAS, our method will provide insight into exploring molecular mechanisms of immune diseases and might be a promising approach for studying other diseases.
Collapse
Affiliation(s)
- Wenhua Lv
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, China.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
13
|
Al-Jaderi Z, Maghazachi AA. Utilization of Dimethyl Fumarate and Related Molecules for Treatment of Multiple Sclerosis, Cancer, and Other Diseases. Front Immunol 2016; 7:278. [PMID: 27499754 PMCID: PMC4956641 DOI: 10.3389/fimmu.2016.00278] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Accepted: 07/06/2016] [Indexed: 11/16/2022] Open
Abstract
Several drugs have been approved for treatment of multiple sclerosis (MS). Dimethyl fumarate (DMF) is utilized as an oral drug to treat this disease and is proven to be potent with less side effects than several other drugs. On the other hand, monomethyl fumarate (MMF), a related compound, has not been examined in greater details although it has the potential as a therapeutic drug for MS and other diseases. The mechanism of action of DMF or MMF is related to their ability to enhance the antioxidant pathways and to inhibit reactive oxygen species. However, other mechanisms have also been described, which include effects on monocytes, dendritic cells, T cells, and natural killer cells. It is also reported that DMF might be useful for treating psoriasis, asthma, aggressive breast cancers, hematopoeitic tumors, inflammatory bowel disease, intracerebral hemorrhage, osteoarthritis, chronic pancreatitis, and retinal ischemia. In this article, we will touch on some of these diseases with an emphasis on the effects of DMF and MMF on various immune cells.
Collapse
Affiliation(s)
- Zaidoon Al-Jaderi
- Department of Clinical Sciences, College of Medicine and Sahrjah Institute for Medical Research, University of Sharjah , Sharjah , United Arab Emirates
| | - Azzam A Maghazachi
- Department of Clinical Sciences, College of Medicine and Sahrjah Institute for Medical Research, University of Sharjah , Sharjah , United Arab Emirates
| |
Collapse
|
|
14
|
Decreased Cytotoxicity of Peripheral and Peritoneal Natural Killer Cell in Endometriosis. BIOMED RESEARCH INTERNATIONAL 2016; 2016:2916070. [PMID: 27294113 PMCID: PMC4880704 DOI: 10.1155/2016/2916070] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 04/20/2016] [Indexed: 11/23/2022]
Abstract
Endometriosis causes significant chronic pelvic pain, dysmenorrhea, and infertility and affects 10% of all women. In endometriosis, ectopic endometrium surviving after retrograde menstruation exhibits an abnormal immune response characterized by increased levels of activated macrophages and inflammatory cytokines. Particularly, dysfunctional natural killer (NK) cells play an important role in the pathogenesis of the disease by either facilitating or inhibiting the survival, implantation, and proliferation of endometrial cells. NK cells in the peritoneum and peritoneal fluid exhibit reduced levels of cytotoxicity in women with endometriosis. Several cytokines and inhibitory factors in the serum and peritoneal fluid also dysregulate NK cell cytotoxicity. Additionally, increased numbers of immature peripheral NK cells and induction of NK cell apoptosis are evident in the peritoneal fluid of women with endometriosis. The high rate of endometriosis recurrence after pharmaceutical or surgical treatment, which is associated with dysfunctional NK cells, indicates that new immunomodulatory management strategies are required. A good understanding of immune dysfunction would enable improvement of current treatments for endometriosis.
Collapse
|
|
15
|
Al-Jaderi Z, Maghazachi AA. Vitamin D₃ and monomethyl fumarate enhance natural killer cell lysis of dendritic cells and ameliorate the clinical score in mice suffering from experimental autoimmune encephalomyelitis. Toxins (Basel) 2015; 7:4730-44. [PMID: 26580651 PMCID: PMC4663530 DOI: 10.3390/toxins7114730] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Revised: 10/26/2015] [Accepted: 10/27/2015] [Indexed: 01/23/2023] Open
Abstract
Experimental autoimmune encephalomyelitis (EAE) is a CD4+ T cell mediated inflammatory demyelinating disease that is induced in mice by administration of peptides derived from myelin proteins. We developed EAE in SJL mice by administration of PLP139–151 peptide. The effect of treating these mice with 1α,25-Dihydroxyvitamin D3 (vitamin D3), or with monomethyl fumarate (MMF) was then examined. We observed that both vitamin D3 and MMF inhibited and/or prevented EAE in these mice. These findings were corroborated with isolating natural killer (NK) cells from vitamin D3-treated or MMF-treated EAE mice that lysed immature or mature dendritic cells. The results support and extend other findings indicating that an important mechanism of action for drugs used to treat multiple sclerosis (MS) is to enhance NK cell lysis of dendritic cells.
Collapse
Affiliation(s)
- Zaidoon Al-Jaderi
- Department of Physiology, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, POB 1103, Oslo N-0317, Norway.
| | | |
Collapse
|
|
16
|
Töpfer K, Cartellieri M, Michen S, Wiedemuth R, Müller N, Lindemann D, Bachmann M, Füssel M, Schackert G, Temme A. DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy. THE JOURNAL OF IMMUNOLOGY 2015; 194:3201-12. [PMID: 25740942 DOI: 10.4049/jimmunol.1400330] [Citation(s) in RCA: 183] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
NK cells are emerging as new effectors for immunotherapy of cancer. In particular, the genetic engraftment of chimeric Ag receptors (CARs) in NK cells is a promising strategy to redirect NK cells to otherwise NK cell-resistant tumor cells. On the basis of DNAX-activation protein 12 (DAP12), a signaling adaptor molecule involved in signal transduction of activating NK cell receptors, we generated a new type of CAR targeting the prostate stem cell Ag (PSCA). We demonstrate in this article that this CAR, designated anti-PSCA-DAP12, consisting of DAP12 fused to the anti-PSCA single-chain Ab fragment scFv(AM1) confers improved cytotoxicity to the NK cell line YTS against PSCA-positive tumor cells when compared with a CAR containing the CD3ζ signaling chain. Further analyses revealed phosphorylation of the DAP12-associated ZAP-70 kinase and IFN-γ release of CAR-engineered cells after contact with PSCA-positive target cells. YTS cells modified with DAP12 alone or with a CAR bearing a phosphorylation-defective ITAM were not activated. Notably, infused YTS cells armed with anti-PSCA-DAP12 caused delayed tumor xenograft growth and resulted in complete tumor eradication in a significant fraction of treated mice. The feasibility of the DAP12-based CAR was further tested in human primary NK cells and confers specific cytotoxicity against KIR/HLA-matched PSCA-positive tumor cells, which was further enhanced by KIR-HLA mismatches. We conclude that NK cells engineered with DAP12-based CARs are a promising tool for adoptive tumor immunotherapy.
Collapse
Affiliation(s)
- Katrin Töpfer
- Section of Experimental Neurosurgery and Tumor Immunology, Department of Neurosurgery, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
| | - Marc Cartellieri
- Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, 01328 Dresden, Germany
| | - Susanne Michen
- Section of Experimental Neurosurgery and Tumor Immunology, Department of Neurosurgery, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
| | - Ralf Wiedemuth
- Section of Experimental Neurosurgery and Tumor Immunology, Department of Neurosurgery, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
| | - Nadja Müller
- Section of Experimental Neurosurgery and Tumor Immunology, Department of Neurosurgery, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
| | - Dirk Lindemann
- Institute of Virology, Medical Faculty Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
| | - Michael Bachmann
- Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, 01328 Dresden, Germany
| | - Monika Füssel
- DKMS Life Science Lab, GmbH, 01307 Dresden, Germany; and
| | - Gabriele Schackert
- Section of Experimental Neurosurgery and Tumor Immunology, Department of Neurosurgery, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
| | - Achim Temme
- Section of Experimental Neurosurgery and Tumor Immunology, Department of Neurosurgery, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; German Cancer Consortium (DKTK), 01307 Dresden, Germany
| |
Collapse
|
|
17
|
Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a. Cell Mol Immunol 2014; 13:57-64. [PMID: 25435072 DOI: 10.1038/cmi.2014.114] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2014] [Revised: 10/17/2014] [Accepted: 10/17/2014] [Indexed: 12/18/2022] Open
Abstract
Dimethyl fumarate (DMF) is a new drug used to treat multiple sclerosis (MS) patients. Here, we examined the effects of DMF and the DMF metabolite monomethyl fumarate (MMF) on various activities of natural killer (NK) cells. We demonstrated that MMF augments the primary CD56(+), but not CD56(-), NK cell lysis of K562 and RAJI tumor cells. MMF induced NKp46 expression on the surface of CD56(+), but not CD56(-), NK cells after incubation for 24 h. This effect was closely correlated with the upregulation of CD107a expression on the surface of CD56(+) NK cells and the induction of Granzyme B release from these cells through this metabolite. An anti-NKp46 antibody inhibited the MMF-induced upregulation of CD107a and the lysis of tumor cells through CD56(+) NK cells. Thus, these results are the first to show that MMF augments CD56(+) NK cell lysis of tumor target cells, an effect mediated through NKp46. This novel effect suggests the use of MMF for therapeutic and/or preventive protocols in cancer.
Collapse
|
|
18
|
Høglund RA, Maghazachi AA. Multiple sclerosis and the role of immune cells. World J Exp Med 2014; 4:27-37. [PMID: 25254187 PMCID: PMC4172701 DOI: 10.5493/wjem.v4.i3.27] [Citation(s) in RCA: 112] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Revised: 05/29/2014] [Accepted: 07/17/2014] [Indexed: 02/06/2023] Open
Abstract
Multiple sclerosis (MS) is a complex disease with many different immune cells involved in its pathogenesis, and in particular T cells as the most recognized cell type. Recently, the innate immune system has also been researched for its effect on the disease. Hence, cells of the immune system play vital roles in either ameliorating or exacerbating the disease. The genetic and environmental factors, as well as the etiology and pathogenesis are of utmost importance for the development of MS. An insight into the roles play by T cells, B cells, natural killer cells, and dendritic cells in MS and the animal model experimental autoimmune encephalomyelitis, will be presented. Understanding the mechanisms of action for current therapeutic modalities should help developing new therapeutic tools to treat this disease and other autoimmune diseases.
Collapse
|
|
19
|
Kang YJ, Jeung IC, Park A, Park YJ, Jung H, Kim TD, Lee HG, Choi I, Yoon SR. An increased level of IL-6 suppresses NK cell activity in peritoneal fluid of patients with endometriosis via regulation of SHP-2 expression. Hum Reprod 2014; 29:2176-89. [PMID: 25035432 DOI: 10.1093/humrep/deu172] [Citation(s) in RCA: 103] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
STUDY QUESTION Is the decreased natural killer (NK) cell cytolytic activity in the peritoneal fluid (PF) of endometriosis patients due to primary cytokine activity? SUMMARY ANSWER An increased level of interleukin-6 (IL-6) in the PF of patients with endometriosis suppresses NK cell cytolytic activity by down-regulating cytolytic granule components, such as granzyme B and perforin, through the modulation of Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2) expression. WHAT IS ALREADY KNOWN Endometriosis is known to be related to a defect in NK cell cytolytic activity. Additionally, the levels of inflammatory cytokines are elevated in the PF of women with endometriosis. STUDY DESIGN, SIZE, DURATION The effects of PF on the differentiation and functional activity of NK cells were investigated in patients with or without endometriosis, and cytokines that reduce NK cell cytolytic activity in endometriosis patients were examined. The study included women who underwent laparoscopic examination for the diagnosis of endometriosis from August 2012 to July 2013 (33 women with, and 15 women without, endometriosis). PARTICIPANTS/MATERIALS, SETTING, METHODS Women of reproductive age (20-40 years old) who underwent laparoscopic examination for endometriosis were included. Cytokines present in the PF were identified by enzyme-linked immunosorbent assay. The cytolytic activity of NK cells in the PF was also analyzed using a calcein-acetoxy methyl ester (AM) release assay. MAIN RESULTS AND THE ROLE OF CHANCE PF from patients with endometriosis suppressed the differentiation and cytotoxicity of NK cells compared with PF from controls (P < 0.05). Increased levels of IL-6 were also found in the PF of patients with endometriosis (P < 0.01), and IL-6 levels were negatively correlated with the cytolytic activity of NK cells (rs = -0.558, P = 0.03). Furthermore, IL-6 reduced the cytolytic activity of NK cells, concomitantly with the down-regulation of granzyme B and perforin (P < 0.05), by modulating SHP-2. Importantly, the addition of anti-IL-6 to the PF of endometriosis patients restored the activity of NK cells (P < 0.01), suggesting that IL-6 plays a crucial role in the reduction of NK cell activity in the PF of patients with endometriosis. LIMITATIONS, REASONS FOR CAUTION PF contains various inflammatory cytokines in addition to IL-6 and so it is possible that other cytokines may affect the differentiation and activity of NK cells. WIDER IMPLICATIONS OF THE FINDINGS Our results imply that the suppression of IL-6 using an anti-IL-6 antibody or soluble IL-6 receptor could rescue the impairment of NK cell activity in patients with endometriosis. STUDY FUNDING/COMPETING INTERESTS This work was supported by the KRIBB Creative Research Program (KCS3051312); the STP project (DTM0111221) of the Ministry of Knowledge & Economy and the Basic Science Research Program (RBM0271312) of the National Research Foundation of Korea (NRF) from the Ministry of Education, Science & Technology. There are no conflicts of interest.
Collapse
Affiliation(s)
- Young-Ju Kang
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon 305-806, Republic of Korea
| | - In Cheul Jeung
- Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Jung-gu, Daejeon 301-723, Republic of Korea
| | - Arum Park
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon 305-806, Republic of Korea Department of Functional Genomics, University of Science & Technology, Yuseong-gu, Daejeon 305-350, Republic of Korea
| | - Young-Jun Park
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon 305-806, Republic of Korea Department of Functional Genomics, University of Science & Technology, Yuseong-gu, Daejeon 305-350, Republic of Korea
| | - Haiyoung Jung
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon 305-806, Republic of Korea Department of Functional Genomics, University of Science & Technology, Yuseong-gu, Daejeon 305-350, Republic of Korea
| | - Tae-Don Kim
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon 305-806, Republic of Korea Department of Functional Genomics, University of Science & Technology, Yuseong-gu, Daejeon 305-350, Republic of Korea
| | - Hee Gu Lee
- Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon 305-806, Republic of Korea
| | - Inpyo Choi
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon 305-806, Republic of Korea Department of Functional Genomics, University of Science & Technology, Yuseong-gu, Daejeon 305-350, Republic of Korea
| | - Suk Ran Yoon
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon 305-806, Republic of Korea Department of Functional Genomics, University of Science & Technology, Yuseong-gu, Daejeon 305-350, Republic of Korea
| |
Collapse
|
|
20
|
Rolin J, Maghazachi AA. Implications of chemokine receptors and inflammatory lipids in cancer. Immunotargets Ther 2013; 3:9-18. [PMID: 27471696 PMCID: PMC4918230 DOI: 10.2147/itt.s32049] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Inflammatory lipids receive much attention due to their important biological activities. Knowledge of the chemokine system has also reached a level that makes it interesting in clinics, which prompted clinical trials into compounds manipulating chemokines or their receptors. However, little attention has been devoted to understand the relations between these two systems. Here, we will review the role of inflammatory lipids and chemokines in innate and adaptive immunity with an attempt to link the two systems and with emphasis on their importance in cancer development.
Collapse
Affiliation(s)
- Johannes Rolin
- Department of Physiology, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Azzam A Maghazachi
- Department of Physiology, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| |
Collapse
|
|
21
|
Al-Jaderi Z, Maghazachi AA. Effects of vitamin D3, calcipotriol and FTY720 on the expression of surface molecules and cytolytic activities of human natural killer cells and dendritic cells. Toxins (Basel) 2013; 5:1932-47. [PMID: 24169587 PMCID: PMC3847708 DOI: 10.3390/toxins5111932] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2013] [Revised: 10/18/2013] [Accepted: 10/22/2013] [Indexed: 12/16/2022] Open
Abstract
We describe here the effects of three drugs that are either approved or have the potential for treating multiple sclerosis (MS) patients through the in vitro activities of human natural killer (NK) cells and dendritic cells (DCs). Our results indicate that 1,25(OH)2D3, the biologically active metabolite vitamin D3, calcipotriol and FTY720 augment IL-2-activated NK cell lysis of K562 and RAJI tumor cell lines as well as immature (i) and mature (m) DCs, with variable efficacies. These results are corroborated with the ability of the drugs to up-regulate the expression of NK cytotoxicity receptors NKp30 and NKp44, as well as NKG2D on the surfaces of NK cells. Also, they down-regulate the expression of the killer inhibitory receptor CD158. The three drugs down-regulate the expression of CCR6 on the surface of iDCs, whereas vitamin D3 and calcipotriol tend to up-regulate the expression of CCR7 on mDCs, suggesting that they may influence the migration of DCs into the lymph nodes. Finally, vitamin D3, calcipotriol and FTY720 enhance NK17/NK1 cell lysis of K562 cells, suggesting that a possible mechanism of action for these drugs is via activating these newly described cells. In conclusion, our results show novel mechanisms of action for vitamin D3, calcipotriol and FTY720 on cells of the innate immune system.
Collapse
Affiliation(s)
- Zaidoon Al-Jaderi
- Department of Physiology, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, POB 1103, Oslo N-0317, Norway.
| | | |
Collapse
|
|
22
|
Chang CJ, Chen YYM, Lu CC, Lin CS, Martel J, Tsai SH, Ko YF, Huang TT, Ojcius DM, Young JD, Lai HC. Ganoderma lucidum stimulates NK cell cytotoxicity by inducing NKG2D/NCR activation and secretion of perforin and granulysin. Innate Immun 2013; 20:301-11. [PMID: 23803412 DOI: 10.1177/1753425913491789] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Ganoderma lucidum (G. lucidum) is a medicinal mushroom long used in Asia as a folk remedy to promote health and longevity. Recent studies indicate that G. lucidum activates NK cells, but the molecular mechanism underlying this effect has not been studied so far. To address this question, we prepared a water extract of G. lucidum and examined its effect on NK cells. We observed that G. lucidum treatment increases NK cell cytotoxicity by stimulating secretion of perforin and granulysin. The mechanism of activation involves an increased expression of NKG2D and natural cytotoxicity receptors (NCRs), as well as increased phosphorylation of intracellular MAPKs. Our results indicate that G. lucidum induces NK cell cytotoxicity against various cancer cell lines by activating NKG2D/NCR receptors and MAPK signaling pathways, which together culminate in exocytosis of perforin and granulysin. These observations provide a cellular and molecular mechanism to account for the reported anticancer effects of G. lucidum extracts in humans.
Collapse
Affiliation(s)
- Chih-Jung Chang
- 1Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan, Taiwan, Republic of China
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Abstract
Although the etiology of multiple sclerosis (MS) is not known, the consensus is that Th1 cells sensitized to myelin proteins in the periphery are recruited into the CNS and damage the myelin sheath. Natural killers (NK) are cells that spontaneously lyse tumor target cells and have immunoregulatory activity secreting multiple cytokines and chemokines, as well as interacting with cells of innate and adaptive immune systems. A great discovery in the field is the cloning of several inhibitory and activating receptors. Another important contribution is the discovery that these cells express many seven-transmembrane-spanning domain receptors which aid them in extravasations into injured tissues. Despite all this progress, the role of NK cells in autoimmune diseases including MS is still not quite clear. In this paper, I will summarize recent findings related to the effects of these cells in both MS and the animal model of experimental autoimmune encephalomyelitis (EAE). Hence, I will discuss the effects of drugs used to treat MS/EAE and then explain their effects on NK cells. These include anti-CD25 or daclizumab, interferon-β (IFN-β), natalizumab, glatiramer acetate (GA), and fingolimod (FTY720). Finally, I will explain the contribution of the recently discovered NK17/NK1 cells in MS disease.
Collapse
Affiliation(s)
- A. A. Maghazachi
- Department of Physiology, Faculty of Medicine, Institute of Basic Medical Sciences, University of Oslo, POB 1103, 0317 Oslo, Norway
| |
Collapse
|
|
24
|
Lai HC, Chang CJ, Yang CH, Hsu YJ, Chen CC, Lin CS, Tsai YH, Huang TT, Ojcius DM, Tsai YH, Lu CC. Activation of NK cell cytotoxicity by the natural compound 2,3-butanediol. J Leukoc Biol 2012; 92:807-14. [PMID: 22802446 DOI: 10.1189/jlb.0112024] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
The natural compound 2,3-BTD has diverse physiological effects in a range of organisms, including acting as a detoxifying product of liver alcohol metabolism in humans and ameliorating endotoxin-induced acute lung injury in rats. In this study, we reveal that 2,3-BTD enhances NK cell cytotoxic activity in human pNK cells and NK92 cells. Treatment of NK cells with 2,3-BTD increased perforin expression in a dose-dependent manner. This was accompanied by elevated JNK and ERK1/2 MAPK activities and enhanced expression of NKG2D/NCRs, upstream signaling molecules of the MAPK pathways. The 2,3-BTD effect was inhibited by pretreatment with inhibitors of JNK (SP) or ERK1/2 (PD) or by depleting NKG2D/NCRs or JNK1 or ERK2 with siRNA. These results indicate that 2,3-BTD activates NK cell cytotoxicity by NKG2D/NCR pathways and represent the first report of the 2,3-BTD effect on activation of innate immunity cells.
Collapse
Affiliation(s)
- Hsin-Chih Lai
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taiwan, Republic of China
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Shegarfi H, Naddafi F, Mirshafiey A. Natural killer cells and their role in rheumatoid arthritis: friend or foe? ScientificWorldJournal 2012; 2012:491974. [PMID: 22547986 PMCID: PMC3322405 DOI: 10.1100/2012/491974] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2011] [Accepted: 11/30/2011] [Indexed: 01/02/2023] Open
Abstract
Rheumatoid arthritis (RA) is a long-term disease that leads to inflammation of the joints and surrounding tissues. Natural killer (NK) cells are an important part of the innate immune system and are responsible for the first line of defense against pathogens during the initial immune challenge before the adaptive immune system eventually eliminates the infectious burden. NK cells have the capacity to damage normal cells or through interaction with other cells such as dendritic cells, macrophages, and T cells cause autoimmune diseases, such as RA. NK cells isolated from the joints of patients with RA suggest that they may play a role in this disease. However, the involvement of NK cells in RA pathology is not fully elucidated. Both protective and detrimental roles of NK cells in RA have recently been reported. A better understanding of NK cells' role in RA might help to develop new therapeutic strategies for treatment of the RA or other autoimmune diseases. We have decided in this paper to focus on the NK cell biology, and attempt to bring the interested readership of this Journal up to date on the NK cell, specifically its possible relation to RA.
Collapse
Affiliation(s)
- Hamid Shegarfi
- Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, 0316 Oslo, Norway
| | - Fatemeh Naddafi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, P.O. Box 6446 Tehran 14155, Iran
| | - Abbas Mirshafiey
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, P.O. Box 6446 Tehran 14155, Iran
| |
Collapse
|
|
26
|
Blaho VA, Hla T. Regulation of mammalian physiology, development, and disease by the sphingosine 1-phosphate and lysophosphatidic acid receptors. Chem Rev 2011; 111:6299-320. [PMID: 21939239 PMCID: PMC3216694 DOI: 10.1021/cr200273u] [Citation(s) in RCA: 127] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Victoria A. Blaho
- Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY 10065
| | - Timothy Hla
- Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY 10065
| |
Collapse
|
|
27
|
Rolin J, Maghazachi AA. Effects of lysophospholipids on tumor microenvironment. CANCER MICROENVIRONMENT 2011; 4:393-403. [PMID: 21904916 DOI: 10.1007/s12307-011-0088-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2010] [Accepted: 08/26/2011] [Indexed: 12/20/2022]
Abstract
The effects of lysophospholipids (LPLs) on cancer microenvironment is a vast and growing field. These lipids are secreted physiologically by various cell types. They play highly important roles in the development, activation and regulation of the immune system. They are also secreted by cancerous cells and there is a strong association between LPLs and cancer. It is clear that these lipids and in particular sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) play major roles in regulating the growth of tumor cells, and in manipulating the immune system. These activities can be divided into two parts; the first involves the ability of S1P and LPA to either directly or through some of the enzymes that generate them such as sphingosine kinases or phospholipases, induce the motility and invasiveness of tumor cells. The second mechanism involves the recently discovered effects of these lipids on the anti-tumor effector natural killer (NK) cells. Whereas S1P and LPA induce the recruitment of these effector cells, they also inhibit their cytolysis of tumor cells. This may support the environment of cancer and the ability of cancer cells to grow, spread and metastasize. Consequently, LPLs or their receptors may be attractive targets for developing drugs in the treatment of cancer where LPLs or their receptors are up-regulated.
Collapse
Affiliation(s)
- Johannes Rolin
- Department of Physiology, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, POB 1103 Blindern, 0317, Oslo, Norway,
| | | |
Collapse
|
|
28
|
Tadiso TM, Krasnov A, Skugor S, Afanasyev S, Hordvik I, Nilsen F. Gene expression analyses of immune responses in Atlantic salmon during early stages of infection by salmon louse (Lepeophtheirus salmonis) revealed bi-phasic responses coinciding with the copepod-chalimus transition. BMC Genomics 2011; 12:141. [PMID: 21385383 PMCID: PMC3062619 DOI: 10.1186/1471-2164-12-141] [Citation(s) in RCA: 120] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2010] [Accepted: 03/07/2011] [Indexed: 12/30/2022] Open
Abstract
Background The salmon louse (Lepeophtheirus salmonis Krøyer), an ectoparasitic copepod with a complex life cycle causes significant losses in salmon aquaculture. Pesticide treatments against the parasite raise environmental concerns and their efficacy is gradually decreasing. Improvement of fish resistance to lice, through biological control methods, needs better understanding of the protective mechanisms. We used a 21 k oligonucleotide microarray and RT-qPCR to examine the time-course of immune gene expression changes in salmon skin, spleen, and head kidney during the first 15 days after challenge, which encompassed the copepod and chalimus stages of lice development. Results Large scale and highly complex transcriptome responses were found already one day after infection (dpi). Many genes showed bi-phasic expression profiles with abrupt changes between 5 and 10 dpi (the copepod-chalimus transitions); the greatest fluctuations (up- and down-regulation) were seen in a large group of secretory splenic proteases with unknown roles. Rapid sensing was witnessed with induction of genes involved in innate immunity including lectins and enzymes of eicosanoid metabolism in skin and acute phase proteins in spleen. Transient (1-5 dpi) increase of T-cell receptor alpha, CD4-1, and possible regulators of lymphocyte differentiation suggested recruitment of T-cells of unidentified lineage to the skin. After 5 dpi the magnitude of transcriptomic responses decreased markedly in skin. Up-regulation of matrix metalloproteinases in all studied organs suggested establishment of a chronic inflammatory status. Up-regulation of putative lymphocyte G0/G1 switch proteins in spleen at 5 dpi, immunoglobulins at 15 dpi; and increase of IgM and IgT transcripts in skin indicated an onset of adaptive humoral immune responses, whereas MHCI appeared to be down-regulated. Conclusions Atlantic salmon develops rapid local and systemic reactions to L. salmonis, which, however, do not result in substantial level of protection. The dramatic changes observed after 5 dpi can be associated with metamorphosis of copepod, immune modulation by the parasite, or transition from innate to adaptive immune responses.
Collapse
|
|
29
|
Expression and functional activity of chemokine receptors in glatiramer acetate–specific T cells isolated from multiple sclerosis patient receiving the drug glatiramer acetate. Hum Immunol 2011; 72:124-34. [DOI: 10.1016/j.humimm.2010.10.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2010] [Revised: 10/13/2010] [Accepted: 10/19/2010] [Indexed: 11/18/2022]
|
|
30
|
Maghazachi AA. Role of chemokines in the biology of natural killer cells. Curr Top Microbiol Immunol 2010; 341:37-58. [PMID: 20369317 DOI: 10.1007/82_2010_20] [Citation(s) in RCA: 125] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Natural killer (NK) cells represent a major subpopulation of lymphocytes. These cells have effector functions as they recognize and kill transformed cells as well as microbially infected cells. In addition, alloreactive NK cells have been successfully used to treat patients with acute myeloid leukemia and other hematological malignancies. NK cells are also endowed with immunoregulatory functions since they secrete cytokines such as IFN-γ, which favor the development of T helper 1 (Th1) cells, and chemokines such as CCL3/MIP-1α and CCL4/MIP-1β, which recruit various inflammatory cells into sites of inflammation. In human blood, NK cells are divided into CD56(bright) CD16(dim) and CD56(dim) CD16(bright) subsets. These subsets have different phenotypic expression and may have different functions; the former subset is more immunoregulatory and the latter is more cytolytic. The CD56(bright)CD16(dim) NK cells home into tissues such as the peripheral lymph nodes (LNs) under physiological conditions because they express the LN homing receptor CCR7 and they respond to CCL19/MIP-3β and CCL21/SLC chemokines. They also distribute into adenoid tissues or decidual uterus following the CXCR3/CXCL10 or CXCR4/CXCL12 axis. On the other hand, both NK cell subsets migrate into inflammatory sites, with more CD56(dim)CD16(bright) NK cells distributing into inflamed liver and lungs. CCR5/CCL5 axis plays an important role in the accumulation of NK cells in virally infected sites as well as during parasitic infections. CD56(bright)CD16(dim) cells also migrate into autoimmune sites such as inflamed synovial fluids in patients having rheumatoid arthritis facilitated by the CCR5/CCL3/CCL4/CCL5 axis, whereas they distribute into inflamed brains aided by the CX₃CR1/CX₃CL1 axis. On the other hand, CD56(dim)CD16(bright) NK cells accumulate in the liver of patients with primary biliary disease aided by the CXCR1/CXCL8 axis. However, the types of chemokines that contribute to their accumulation in target organs during graft vs. host (GvH) disease are not known. Further, chemokines activate NK cells to become highly cytolytic cells known as CC chemokine-activated killer (CHAK) cells that kill tumor cells. In summary, chemokines whether secreted in an autocrine or paracrine fashion regulate various biological functions of NK cells. Depending on the tissue and the chemokine secreted, NK cells may ameliorate the disease such as their roles in combating tumors or virally infected cells, and their therapeutic potentials in treating leukemias and other hematological malignancies, as well as reducing the incidence of GvH disease. In contrast, they may exacerbate the disease by damaging the affected tissues through direct cytotoxicity or by the release of multiple inflammatory cytokines and chemokines. Examples are their deleterious roles in autoimmune diseases such as rheumatoid arthritis and primary biliary cirrhosis.
Collapse
Affiliation(s)
- Azzam A Maghazachi
- Department of Physiology, Faculty of Medicine, Institute of Basic Medical Sciences, Blindern, 0317 Oslo, Norway.
| |
Collapse
|
|
31
|
Kim SD, Kim JM, Jo SH, Lee HY, Lee SY, Shim JW, Seo SK, Yun J, Bae YS. Functional expression of formyl peptide receptor family in human NK cells. THE JOURNAL OF IMMUNOLOGY 2009; 183:5511-7. [PMID: 19843937 DOI: 10.4049/jimmunol.0802986] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
We determined the expression of the formyl peptide receptor (FPR) family and the functional roles of the FPR family in NK cells. All tested human NK cells express two members of the FPR family (FPR1 and FPR2). The expression of FPR3 was noted to occur in a donor-specific manner. The stimulation of NK cells with FPR family-selective agonists (fMLF (N-formyl-Met-Leu-Phe), MMK-1, F2L, and WKYMVm (Trp-Lys-Tyr-Met-Val-d-Met)) elicited cytolytic activity in resting NK cells, but not in IL-2-activated NK cells; the cytolytic activity was not inhibited by pertussis toxin. The FPR family agonists also stimulated chemotactic migration of IL-2-activated NK cells, but not resting NK cells; the chemotactic migration was completely inhibited by pertussis toxin. WKYMVm stimulates ERK, p38 MAPK, and JNK activities in both resting and IL-2-activated NK cells. WKYMVm-induced chemotactic migration was partially inhibited by PD98059 (2'-amino-3'-methoxyflavone); however, the inhibition of JNK by its selective inhibitor (SP600125, anthra[1,9-cd]pyrazol-6(2H)-one) dramatically inhibited the WKYMVm-induced cytolytic activity. Furthermore, WKYMVm-induced chemotactic migration and cytolytic activity were partly inhibited by FPR family-selective antagonists (cyclosporin H and WRWWWW). Taken together, our findings indicate that human NK cells express functional members of the FPR family, and in turn the activation of the three members of the FPR receptor family elicit cytolytic activity in NK cells, thus suggesting that the receptors are potentially important therapeutic targets for the modulation of NK cell-mediated immune responses.
Collapse
Affiliation(s)
- Sang Doo Kim
- Department of Biochemistry, College of Medicine, Dong-A University, Busan, Korea
| | | | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Oxazolone-induced delayed type hypersensitivity reaction in the adult yucatan pigs. A useful model for drug development and validation. Toxins (Basel) 2009; 1:25-36. [PMID: 22069530 PMCID: PMC3202774 DOI: 10.3390/toxins1010025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2009] [Revised: 08/19/2009] [Accepted: 08/21/2009] [Indexed: 11/16/2022] Open
Abstract
The purpose of this study was to establish a model of delayed type hypersensitivity (DTH) reaction in the ear skin of large animals such as adult Yucatan pigs, which may aid in evaluating the efficacy of therapeutic modalities of newly developed anti-inflammatory drugs. The pigs were sensitized with oxazolone, re-challenged with the same irritant six days later, and dosed with either vehicle or with cyclosporine A (CsA) before and after challenge. CsA reduced the redness, inhibited the accumulation of ear fluid and inflammatory cells, as well as the release of the inflammatory mediators. Further, CsA inhibited the proliferation of T cells collected from the spleens or PBMCs of CsA-treated pigs when these cells were stimulated in vitro with PMA plus Ionomycin. These results indicate that pig skin can be used to evaluate modalities for the purpose of developing drugs that may be used to treat DTH in humans.
Collapse
|
|
33
|
Eleftheriadis T, Kartsios C, Yiannaki E, Antoniadi G, Kazila P, Pliakos K, Liakopoulos V, Markala D. Decreased CD3+CD16+ natural killer-like T-cell percentage and zeta-chain expression accompany chronic inflammation in haemodialysis patients. Nephrology (Carlton) 2009; 14:471-475. [PMID: 19486472 DOI: 10.1111/j.1440-1797.2008.01041.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
AIM Clinical and experimental data indicate a deficient immune response in haemodialysis (HD) patients. Natural killer-like (NKL) T cells express on their surface both the T-cell antigen receptor (TCR) and a diverse set of NK-cell receptors (NKR) and share properties of both T cells and NK cells. zeta-Chain phosphorylation is an early event that follows TCR activation or some NKR activation. The zeta-chain of both T cell and NK cells is downregulated in many chronic inflammatory states, HD included. In the present study, NKL T-cell percentage and zeta-chain expression in HD patients were evaluated. METHODS Thirty-three stable HD patients and 30 healthy volunteers were enrolled into the study. NKL T-cell percentage and NKL T-cell zeta-chain mean fluorescence intensity (MFI) were evaluated with flow cytometry. The inflammatory markers C-reactive protein, interleukin-6 and tumour necrosis factor-alpha were measured in the serum by means of enzyme-linked immunosorbent assay. RESULTS All the evaluated markers of inflammation were increased in HD patients. In these patients, NKL T-cell percentage (1.71 +/- 1.69% vs 3.94 +/- 3.86%) and zeta-chain MFI (3.66 +/- 2.79 vs 7.03 +/- 7.91) were decreased. CONCLUSIONS NKL T-cell percentage and zeta-chain expression is decreased in HD patients. Taking into consideration the continuously increasing age of the HD patients and that normally NKL T-cell numbers increase with age counteracting the impaired T-cell and NK-cell function accompanying advancing age, the above NKL T-cell disturbances could contribute to the impaired immune response in this population. Measures towards alleviating chronic inflammation could partially restore NKL T-cell impairment.
Collapse
|
|
34
|
Al-Falahi Y, Sand KL, Knudsen E, Damaj BB, Rolin J, Maghazachi AA. Splenic natural killer cell activity in two models of experimental neurodegenerative diseases. J Cell Mol Med 2008. [PMID: 19397784 DOI: 10.1111/j.1582-4934.2008.00640] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Natural killer (NK) cells are antitumour/anti-viral effectors and play important roles in shaping the immune system, but their role in neurodegenerative diseases is not clear. Here, we investigated the fate of these cells in two neurodegenerative diseases. In the first model, the activity of NK cells was examined in mice with experimental autoimmune encephalomyelitis (EAE) treated with glatiramer acetate (GA or Copaxone), a drug used to treat EAE in animals and multiple sclerosis in human. The second disease model is twitcher (Galc(twi)/Galc(twi)) mice, which represents an authentic model of human Krabbe's disease. Administration of GA ameliorated EAE in SJL mice corroborated with isolating NK cells that expressed higher killing than cells isolated from vehicle-dosed animals against immature or mature dendritic cells (DCs). However, this drug showed no effect on the numbers of NK cells or the expression of CD69 molecule. On the other hand, NK cells either disappeared from the spleens or were present in low numbers in the white pulp areas of Galc(twi)/Galc(twi) mice, which have increased D-galactosyl-beta1-1'-sphingosine (GalSph) levels. Analysis by confocal microscopy shows that NK cells found in the spleens of Galc(twi)/Galc(twi) mice were apoptotic. Incubating NK cells in vitro with GalSph induced the apoptosis in these cells, confirming the results of twitcher mice. Our results provide the first evidence showing that amelioration of EAE in mice is corroborated with NK cell lysis of antigen-presenting DCs, whereas NK cell distribution into the spleen is altered in a devastating lipid disorder corroborated with induction of their apoptosis.
Collapse
Affiliation(s)
- Yassin Al-Falahi
- Department of Physiology, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Kristin L Sand
- Department of Physiology, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Eirunn Knudsen
- Department of Physiology, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | | | - Johannes Rolin
- Department of Physiology, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Azzam A Maghazachi
- Department of Physiology, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| |
Collapse
|
|
35
|
Al-Falahi Y, Sand KL, Knudsen E, Damaj BB, Rolin J, Maghazachi AA. Splenic natural killer cell activity in two models of experimental neurodegenerative diseases. J Cell Mol Med 2008; 13:2693-2703. [PMID: 19397784 DOI: 10.1111/j.1582-4934.2008.00640.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Natural killer (NK) cells are antitumour/anti-viral effectors and play important roles in shaping the immune system, but their role in neurodegenerative diseases is not clear. Here, we investigated the fate of these cells in two neurodegenerative diseases. In the first model, the activity of NK cells was examined in mice with experimental autoimmune encephalomyelitis (EAE) treated with glatiramer acetate (GA or Copaxone), a drug used to treat EAE in animals and multiple sclerosis in human. The second disease model is twitcher (Galc(twi)/Galc(twi)) mice, which represents an authentic model of human Krabbe's disease. Administration of GA ameliorated EAE in SJL mice corroborated with isolating NK cells that expressed higher killing than cells isolated from vehicle-dosed animals against immature or mature dendritic cells (DCs). However, this drug showed no effect on the numbers of NK cells or the expression of CD69 molecule. On the other hand, NK cells either disappeared from the spleens or were present in low numbers in the white pulp areas of Galc(twi)/Galc(twi) mice, which have increased D-galactosyl-beta1-1'-sphingosine (GalSph) levels. Analysis by confocal microscopy shows that NK cells found in the spleens of Galc(twi)/Galc(twi) mice were apoptotic. Incubating NK cells in vitro with GalSph induced the apoptosis in these cells, confirming the results of twitcher mice. Our results provide the first evidence showing that amelioration of EAE in mice is corroborated with NK cell lysis of antigen-presenting DCs, whereas NK cell distribution into the spleen is altered in a devastating lipid disorder corroborated with induction of their apoptosis.
Collapse
Affiliation(s)
- Yassin Al-Falahi
- Department of Physiology, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Kristin L Sand
- Department of Physiology, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Eirunn Knudsen
- Department of Physiology, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | | | - Johannes Rolin
- Department of Physiology, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Azzam A Maghazachi
- Department of Physiology, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| |
Collapse
|
|
36
|
Damaj BB, Becerra CB, Esber HJ, Wen Y, Maghazachi AA. Functional Expression of H4 Histamine Receptor in Human Natural Killer Cells, Monocytes, and Dendritic Cells. THE JOURNAL OF IMMUNOLOGY 2007; 179:7907-15. [DOI: 10.4049/jimmunol.179.11.7907] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
|
|
37
|
Ostrakhovitch EA, Li SSC. The role of SLAM family receptors in immune cell signaling. Biochem Cell Biol 2007; 84:832-43. [PMID: 17215871 DOI: 10.1139/o06-191] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
The signaling lymphocyte-activating molecule (SLAM) family immunoreceptors are expressed in a wide array of immune cells, including both T and B lymphocytes. By virtue of their ability to transduce tyrosine phosphorylation signals through the so-called ITSM (immunoreceptor tyrosine-based switch motif) sequences, they play an important part in regulating both innate and adaptive immune responses. The critical role of the SLAM immunoreceptors in mediating normal immune reactions was highlighted in recent findings that SAP, a SLAM-associated protein, modulates the activities of various immune cells through interactions with different members of the SLAM family expressed in these cells. Importantly, mutations or deletions of the sap gene in humans result in the X-linked lymphoproliferative syndrome. In this review, we summarize current knowledge and survey the latest developments in signal transduction events triggered by the activation of SLAM family receptors in different cell types.
Collapse
Affiliation(s)
- Elena A Ostrakhovitch
- Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada
| | | |
Collapse
|
|
38
|
Ator MA, Mallamo JP, Williams M. Overview of Drug Discovery and Development. ACTA ACUST UNITED AC 2006; Chapter 9:Unit9.9. [PMID: 22294181 DOI: 10.1002/0471141755.ph0909s35] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
|