|
1
|
Perez-Quintero LA, Abidin BM, Tremblay ML. Immunotherapeutic implications of negative regulation by protein tyrosine phosphatases in T cells: the emerging cases of PTP1B and TCPTP. Front Med (Lausanne) 2024; 11:1364778. [PMID: 38707187 PMCID: PMC11066278 DOI: 10.3389/fmed.2024.1364778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 03/27/2024] [Indexed: 05/07/2024] Open
Abstract
In the context of inflammation, T cell activation occurs by the concerted signals of the T cell receptor (TCR), co-stimulatory receptors ligation, and a pro-inflammatory cytokine microenvironment. Fine-tuning these signals is crucial to maintain T cell homeostasis and prevent self-reactivity while offering protection against infectious diseases and cancer. Recent developments in understanding the complex crosstalk between the molecular events controlling T cell activation and the balancing regulatory cues offer novel approaches for the development of T cell-based immunotherapies. Among the complex regulatory processes, the balance between protein tyrosine kinases (PTK) and the protein tyrosine phosphatases (PTPs) controls the transcriptional and metabolic programs that determine T cell function, fate decision, and activation. In those, PTPs are de facto regulators of signaling in T cells acting for the most part as negative regulators of the canonical TCR pathway, costimulatory molecules such as CD28, and cytokine signaling. In this review, we examine the function of two close PTP homologs, PTP1B (PTPN1) and T-cell PTP (TCPTP; PTPN2), which have been recently identified as promising candidates for novel T-cell immunotherapeutic approaches. Herein, we focus on recent studies that examine the known contributions of these PTPs to T-cell development, homeostasis, and T-cell-mediated immunity. Additionally, we describe the signaling networks that underscored the ability of TCPTP and PTP1B, either individually and notably in combination, to attenuate TCR and JAK/STAT signals affecting T cell responses. Thus, we anticipate that uncovering the role of these two PTPs in T-cell biology may lead to new treatment strategies in the field of cancer immunotherapy. This review concludes by exploring the impacts and risks that pharmacological inhibition of these PTP enzymes offers as a therapeutic approach in T-cell-based immunotherapies.
Collapse
Affiliation(s)
- Luis Alberto Perez-Quintero
- Rosalind and Morris Goodman Cancer Institute, Faculty of Medicine, McGill University, Montreal, QC, Canada
- Department of Biochemistry, McGill University, Montreal, QC, Canada
| | - Belma Melda Abidin
- Rosalind and Morris Goodman Cancer Institute, Faculty of Medicine, McGill University, Montreal, QC, Canada
- Department of Biochemistry, McGill University, Montreal, QC, Canada
| | - Michel L. Tremblay
- Rosalind and Morris Goodman Cancer Institute, Faculty of Medicine, McGill University, Montreal, QC, Canada
- Department of Biochemistry, McGill University, Montreal, QC, Canada
| |
Collapse
|
|
2
|
Stanford SM, Bottini N. Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders. Nat Rev Drug Discov 2023; 22:273-294. [PMID: 36693907 PMCID: PMC9872771 DOI: 10.1038/s41573-022-00618-w] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2022] [Indexed: 01/25/2023]
Abstract
Protein phosphatases act as key regulators of multiple important cellular processes and are attractive therapeutic targets for various diseases. Although extensive effort has been dedicated to phosphatase-targeted drug discovery, early expeditions for competitive phosphatase inhibitors were plagued by druggability issues, leading to the stigmatization of phosphatases as difficult targets. Despite challenges, persistent efforts have led to the identification of several drug-like, non-competitive modulators of some of these enzymes - including SH2 domain-containing protein tyrosine phosphatase 2, protein tyrosine phosphatase 1B, vascular endothelial protein tyrosine phosphatase and protein phosphatase 1 - reigniting interest in therapeutic targeting of phosphatases. Here, we discuss recent progress in phosphatase drug discovery, with emphasis on the development of selective modulators that exhibit biological activity. The roles and regulation of protein phosphatases in immune cells and their potential as powerful targets for immuno-oncology and autoimmunity indications are assessed.
Collapse
Affiliation(s)
| | - Nunzio Bottini
- Department of Medicine, University of California, San Diego, CA, USA.
| |
Collapse
|
|
3
|
Spalinger MR, Canale V, Becerra A, Shawki A, Crawford M, Santos AN, Chatterjee P, Li J, Nair MG, McCole DF. PTPN2 regulates bacterial clearance in a mouse model of enteropathogenic and enterohemorrhagic E. coli infection. JCI Insight 2023; 8:156909. [PMID: 36810248 PMCID: PMC9977497 DOI: 10.1172/jci.insight.156909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 01/11/2023] [Indexed: 02/23/2023] Open
Abstract
Macrophages intimately interact with intestinal epithelial cells, but the consequences of defective macrophage-epithelial cell interactions for protection against enteric pathogens are poorly understood. Here, we show that in mice with a deletion in protein tyrosine phosphatase nonreceptor type 2 (PTPN2) in macrophages, infection with Citrobacter rodentium, a model of enteropathogenic and enterohemorrhagic E. coli infection in humans, promoted a strong type 1/IL-22-driven immune response, culminating in accelerated disease but also faster clearance of the pathogen. In contrast, deletion of PTPN2 specifically in epithelial cells rendered the epithelium unable to upregulate antimicrobial peptides and consequently resulted in a failure to eliminate the infection. The ability of PTPN2-deficient macrophages to induce faster recovery from C. rodentium was dependent on macrophage-intrinsic IL-22 production, which was highly increased in macrophages deficient in PTPN2. Our findings demonstrate the importance of macrophage-mediated factors, and especially macrophage-derived IL-22, for the induction of protective immune responses in the intestinal epithelium, and show that normal PTPN2 expression in the epithelium is crucial to allow for protection against enterohemorrhagic E. coli and other intestinal pathogens.
Collapse
Affiliation(s)
- Marianne R Spalinger
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, California, USA.,Department for Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Vinicius Canale
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, California, USA
| | - Anica Becerra
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, California, USA
| | - Ali Shawki
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, California, USA
| | - Meli'sa Crawford
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, California, USA
| | - Alina N Santos
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, California, USA
| | - Pritha Chatterjee
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, California, USA
| | - Jiang Li
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, California, USA
| | - Meera G Nair
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, California, USA
| | - Declan F McCole
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, California, USA
| |
Collapse
|
|
4
|
Zullo KM, Douglas B, Maloney NM, Ji Y, Wei Y, Herbine K, Cohen R, Pastore C, Cramer Z, Wang X, Wei W, Somsouk M, Hung LY, Lengner C, Kohanski MH, Cohen NA, Herbert DR. LINGO3 regulates mucosal tissue regeneration and promotes TFF2 dependent recovery from colitis. Scand J Gastroenterol 2021; 56:791-805. [PMID: 33941035 PMCID: PMC8647134 DOI: 10.1080/00365521.2021.1917650] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Aim: Recovery of damaged mucosal surfaces following inflammatory insult requires diverse regenerative mechanisms that remain poorly defined. Previously, we demonstrated that the reparative actions of Trefoil Factor 3 (TFF3) depend upon the enigmatic receptor, leucine rich repeat and immunoglobulin-like domain containing nogo receptor 2 (LINGO2). This study examined the related orphan receptor LINGO3 in the context of intestinal tissue damage to determine whether LINGO family members are generally important for mucosal wound healing and maintenance of the intestinal stem cell (ISC) compartment needed for turnover of mucosal epithelium.Methods and Results: We find that LINGO3 is broadly expressed on human enterocytes and sparsely on discrete cells within the crypt niche, that contains ISCs. Loss of function studies indicate that LINGO3 is involved in recovery of normal intestinal architecture following dextran sodium sulfate (DSS)-induced colitis, and that LINGO3 is needed for therapeutic action of the long acting TFF2 fusion protein (TFF2-Fc), including a number of signaling pathways critical for cell proliferation and wound repair. LINGO3-TFF2 protein-protein interactions were relatively weak however and LINGO3 was only partially responsible for TFF2 induced MAPK signaling suggesting additional un-identified components of a receptor complex. However, deficiency in either TFF2 or LINGO3 abrogated budding/growth of intestinal organoids and reduced expression of the intestinal ISC gene leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), indicating homologous roles for these proteins in tissue regeneration, possibly via regulation of ISCs in the crypt niche.Conclusion: We propose that LINGO3 serves a previously unappreciated role in promoting mucosal wound healing.
Collapse
Affiliation(s)
- Kelly M. Zullo
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
| | - Bonnie Douglas
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
| | - Nicole M. Maloney
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
| | - Yingbiao Ji
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
| | - Yun Wei
- Department of Medicine, Division of Experimental Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Karl Herbine
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
| | - Rachel Cohen
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
| | - Christopher Pastore
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
| | - Zvi Cramer
- Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
| | - Xin Wang
- Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
| | - Wenjie Wei
- Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19147
| | - Ma Somsouk
- Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Li Yin Hung
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104,Department of Medicine, Division of Experimental Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Christopher Lengner
- Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
| | - Michael H. Kohanski
- Department of Otorhinolaryngology—Head and Neck Surgery, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104,The Corporal Michael J. Crescenz VA Medical Center Surgical Service, Philadelphia, PA 19104
| | - Noam A. Cohen
- Department of Otorhinolaryngology—Head and Neck Surgery, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104,The Corporal Michael J. Crescenz VA Medical Center Surgical Service, Philadelphia, PA 19104,Monell Chemical Senses Center, Philadelphia, PA 19104
| | - De’Broski R. Herbert
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104,Department of Medicine, Division of Experimental Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| |
Collapse
|
|
5
|
Al-Sadi R, Engers J, Haque M, King S, Al-Omari D, Ma TY. Matrix Metalloproteinase-9 (MMP-9) induced disruption of intestinal epithelial tight junction barrier is mediated by NF-κB activation. PLoS One 2021; 16:e0249544. [PMID: 33826658 PMCID: PMC8026081 DOI: 10.1371/journal.pone.0249544] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 03/20/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Matrix Metalloproteinase-9 (MMP-9) has been shown to play a key role in mediating inflammation and tissue damage in inflammatory bowel disease (IBD). In patients with IBD, the intestinal tight junction (TJ) barrier is compromised as characterized by an increase in intestinal permeability. MMP-9 is elevated in intestinal tissue, serum and stool of patients with IBD. Previous studies from our laboratory showed that MMP-9 causes an increase in intestinal epithelial TJ permeability and that the MMP-9 induced increase in intestinal permeability is an important pathogenic factor contributing to the development of intestinal inflammation in IBD. However, the intracellular mechanisms that mediate the MMP-9 modulation of intestinal barrier function remain unclear. AIMS The main aim of this study was to further elucidate the molecular mechanisms involved in MMP-9 induced increase in intestinal epithelial TJ permeability using Caco-2 monolayers as an in-vitro model system. RESULTS MMP-9 induced increase in Caco-2 TJ permeability was associated with activation and cytoplasmic-to-nuclear translocation of NF-κB p65. Knocking-down NF-κB p65 by siRNA transfection prevented the MMP-9 induced expression of the NF-κB target gene IL-8, myosin light chain kinase (MLCK) protein expression, and subsequently prevented the increase in Caco-2 TJ permeability. In addition, the effect of MMP-9 on Caco-2 intestinal epithelial TJ barrier function was not mediated by apoptosis or necrosis. CONCLUSION Our data show that the MMP-9 induced disruption of Caco-2 intestinal epithelial TJ barrier function is regulated by NF-κB pathway activation of MLCK.
Collapse
Affiliation(s)
- Rana Al-Sadi
- Department of Medicine, Penn State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania, United States of America
- * E-mail:
| | - Jessica Engers
- Department of Medicine, Penn State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania, United States of America
| | - Mohammad Haque
- Department of Medicine, Penn State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania, United States of America
| | - Steven King
- Department of Medicine, Penn State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania, United States of America
| | - Deemah Al-Omari
- Department of Biology, University of New Mexico, Albuquerque, New Mexico, United States of America
| | - Thomas Y. Ma
- Department of Medicine, Penn State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania, United States of America
| |
Collapse
|
|
6
|
Hsieh WC, Svensson MN, Zoccheddu M, Tremblay ML, Sakaguchi S, Stanford SM, Bottini N. PTPN2 links colonic and joint inflammation in experimental autoimmune arthritis. JCI Insight 2020; 5:141868. [PMID: 33055428 PMCID: PMC7605542 DOI: 10.1172/jci.insight.141868] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 09/09/2020] [Indexed: 12/28/2022] Open
Abstract
Loss-of-function variants of protein tyrosine phosphatase non-receptor type 2 (PTPN2) enhance risk of inflammatory bowel disease and rheumatoid arthritis; however, whether the association between PTPN2 and autoimmune arthritis depends on gut inflammation is unknown. Here we demonstrate that induction of subclinical intestinal inflammation exacerbates development of autoimmune arthritis in SKG mice. Ptpn2-haploinsufficient SKG mice — modeling human carriers of disease-associated variants of PTPN2 — displayed enhanced colitis-induced arthritis and joint accumulation of Tregs expressing RAR-related orphan receptor γT (RORγt) — a gut-enriched Treg subset that can undergo conversion into FoxP3–IL-17+ arthritogenic exTregs. SKG colonic Tregs underwent higher conversion into arthritogenic exTregs when compared with peripheral Tregs, which was exacerbated by haploinsufficiency of Ptpn2. Ptpn2 haploinsufficiency led to selective joint accumulation of RORγt-expressing Tregs expressing the colonic marker G protein–coupled receptor 15 (GPR15) in arthritic mice and selectively enhanced conversion of GPR15+ Tregs into exTregs in vitro and in vivo. Inducible Treg-specific haploinsufficiency of Ptpn2 enhanced colitis-induced SKG arthritis and led to specific joint accumulation of GPR15+ exTregs. Our data validate the SKG model for studies at the interface between intestinal and joint inflammation and suggest that arthritogenic variants of PTPN2 amplify the link between gut inflammation and arthritis through conversion of colonic Tregs into exTregs. Loss of protein tyrosine phosphatase non-receptor type 2 amplifies the link between gut and joint inflammation through conversion of colonic Tregs into arthritogenic exTregs.
Collapse
Affiliation(s)
- Wan-Chen Hsieh
- Department of Medicine, UCSD School of Medicine, La Jolla, California, USA
| | - Mattias Nd Svensson
- Department of Medicine, UCSD School of Medicine, La Jolla, California, USA.,Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Martina Zoccheddu
- Department of Medicine, UCSD School of Medicine, La Jolla, California, USA
| | - Michael L Tremblay
- Rosalind and Morris Goodman Cancer Research Centre.,Department of Biochemistry, and.,Division of Experimental Medicine, Department of Medicine, Faculty of Medicine and Health Sciences, McGill University, Montréal, Québec, Canada
| | - Shimon Sakaguchi
- Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita, Japan.,Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
| | | | - Nunzio Bottini
- Department of Medicine, UCSD School of Medicine, La Jolla, California, USA
| |
Collapse
|
|
7
|
Baicalin Is Curative Against Rotavirus Damp Heat Diarrhea by Tuning Colonic Mucosal Barrier and Lung Immune Function. Dig Dis Sci 2020; 65:2234-2245. [PMID: 31802384 DOI: 10.1007/s10620-019-05977-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 11/27/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND Previous studies have indicated that rotavirus (RV) is a causative factor for diarrhea and gastroenteritis in pediatric and neonatal settings. Baicalin has many functions, including antibacterial, antiinflammatory, and antihypertensive activities. However, the immunological mechanism of RV-induced diarrhea with heat-dampness syndrome (RV-DH) remains unclear. AIMS The aim of this study is to explore the role of baicalin in RV-DH diarrhea and its underlying mechanism. METHODS A mouse model of pediatric RV-DH diarrhea was established and treated with baicalin. The concentrations of cytokines were detected by enzyme-linked immunosorbent assay. Messenger RNA (mRNA) expression levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR), while protein expression levels were determined by Western blotting and immunohistochemistry. Flow cytometry was used to detect the frequency of lymphocytes. RESULTS The concentrations of interleukin-1β (IL-1β), IL-2, IL-6, IL-8, RVvb, and secretory immunoglobulin A (SIgA) in bronchoalveolar lavage fluid (BALF) and colonic mucosa were significantly increased in the RV-DH group. Decreased expression of occludin, claudin-1, and zonula occludens-1 (ZO-1) indicated loss of tight junction function and disturbances in intestinal mucosal permeability in the RV-DH group. Flow cytometry analysis showed a high rate of CD8+ lymphocytes and low amount of CD4+ lymphocytes in the RV-DH group. Treatment of RV-DH mice with baicalin significantly reduced the duration of diarrhea and ameliorated the symptoms and pathological and immunological changes. Furthermore, baicalin inhibited STAT1 and activated STAT3 signaling pathways. CONCLUSIONS These findings indicate the curative and immunoregulatory properties of baicalin and have direct practical and clinical relevance for the treatment of RV-DH enteritis in humans.
Collapse
|
|
8
|
Zhang P, Zhang W, Zhang D, Wang M, Aprecio R, Ji N, Mohamed O, Li Y, Ding Y, Wang Q. 25-Hydroxyvitamin D 3 -enhanced PTPN2 positively regulates periodontal inflammation through the JAK/STAT pathway in human oral keratinocytes and a mouse model of type 2 diabetes mellitus. J Periodontal Res 2018. [PMID: 29516520 DOI: 10.1111/jre.12535] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND OBJECTIVE Periodontitis is an increasingly prevalent complication of diabetes mellitus (known as diabetes mellitus-associated periodontitis), and 25-hydroxyvitamin D3 (25VD3 ) was recently found to be a critical regulator of innate immunity in this disease, but the underlying mechanisms remain poorly understood. T-cell protein tyrosine phosphatase non-receptor type 2 (PTPN2) is a potential downstream protein of the 25VD3 /vitamin D receptor pathway. The aim of this study was to investigate the regulation of PTPN2 in periodontal inflammation in diabetes mellitus-associated periodontitis. MATERIAL AND METHODS Porphyromonas gingivalis-infected db/db mice were treated with 25VD3 . Their fasting blood glucose and body weight were monitored every other week, and the levels of alveolar bone loss and serum inflammatory cytokines (tumor necrosis factor-α, interferon-γ and interleukin-6) were determined at the time of killing. The effect of PTPN2 on human OKF6-TERT2 oral keratinocytes was examined through the knockout of PTPN2 using the CRISPR/Cas9 knockout plasmid. The expression levels of the PTPN2, vitamin D receptor and JAK1/STAT3 signaling proteins in the gingival epithelium and OKF6-TERT2 cells were determined through western blot and immunohistochemical analyses. RESULTS After 25VD3 treatment, db/db mice exhibited alleviated serum inflammatory cytokines and alveolar bone loss, and 25VD3 -enhanced PTPN2 expression decreased the expression of the JAK1/STAT3 signaling proteins in the gingival epithelium. Analyses of human oral keratinocytes showed that 25VD3 increased the expression of PTPN2, which dephosphorylates protein substrates in the JAK1/STAT3 signaling pathway. CONCLUSION PTPN2 contributed to a decrease in periodontal inflammation in type 2 diabetes mellitus via dephosphorylate protein substrates in the JAK1/STAT3 signaling pathway after 25VD3 treatment in human oral keratinocytes and a mouse model of type 2 diabetes mellitus. A thorough understanding of PTPN2 and its involvement in inhibiting inflammation might provide alternative therapeutic approaches for the pathogenesis and treatment of diabetes mellitus-associated periodontitis.
Collapse
Affiliation(s)
- P Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - W Zhang
- Center for Dental Research, School of Dentistry, Loma Linda University, Loma Linda, CA, USA
| | - D Zhang
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, China
| | - M Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - R Aprecio
- Center for Dental Research, School of Dentistry, Loma Linda University, Loma Linda, CA, USA
| | - N Ji
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - O Mohamed
- Center for Dental Research, School of Dentistry, Loma Linda University, Loma Linda, CA, USA
| | - Y Li
- Center for Dental Research, School of Dentistry, Loma Linda University, Loma Linda, CA, USA
| | - Y Ding
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Periodontology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Q Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| |
Collapse
|
|
9
|
Loss of T-cell protein tyrosine phosphatase in the intestinal epithelium promotes local inflammation by increasing colonic stem cell proliferation. Cell Mol Immunol 2017; 15:367-376. [PMID: 28287113 PMCID: PMC6052838 DOI: 10.1038/cmi.2016.72] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 12/20/2016] [Accepted: 12/21/2016] [Indexed: 12/27/2022] Open
Abstract
T-cell protein tyrosine phosphatase (TC-PTP) has a critical role in the development of the immune system and has been identified as a negative regulator of inflammation. Single-nucleotide polymorphisms in the TC-PTP locus have been associated with increased susceptibility to inflammatory bowel diseases (IBDs) in patients. To further understand how TC-PTP is related to IBDs, we investigated the role of TC-PTP in maintaining the intestinal epithelial barrier using an in vivo genetic approach. Intestinal epithelial cell (IEC)-specific deletion of TC-PTP was achieved in a mouse model at steady state and in the context of dextran sulphate sodium (DSS)-induced colitis. Knockout (KO) of TC-PTP in IECs did not result in an altered intestinal barrier. However, upon DSS treatment, IEC-specific TC-PTP KO mice displayed a more severe colitis phenotype with a corresponding increase in the immune response and inflammatory cytokine profile. The absence of TC-PTP caused an altered turnover of IECs, which is further explained by the role of the tyrosine phosphatase in colonic stem cell (CoSC) proliferation. Our results suggest a novel role for TC-PTP in regulating the homeostasis of CoSC proliferation. This supports the protective function of TC-PTP against IBDs, independently of its previously demonstrated role in intestinal immunity.
Collapse
|
|
10
|
Spalinger MR, McCole DF, Rogler G, Scharl M. Protein tyrosine phosphatase non-receptor type 2 and inflammatory bowel disease. World J Gastroenterol 2016; 22:1034-1044. [PMID: 26811645 PMCID: PMC4716018 DOI: 10.3748/wjg.v22.i3.1034] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 08/31/2015] [Accepted: 11/19/2015] [Indexed: 02/06/2023] Open
Abstract
Genome wide association studies have associated single nucleotide polymorphisms within the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) with the onset of inflammatory bowel disease (IBD) and other inflammatory disorders. Expression of PTPN2 is enhanced in actively inflamed intestinal tissue featuring a marked up-regulation in intestinal epithelial cells. PTPN2 deficient mice suffer from severe intestinal and systemic inflammation and display aberrant innate and adaptive immune responses. In particular, PTPN2 is involved in the regulation of inflammatory signalling cascades, and critical for protecting intestinal epithelial barrier function, regulating innate and adaptive immune responses, and finally for maintaining intestinal homeostasis. On one hand, dysfunction of PTPN2 has drastic effects on innate host defence mechanisms, including increased secretion of pro-inflammatory cytokines, limited autophagosome formation in response to invading pathogens, and disruption of the intestinal epithelial barrier. On the other hand, PTPN2 function is crucial for controlling adaptive immune functions, by regulating T cell proliferation and differentiation as well as maintaining T cell tolerance. In this way, dysfunction of PTPN2 contributes to the manifestation of IBD. The aim of this review is to present an overview of recent findings on the role of PTPN2 in intestinal homeostasis and the impact of dysfunctional PTPN2 on intestinal inflammation.
Collapse
|
|
11
|
Wang Q, Zhang P, Aprecio R, Zhang D, Li H, Ji N, Mohamed O, Zhang W, Li Y, Ding Y. Comparison of Experimental Diabetic Periodontitis Induced by Porphyromonas gingivalis in Mice. J Diabetes Res 2016; 2016:4840203. [PMID: 27995146 PMCID: PMC5141310 DOI: 10.1155/2016/4840203] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 11/02/2016] [Indexed: 02/05/2023] Open
Abstract
Periodontitis is one of the severe complications in diabetic patients and gingival epithelium plays an initial role on the onset and progression of this disease. However the potential mechanism is yet sufficiently understood. Meanwhile, the research on the correlational experimental animal models was also insufficient. Here, we established periodontitis with type 2 diabetes in db/db and Tallyho/JngJ (TH) mice and periodontitis with type 1 diabetes in streptozotocin induced diabetes C57BL/6J (STZ-C57) mice by oral infection of periodontal pathogen Porphyromonas gingivalis W50. We demonstrated that periodontal infected mice with high blood glucose levels showed dramatically more alveolar bone loss than their counterparts, in which infected db/db mice exhibited the most bone defects. No contrary impact could be observed between this periodontal infection and onset and severity of diabetes. The expressions of PTPN2 were inhibited whereas the expression of JAK1, STAT1, and STAT3 increased dramatically in gingival epithelia and the serum TNF-α also significantly increased in the mice with diabetic periodontitis. Our results indicated that the variations of inflammation-related protein expressions in gingival epithelia might lead to the phenotype differences in the mice with diabetic periodontitis.
Collapse
MESH Headings
- Alveolar Bone Loss
- Animals
- Blood Glucose/metabolism
- Diabetes Complications/etiology
- Diabetes Complications/metabolism
- Diabetes Mellitus, Experimental/complications
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Type 1/complications
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/metabolism
- Disease Models, Animal
- Gingiva/metabolism
- Janus Kinase 1/metabolism
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Inbred Strains
- Periodontitis/etiology
- Periodontitis/metabolism
- Porphyromonas gingivalis
- Protein Tyrosine Phosphatase, Non-Receptor Type 2/metabolism
- STAT1 Transcription Factor/metabolism
- STAT3 Transcription Factor/metabolism
- Tumor Necrosis Factor-alpha/metabolism
Collapse
Affiliation(s)
- Qi Wang
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, 3rd Section S. Renmin Road, Chengdu, China
- *Qi Wang: and
| | - Peng Zhang
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, 3rd Section S. Renmin Road, Chengdu, China
| | - Ray Aprecio
- Center for Dental Research, School of Dentistry, Loma Linda University, 11175 Campus Street, Loma Linda, CA, USA
| | - Dongjiao Zhang
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, 44-1 Wenhua W. Road, Jinan, China
| | - Hao Li
- Department of Prosthodontics, The Affiliated Hospital of Stomatology, Guangxi Medical University, 10 Shuangyong Road, Nanning 530021, China
| | - Ning Ji
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, 3rd Section S. Renmin Road, Chengdu, China
| | - Omaima Mohamed
- Center for Dental Research, School of Dentistry, Loma Linda University, 11175 Campus Street, Loma Linda, CA, USA
| | - Wu Zhang
- Center for Dental Research, School of Dentistry, Loma Linda University, 11175 Campus Street, Loma Linda, CA, USA
| | - Yiming Li
- Center for Dental Research, School of Dentistry, Loma Linda University, 11175 Campus Street, Loma Linda, CA, USA
| | - Yi Ding
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, 3rd Section S. Renmin Road, Chengdu, China
- *Yi Ding:
| |
Collapse
|
|
12
|
Hasi-Zogaj M, Sebold C, Heard P, Carter E, Soileau B, Hill A, Rupert D, Perry B, Atkinson S, O'Donnell L, Gelfond J, Lancaster J, Fox PT, Hale DE, Cody JD. A review of 18p deletions. AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS 2015; 169:251-64. [PMID: 26250845 DOI: 10.1002/ajmg.c.31445] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Since 18p- was first described in 1963, much progress has been made in our understanding of this classic deletion condition. We have been able to establish a fairly complete picture of the phenotype when the deletion breakpoint occurs at the centromere, and we are working to establish the phenotypic effects when each gene on 18p is hemizygous. Our aim is to provide genotype-specific anticipatory guidance and recommendations to families with an 18p- diagnosis. In addition, establishing the molecular underpinnings of the condition will potentially suggest targets for molecular treatments. Thus, the next step is to establish the precise effects of specific gene deletions. As we look forward to deepening our understanding of 18p-, our focus will continue to be on the establishment of robust genotype-phenotype correlations and the penetrance of these phenotypes. We will continue to follow our 18p- cohort closely as they age to determine the presence or absence of some of these diagnoses, including spinocerebellar ataxia (SCA), facioscapulohumeral muscular dystrophy (FSHD), and dystonia. We will also continue to refine the critical regions for other phenotypes as we enroll additional (hopefully informative) participants into the research study and as the mechanisms of the genes in these regions are elucidated. Mouse models will also be developed to further our understanding of the effects of hemizygosity as well as to serve as models for treatment development.
Collapse
|
|
13
|
Role of protein tyrosine phosphatases in regulating the immune system: implications for chronic intestinal inflammation. Inflamm Bowel Dis 2015; 21:645-55. [PMID: 25581833 PMCID: PMC4329025 DOI: 10.1097/mib.0000000000000297] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Current hypothesis suggests that genetic, immunological, and bacterial factors contribute essentially to the pathogenesis of inflammatory bowel disease. Variations within the gene loci encoding protein tyrosine phosphatases (PTPs) have been associated with the onset of inflammatory bowel disease. PTPs modulate the activity of their substrates by dephosphorylation of tyrosine residues and are critical for the regulation of fundamental cellular signaling processes. Evidence emerges that expression levels of PTPN2, PTPN11, and PTPN22 are altered in actively inflamed intestinal tissue. PTPN2 seems to be critical for protecting intestinal epithelial barrier function, regulating innate and adaptive immune responses and finally for maintaining intestinal homeostasis. These observations have been confirmed in PTPN2 knockout mice in vivo. Those animals are clearly more susceptible to intestinal and systemic inflammation and feature alterations in innate and adaptive immune responses. PTPN22 controls inflammatory signaling in lymphocytes and mononuclear cells resulting in aberrant cytokine secretion pattern and autophagosome formation. PTPN22 deficiency in vivo results in more severe colitis demonstrating the relevance of PTPN22 for intestinal homeostasis in vivo. Of note, loss of PTPN22 promotes mitogen-activated protein kinase-induced cytokine secretion but limits secretion of nuclear factor κB-associated cytokines and autophagy in mononuclear cells. Loss of PTPN11 is also associated with increased colitis severity in vivo. In summary, dysfunction of those PTPs results in aberrant and uncontrolled immune responses that result in chronic inflammatory conditions. This way, it becomes more and more evident that dysfunction of PTPs displays an important factor in the pathogenesis of chronic intestinal inflammation, in particular inflammatory bowel disease.
Collapse
|
|
14
|
Genetics of serum concentration of IL-6 and TNFα in systemic lupus erythematosus and rheumatoid arthritis: a candidate gene analysis. Clin Rheumatol 2015; 34:1375-82. [PMID: 25652333 DOI: 10.1007/s10067-015-2881-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Revised: 01/05/2015] [Accepted: 01/19/2015] [Indexed: 12/19/2022]
Abstract
Elevated concentrations of inflammatory mediators are characteristic of autoimmune disease accompanied by chronic or recurrent inflammation. We examined the hypothesis that mediators of inflammation known to be elevated in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are associated with genetic polymorphism previously identified in studies of inflammatory disease. Serum interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) concentrations in patients with SLE (n = 117) or RA (n = 164) and in inflammatory disease-free control subjects (n = 172) were measured by multiplex ELISA. Candidate genes were chosen from studies of autoimmune and inflammatory disease. Genotypes were determined for 345 SNP markers in 75 genes. Association between serum analytes and single alleles was tested by linear regression. Polymorphisms in several genes were associated with IL-6 levels (including IL10, TYK2, and CD40L in SLE and DRB1, NOD2, and CSF1 in RA) or with TNFα levels (including TNFSF4 and CSF2 in SLE and PTPN2, DRB1, and NOD2 in RA). Some associations were shared between disease and control groups or between IL-6 and TNFα within a group. In conclusion, variation in genes implicated in disease pathology is associated with serum IL-6 or TNFα concentration. Some genetic associations are more apparent in healthy controls than in SLE or RA, suggesting dysregulation of the principal mediators of chronic inflammation in disease. Susceptibility genes may affect inflammatory response with variable effect on disease etiology.
Collapse
|
|
15
|
Guo CC, Deng Y, Ye H, Zhu YZ, Zheng XB. Role of MAPK signaling pathways in inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2015; 23:229-235. [DOI: 10.11569/wcjd.v23.i2.229] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Mitogen-activated protein kinases (MAPKs) are a group of highly conserved serine protein kinases which are distributed in the cytoplasm. MAPK signal transduction pathways play a major role in inflammatory reactions and have a close relation with inflammatory bowel disease (IBD). They could be involved in the regulation of inflammatory mediators as well as IBD-associated genes. This paper reviews the role of MAPK signaling pathways in the pathogenesis of IBD, aiming at providing a new method for the treatment of IBD.
Collapse
|
|
16
|
Han SH, Kim JS, Woo JH, Jeong SJ, Shin JS, Ahn YS, Kim JM. The effect of bortezomib on expression of inflammatory cytokines and survival in a murine sepsis model induced by cecal ligation and puncture. Yonsei Med J 2015; 56:112-23. [PMID: 25510754 PMCID: PMC4276744 DOI: 10.3349/ymj.2015.56.1.112] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
PURPOSE Although the proteasome inhibitor known as bortezomib can modulate the inflammatory process through the nuclear factor-kappa B signaling pathway, the immunomodulatory effect of pre-incubated bortezomib has not been fully evaluated for inflammation by infectious agents. Therefore, we evaluated the effect of bortezomib on the expression of inflammatory cytokines and mediators in macrophage cell lines and on survival in a murine peritonitis sepsis model. MATERIALS AND METHODS Bortezomib was applied 1 hr before lipopolysaccharide (LPS) stimulation in RAW 264.7 cells. The cecal ligation and puncture (CLP) experiments were performed in C57BL/6J mice. RESULTS Pre-incubation with bortezomib (25 nM or 50 nM) prior to LPS (50 ng/mL or 100 ng/mL) stimulation significantly recovered the number of viable RAW 264.7 cells compared to those samples without pre-incubation. Bortezomib decreased various inflammatory cytokines as well as nitric oxide production in LPS-stimulated cells. The 7-day survival rate in mice that had received bortezomib at 0.01 mg/kg concentration 1 hr prior to CLP was significantly higher than in the mice that had only received a normal saline solution of 1 mL 1 hr prior to CLP. In addition, the administration of bortezomib at 0.01 mg/kg concentration 1 hr before CLP resulted in a significant decrease in inflammation of the lung parenchyma. Collectively, pretreatment with bortezomib showed an increase in the survival rate and changes in the levels of inflammatory mediators. CONCLUSION These results support the possibility of pretreatment with bortezomib as a new therapeutic target for the treatment of overwhelming inflammation, which is a characteristic of severe sepsis.
Collapse
Affiliation(s)
- Sang Hoon Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Jin Seok Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Jun Hee Woo
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Su Jin Jeong
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Jeon Soo Shin
- Department of Microbiology, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Young Soo Ahn
- Brain Korea 21 Project for Medical Science, Brain Research Institute and Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea
| | - June Myung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
| |
Collapse
|
|
17
|
Jiang R, Chen D, Hou J, Tan Z, Wang Y, Huang X, Wang X, Sun B. Survival and inflammation promotion effect of PTPRO in fulminant hepatitis is associated with NF-κB activation. THE JOURNAL OF IMMUNOLOGY 2014; 193:5161-70. [PMID: 25339662 DOI: 10.4049/jimmunol.1303354] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Previous investigations demonstrated that protein tyrosine phosphatase, receptor type, O (PTPRO) acts as a tumor suppressor in liver cancer; however, little is known about its role in liver inflammation. Thus, we investigated the role of PTPRO in fulminant hepatitis (FH) using a Con A-induced mouse model. Significantly more severe liver damage, but attenuated inflammation, was detected in PTPRO-knockout (KO) mice, and PTPRO deficiency could confer this phenotype to wild-type mice in bone marrow transplantation. Moreover, hepatocytes with PTPRO depletion were more sensitive to TNF-α-induced apoptosis, and secretion of cytokines was significantly decreased in both T and NK/NKT cells and led to marked impairment of NF-κB activation. Intriguingly, wild-type and PTPRO-KO cells responded equally to TNF-α in activation of IKK, but NF-κB activation was clearly decreased in PTPRO-KO cells. PTPRO associated with ErbB2, and loss of PTPRO potentiated activation of the ErbB2/Akt/GSK-3β/β-catenin cascade. Increased β-catenin formed a complex with NF-κB and attenuated its nuclear translocation and activation. Importantly, in humans, PTPRO was much decreased in FH, and this was associated with enhanced β-catenin accumulation but reduced IFN-γ secretion. Taken together, our study identified a novel PTPRO/ErbB2/Akt/GSK-3β/β-catenin/NF-κB axis in FH, which suggests that PTPRO may have therapeutic potential in this liver disease.
Collapse
Affiliation(s)
- Runqiu Jiang
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China; Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, People's Republic of China; and
| | - Dianyu Chen
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China; Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, People's Republic of China; and
| | - Jiajie Hou
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China; Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, People's Republic of China; and
| | - Zhongming Tan
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China; Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, People's Republic of China; and
| | - Youjing Wang
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China; Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, People's Republic of China; and
| | - Xingxu Huang
- Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of Nanjing University, Nanjing 210061, People's Republic of China
| | - Xuehao Wang
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China; Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, People's Republic of China; and
| | - Beicheng Sun
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China; Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, People's Republic of China; and
| |
Collapse
|
|
18
|
Abstract
Technological advances in the large scale analysis of human genetics have generated profound insights into possible genetic contributions to chronic diseases including the inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis. To date, 163 distinct genetic risk loci have been associated with either Crohn's disease or ulcerative colitis, with a substantial degree of genetic overlap between these 2 conditions. Although many risk variants show a reproducible correlation with disease, individual gene associations only affect a subset of patients, and the functional contribution(s) of these risk variants to the onset of IBD is largely undetermined. Although studies in twins have demonstrated that the development of IBD is not mediated solely by genetic risk, it is nevertheless important to elucidate the functional consequences of risk variants for gene function in relevant cell types known to regulate key physiological processes that are compromised in IBD. This article will discuss IBD candidate genes that are known to be, or are suspected of being, involved in regulating the intestinal epithelial barrier and several of the physiological processes presided over by this dynamic and versatile layer of cells. This will include assembly and regulation of tight junctions, cell adhesion and polarity, mucus and glycoprotein regulation, bacterial sensing, membrane transport, epithelial differentiation, and restitution.
Collapse
|
|
19
|
Suratanee A, Plaimas K. Identification of inflammatory bowel disease-related proteins using a reverse k-nearest neighbor search. J Bioinform Comput Biol 2014; 12:1450017. [DOI: 10.1142/s0219720014500176] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic disease whose incidence and prevalence increase every year; however, the pathogenesis of IBD is still unclear. Thus, identifying IBD-related proteins is important for understanding its complex disease mechanism. Here, we propose a new and simple network-based approach using a reverse k-nearest neighbor ( R k NN ) search to identify novel IBD-related proteins. Protein–protein interactions (PPI) and Genome-Wide Association Studies (GWAS) were used in this study. After constructing the PPI network, the R k NN search was applied to all of the proteins to identify sets of influenced proteins among their k-nearest neighbors ( R k NNs ). An observed protein whose influenced proteins were mostly known IBD-related proteins was statistically identified as a novel IBD-related protein. Our method outperformed a random aspect, k NN search, and centrality measures based on the network topology. A total of 39 proteins were identified as IBD-related proteins. Of these proteins, 71% were reported at least once in the literature as related to IBD. Additionally, these proteins were found over-represented in the IBD pathway and enriched in importantly functional pathways in IBD. In conclusion, the R k NN search with the statistical enrichment test is a great tool to identify IBD-related proteins to better understand its complex disease mechanism.
Collapse
Affiliation(s)
- Apichat Suratanee
- Department of Mathematics, Faculty of Applied Science, King Mongkut's University of Technology North Bangkok, 1518 Pracharat 1 Road, Wongsawang, Bangsue, Bangkok 10800, Thailand
| | - Kitiporn Plaimas
- Integrative Bioinformatics and Systems Biology Group, Advanced Virtual and Intelligent Computing Research Center (AVIC), Department of Mathematics and Computer Science, Faculty of Science, Chulalongkorn University, Phyathai Road, Patumwan, Bangkok 10330, Thailand
| |
Collapse
|
|
20
|
Li H, Spagnol G, Naslavsky N, Caplan S, Sorgen PL. TC-PTP directly interacts with connexin43 to regulate gap junction intercellular communication. J Cell Sci 2014; 127:3269-79. [PMID: 24849651 DOI: 10.1242/jcs.145193] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Protein kinases have long been reported to regulate connexins; however, little is known about the involvement of phosphatases in the modulation of intercellular communication through gap junctions and the subsequent downstream effects on cellular processes. Here, we identify an interaction between the T-cell protein tyrosine phosphatase (TC-PTP, officially known as PTPN2) and the carboxyl terminus of connexin43 (Cx43, officially known as GJA1). Two cell lines, normal rat kidney (NRK) cells endogenously expressing Cx43 and an NRK-derived cell line expressing v-Src with temperature-sensitive activity, were used to demonstrate that EGF and v-Src stimulation, respectively, induced TC-PTP to colocalize with Cx43 at the plasma membrane. Cell biology experiments using phospho-specific antibodies and biophysical assays demonstrated that the interaction is direct and that TC-PTP dephosphorylates Cx43 residues Y247 and Y265, but does not affect v-Src. Transfection of TC-PTP also indirectly led to the dephosphorylation of Cx43 S368, by inactivating PKCα and PKCδ, with no effect on the phosphorylation of S279 and S282 (MAPK-dependent phosphorylation sites). Dephosphorylation maintained Cx43 gap junctions at the plaque and partially reversed the channel closure caused by v-Src-mediated phosphorylation of Cx43. Understanding dephosphorylation, along with the well-documented roles of Cx43 phosphorylation, might eventually lead to methods to modulate the regulation of gap junction channels, with potential benefits for human health.
Collapse
Affiliation(s)
- Hanjun Li
- Department of Biochemistry and Molecular Biology and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Gaelle Spagnol
- Department of Biochemistry and Molecular Biology and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Naava Naslavsky
- Department of Biochemistry and Molecular Biology and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Steve Caplan
- Department of Biochemistry and Molecular Biology and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Paul L Sorgen
- Department of Biochemistry and Molecular Biology and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| |
Collapse
|
|
21
|
McCole DF. Phosphatase regulation of intercellular junctions. Tissue Barriers 2013; 1:e26713. [PMID: 24868494 DOI: 10.4161/tisb.26713] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2013] [Revised: 10/03/2013] [Accepted: 10/04/2013] [Indexed: 02/06/2023] Open
Abstract
Intercellular junctions represent the key contact points and sites of communication between neighboring cells. Assembly of these junctions is absolutely essential for the structural integrity of cell monolayers, tissues and organs. Disruption of junctions can have severe consequences such as diarrhea, edema and sepsis, and contribute to the development of chronic inflammatory diseases. Cell junctions are not static structures, but rather they represent highly dynamic micro-domains that respond to signals from the intracellular and extracellular environments to modify their composition and function. This review article will focus on the regulation of tight junctions and adherens junctions by phosphatase enzymes that play an essential role in preserving and modulating the properties of intercellular junction proteins.
Collapse
Affiliation(s)
- Declan F McCole
- Division of Biomedical Sciences; University of California, Riverside; Riverside, CA USA
| |
Collapse
|
|
22
|
Randall-Demllo S, Chieppa M, Eri R. Intestinal epithelium and autophagy: partners in gut homeostasis. Front Immunol 2013; 4:301. [PMID: 24137160 PMCID: PMC3786390 DOI: 10.3389/fimmu.2013.00301] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Accepted: 09/10/2013] [Indexed: 12/21/2022] Open
Abstract
One of the most significant challenges of cell biology is to understand how each type of cell copes with its specific workload without suffering damage. Among the most intriguing questions concerns intestinal epithelial cells in mammals; these cells act as a barrier between the internally protected region and the external environment that is exposed constantly to food and microbes. A major process involved in the processing of microbes is autophagy. In the intestine, through multiple, complex signaling pathways, autophagy including macroautophagy and xenophagy is pivotal in mounting appropriate intestinal immune responses and anti-microbial protection. Dysfunctional autophagy mechanism leads to chronic intestinal inflammation, such as inflammatory bowel disease (IBD). Studies involving a number of in vitro and in vivo mouse models in addition to human clinical studies have revealed a detailed role for autophagy in the generation of chronic intestinal inflammation. A number of genome-wide association studies identified roles for numerous autophagy genes in IBD, especially in Crohn’s disease. In this review, we will explore in detail the latest research linking autophagy to intestinal homeostasis and how alterations in autophagy pathways lead to intestinal inflammation.
Collapse
Affiliation(s)
- Sarron Randall-Demllo
- Mucosal Biology Laboratory, School of Human Life Sciences, University of Tasmania , Launceston, TAS , Australia
| | | | | |
Collapse
|
|
23
|
Protein tyrosine phosphatase 1B deficiency ameliorates murine experimental colitis via the expansion of myeloid-derived suppressor cells. PLoS One 2013; 8:e70828. [PMID: 23951017 PMCID: PMC3739765 DOI: 10.1371/journal.pone.0070828] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Accepted: 06/23/2013] [Indexed: 12/11/2022] Open
Abstract
Protein tyrosine phosphatase 1B (PTP1B) is a key molecule in modulating low-degree inflammatory conditions such as diabetes. The role of PTP1B in other chronic inflammations, however, remains unknown. Here, we report that PTP1B deficiency ameliorates Dextran Sulfate Sodium (DSS)-induced murine experimental colitis via expanding CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs). Employing DSS-induced murine experimental colitis as inflammatory animal model, we found that, compared with wild-type littermates, PTP1B-null mice demonstrated greater resistance to DSS-induced colitis, as reflected by slower weight-loss, greater survival rates and decreased PMN and macrophage infiltration into the colon. The evidence collectively also demonstrated that the resistance of PTP1B-null mice to DSS-induced colitis is based on the expansion of MDSCs. First, PTP1B-null mice exhibited a greater frequency of MDSCs in the bone marrow (BM), peripheral blood and spleen when compared with wild-type littermates. Second, PTP1B levels in BM leukocytes were significantly decreased after cells were induced into MDSCs by IL-6 and GM-CSF, and the MDSC induction occurred more rapidly in PTP1B-null mice than in wild-type littermates, suggesting PTP1B as a negative regulator of MDSCs. Third, the adoptive transfer of MDSCs into mice with DSS-colitis significantly attenuated colitis, which accompanies with a decreased serum IL-17 level. Finally, PTP1B deficiency increased the frequency of MDSCs from BM cells likely through enhancing the activities of signal transducer and activator of transcription 3 (STAT3) and Janus kinase 2 (JAK2). In conclusion, our study provides the first evidences that PTP1B deficiency ameliorates murine experimental colitis via expanding MDSCs.
Collapse
|
|
24
|
Epithelial tyrosine phosphatase SHP-2 protects against intestinal inflammation in mice. Mol Cell Biol 2013; 33:2275-84. [PMID: 23530062 DOI: 10.1128/mcb.00043-13] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Polymorphisms of PTPN11 encoding SHP-2 are biomarkers for ulcerative colitis (UC) susceptibility. However, their functional relevance is unknown. We thus investigated the role of epithelial SHP-2 in the control of intestinal homeostasis. Mice with an intestinal epithelial cell-specific SHP-2 deletion (SHP-2(IEC-KO) mice) were generated. Control and SHP-2(IEC-KO) mice were monitored for clinical symptoms and sacrificed for histological staining and Western blot analyses. Cytokines and chemokines, as well as intestinal permeability, were quantified. SHP-2 mRNA expression was evaluated in control and UC patients. SHP-2(IEC-KO) mice showed growth retardation compared to control littermates and rapidly developed severe colitis. Colon architecture was markedly altered with infiltration of immune cells, crypt abscesses, neutrophil accumulation, and reduced goblet cell numbers. Decreased expression of claudins was associated with enhanced intestinal permeability in mutant SHP-2(IEC-KO) mice. Inflammatory transcription factors Stat3 and NF-κB were hyperactivated early in the mutant colonic epithelium. Levels of several epithelial chemokines and cytokines were markedly enhanced in SHP-2(IEC-KO) mice. Of note, antibiotic treatment remarkably impaired the development of colitis in SHP-2(IEC-KO) mice. Finally, SHP-2 mRNA levels were significantly reduced in intestinal biopsy specimens from UC patients. Our results establish intestinal epithelial SHP-2 as a critical determinant for prevention of gut inflammation.
Collapse
|
|
25
|
Scharl M, Rogler G. The role for protein tyrosine phosphatase nonreceptor type 2 in regulating autophagosome formation. Ann N Y Acad Sci 2012; 1257:93-102. [PMID: 22671594 DOI: 10.1111/j.1749-6632.2012.06578.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Genome-wide association studies have identified single nucleotide polymorphisms within the gene locus encoding protein tyrosine phosphatase nonreceptor type 2 (PTPN2) as a risk factor for the development of chronic inflammatory diseases, such as inflammatory bowel disease (IBD), type 1 diabetes, and rheumatoid arthritis. IBD is characterized by a breakdown of the intestinal epithelial barrier function leading to an overwhelming and uncontrolled immune response to bacterial antigens. Recent studies demonstrated that PTPN2 regulates cytokine-induced signaling pathways, epithelial barrier function, and cytokine secretion in human intestinal cells. Dysfunction of PTPN2 is also associated with impaired autophagosome formation and defective bacterial handling in intestinal cells. All of these cellular functions have been demonstrated to play a crucial role in the pathogenesis of IBD. The genetic variations within the PTPN2 gene may result in altered protein function, thereby essentially contributing to the onset and perpetuation of chronic inflammatory conditions in the intestine.
Collapse
Affiliation(s)
- Michael Scharl
- Department of Oncology, University Hospital Zurich, Switzerland.
| | | |
Collapse
|
|
26
|
McCole DF. Regulation of epithelial barrier function by the inflammatory bowel disease candidate gene, PTPN2. Ann N Y Acad Sci 2012; 1257:108-14. [PMID: 22671596 DOI: 10.1111/j.1749-6632.2012.06522.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) has been identified as an inflammatory bowel disease (IBD) candidate gene. However, the mechanism through which mutations in the PTPN2 gene contribute to the pathogenesis of IBD has not been identified. PTPN2 acts as a negative regulator of signaling induced by the proinflammatory cytokine, interferon-gamma (IFN-γ). IFN-γ is known not only to play an important role in the pathogenesis of Crohn's disease (CD), but also to increase permeability of the intestinal epithelial barrier. We have shown that PTPN2 protects epithelial barrier function by restricting the capacity of IFN-γ to increase epithelial permeability and prevent induction of expression of the pore-forming protein, claudin-2. These data identify an important functional role for PTPN2 as a protector of the intestinal epithelial barrier and provide clues as to how PTPN2 mutations may contribute to the pathophysiology of CD.
Collapse
Affiliation(s)
- Declan F McCole
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, 92093-0063, USA.
| |
Collapse
|
|
27
|
Labbé DP, Hardy S, Tremblay ML. Protein tyrosine phosphatases in cancer: friends and foes! PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2012; 106:253-306. [PMID: 22340721 DOI: 10.1016/b978-0-12-396456-4.00009-2] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Tyrosine phosphorylation of proteins serves as an exquisite switch in controlling several key oncogenic signaling pathways involved in cell proliferation, apoptosis, migration, and invasion. Since protein tyrosine phosphatases (PTPs) counteract protein kinases by removing phosphate moieties on target proteins, one may intuitively think that PTPs would act as tumor suppressors. Indeed, one of the most described PTPs, namely, the phosphatase and tensin homolog (PTEN), is a tumor suppressor. However, a growing body of evidence suggests that PTPs can also function as potent oncoproteins. In this chapter, we provide a broad historical overview of the PTPs, their mechanism of action, and posttranslational modifications. Then, we focus on the dual properties of classical PTPs (receptor and nonreceptor) and dual-specificity phosphatases in cancer and summarize the current knowledge of the signaling pathways regulated by key PTPs in human cancer. In conclusion, we present our perspective on the potential of these PTPs to serve as therapeutic targets in cancer.
Collapse
Affiliation(s)
- David P Labbé
- Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada
| | | | | |
Collapse
|
|
28
|
Scharl M, Wojtal KA, Becker HM, Fischbeck A, Frei P, Arikkat J, Pesch T, Kellermeier S, Boone DL, Weber A, Loessner MJ, Vavricka SR, Fried M, McCole DF, Rogler G. Protein tyrosine phosphatase nonreceptor type 2 regulates autophagosome formation in human intestinal cells. Inflamm Bowel Dis 2012; 18:1287-302. [PMID: 21987459 DOI: 10.1002/ibd.21891] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2011] [Accepted: 08/16/2011] [Indexed: 12/12/2022]
Abstract
BACKGROUND Autophagy is a process of central importance for maintaining cell homeostasis, survival, and the regulation of inflammation. Recent studies associated variants within the gene loci, encoding protein tyrosine phosphatase nonreceptor type 2 (PTPN2), and autophagy genes, such as autophagy-related 16-like 1 (ATG16L1), with chronic inflammatory disorders, such as Crohn's disease (CD). We show that PTPN2 regulates autophagy in human intestinal epithelial cells (IEC) and primary colonic lamina propria fibroblasts (CLPF). METHODS Protein analysis in IEC and CLPF was performed by western blotting. Autophagososme formation was assessed by LC3B immunofluorescence or immunohistochemistry. Human intestinal tissue samples were obtained from noninflammatory bowel disease (IBD) control or from CD patients and genotyped for disease-associated PTPN2 or ATG16L1 variations. RESULTS Knockdown of PTPN2 causes impaired autophagosome formation and dysfunctional autophagy resulted in increased levels of intracellular Listeria monocytogenes (LM) and elevated IEC apoptosis in response to tumor necrosis factor (TNF) and interferon gamma (IFN-γ). Similar findings were observed in primary CLPF derived from CD patients carrying the CD-associated PTPN2 variant. Presence of the ATG16L1 variant prevented the cytokine-induced rise in PTPN2 protein, finally resulting in impaired LC3B-II levels in IEC. Actively inflamed intestinal biopsies from CD patients carrying either ATG16L1 or PTPN2 genetic variants revealed aberrant LC3B expression patterns when compared with samples from non-IBD control patients. CONCLUSIONS Our results demonstrate that PTPN2 regulates autophagosome formation in human intestinal cells. We provide a model of how a dysfunction of the CD susceptibility genes, PTPN2 and/or ATG16L1, may contribute to the onset and perpetuation of chronic intestinal inflammation.
Collapse
Affiliation(s)
- Michael Scharl
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Wiede F, Chew SH, van Vliet C, Poulton IJ, Kyparissoudis K, Sasmono T, Loh K, Tremblay ML, Godfrey DI, Sims NA, Tiganis T. Strain-dependent differences in bone development, myeloid hyperplasia, morbidity and mortality in ptpn2-deficient mice. PLoS One 2012; 7:e36703. [PMID: 22590589 PMCID: PMC3348136 DOI: 10.1371/journal.pone.0036703] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2011] [Accepted: 04/05/2012] [Indexed: 12/14/2022] Open
Abstract
Single nucleotide polymorphisms in the gene encoding the protein tyrosine phosphatase TCPTP (encoded by PTPN2) have been linked with the development of autoimmunity. Here we have used Cre/LoxP recombination to generate Ptpn2(ex2-/ex2-) mice with a global deficiency in TCPTP on a C57BL/6 background and compared the phenotype of these mice to Ptpn2(-/-) mice (BALB/c-129SJ) generated previously by homologous recombination and backcrossed onto the BALB/c background. Ptpn2(ex2-/ex2-) mice exhibited growth retardation and a median survival of 32 days, as compared to 21 days for Ptpn2(-/-) (BALB/c) mice, but the overt signs of morbidity (hunched posture, piloerection, decreased mobility and diarrhoea) evident in Ptpn2(-/-) (BALB/c) mice were not detected in Ptpn2(ex2-/ex2-) mice. At 14 days of age, bone development was delayed in Ptpn2(-/-) (BALB/c) mice. This was associated with increased trabecular bone mass and decreased bone remodeling, a phenotype that was not evident in Ptpn2(ex2-/ex2-) mice. Ptpn2(ex2-/ex2-) mice had defects in erythropoiesis and B cell development as evident in Ptpn2(-/-) (BALB/c) mice, but not splenomegaly and did not exhibit an accumulation of myeloid cells in the spleen as seen in Ptpn2(-/-) (BALB/c) mice. Moreover, thymic atrophy, another feature of Ptpn2(-/-) (BALB/c) mice, was delayed in Ptpn2(ex2-/ex2-) mice and preceded by an increase in thymocyte positive selection and a concomitant increase in lymph node T cells. Backcrossing Ptpn2(-/-) (BALB/c) mice onto the C57BL/6 background largely recapitulated the phenotype of Ptpn2(ex2-/ex2-) mice. Taken together these results reaffirm TCPTP's important role in lymphocyte development and indicate that the effects on morbidity, mortality, bone development and the myeloid compartment are strain-dependent.
Collapse
Affiliation(s)
- Florian Wiede
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | - Sock Hui Chew
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | - Catherine van Vliet
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | | | | | - Tedjo Sasmono
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | - Kim Loh
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | - Michel L. Tremblay
- McGill Cancer Centre and Department of Biochemistry, McGill University, Montreal, Quebec, Canada
| | - Dale I. Godfrey
- Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia
| | - Natalie A. Sims
- St. Vincent's Institute of Medical Research, Victoria, Australia
| | - Tony Tiganis
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| |
Collapse
|
|
30
|
Scharl M, Mwinyi J, Fischbeck A, Leucht K, Eloranta JJ, Arikkat J, Pesch T, Kellermeier S, Mair A, Kullak-Ublick GA, Truninger K, Noreen F, Regula J, Gaj P, Pittet V, Mueller C, Hofmann C, Fried M, McCole DF, Rogler G. Crohn's disease-associated polymorphism within the PTPN2 gene affects muramyl-dipeptide-induced cytokine secretion and autophagy. Inflamm Bowel Dis 2012; 18:900-12. [PMID: 22021207 DOI: 10.1002/ibd.21913] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2011] [Accepted: 09/08/2011] [Indexed: 12/17/2022]
Abstract
BACKGROUND The single nucleotide polymorphism (SNP) rs2542151 within the gene locus region encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) has been associated with Crohn's disease (CD), ulcerative colitis (UC), type-I diabetes, and rheumatoid arthritis. We have previously shown that PTPN2 regulates mitogen-activated protein kinase (MAPK) signaling and cytokine secretion in human THP-1 monocytes and intestinal epithelial cells (IEC). Here, we studied whether intronic PTPN2 SNP rs1893217 regulates immune responses to the nucleotide-oligomerization domain 2 (NOD2) ligand, muramyl-dipeptide (MDP). MATERIALS AND METHODS Genomic DNA samples from 343 CD and 663 non-IBD control patients (male and female) from a combined German, Swiss, and Polish cohort were genotyped for the presence of the PTPN2 SNPs, rs2542151, and rs1893217. PTPN2-variant rs1893217 was introduced into T(84) IEC or THP-1 cells using a lentiviral vector. RESULTS We identified a novel association between the genetic variant, rs1893217, located in intron 7 of the PTPN2 gene and CD. Human THP-1 monocytes carrying this variant revealed increased MAPK activation as well as elevated mRNA expression of T-bet transcription factor and secretion of interferon-γ in response to the bacterial wall component, MDP. In contrast, secretion of interleukin-8 and tumor necrosis factor were reduced. In both, T(84) IEC and THP-1 monocytes, autophagosome formation was impaired. CONCLUSIONS We identified a novel CD-associated PTPN2 variant that modulates innate immune responses to bacterial antigens. These findings not only provide key insights into the effects of a functional mutation on a clinically relevant gene, but also reveal how such a mutation could contribute to the onset of disease.
Collapse
Affiliation(s)
- Michael Scharl
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Doody KM, Bussières-Marmen S, Li A, Paquet M, Henderson JE, Tremblay ML. T cell protein tyrosine phosphatase deficiency results in spontaneous synovitis and subchondral bone resorption in mice. ACTA ACUST UNITED AC 2012; 64:752-61. [DOI: 10.1002/art.33399] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
|
|
32
|
Zikherman J, Weiss A. Unraveling the functional implications of GWAS: how T cell protein tyrosine phosphatase drives autoimmune disease. J Clin Invest 2011; 121:4618-21. [PMID: 22080861 DOI: 10.1172/jci60001] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Genome-wide association studies (GWAS) have identified a large number of SNPs that are linked to human autoimmune diseases. However, the functional consequences of most of these genetic variations remain undefined. T cell protein tyrosine phosphatase (TCPTP, which is encoded by PTPN2) is a JAK/STAT and growth factor receptor phosphatase that has been linked to the pathogenesis of type 1 diabetes, rheumatoid arthritis, and Crohn's disease by GWAS. In this issue of the JCI, Wiede and colleagues have generated a T cell-specific deletion of TCPTP and identified a novel role for this phosphatase as a negative regulator of TCR signaling. These data provide new insight as to how noncoding PTPN2 SNPs identified in GWAS could drive human autoimmune diseases.
Collapse
Affiliation(s)
- Julie Zikherman
- Division of Rheumatology, Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, UCSF, San Francisco, California, USA
| | | |
Collapse
|
|
33
|
Paul G, Marchelletta RR, McCole DF, Barrett KE. Interferon-γ alters downstream signaling originating from epidermal growth factor receptor in intestinal epithelial cells: functional consequences for ion transport. J Biol Chem 2011; 287:2144-55. [PMID: 22069319 DOI: 10.1074/jbc.m111.318139] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The epidermal growth factor receptor (EGFr) regulates many cellular functions, such as proliferation, apoptosis, and ion transport. Our aim was to investigate whether long term treatment with interferon-γ (IFN-γ) modulates EGF activation of downstream signaling pathways in intestinal epithelial cells and if this contributes to dysregulation of epithelial ion transport in inflammation. Polarized monolayers of T(84) and HT29/cl.19A colonocytes were preincubated with IFN-γ prior to stimulation with EGF. Basolateral potassium transport was studied in Ussing chambers. We also studied inflamed colonic mucosae from C57BL/6 mice treated with dextran sulfate sodium or mdr1a knock-out mice and controls. IFN-γ increased intestinal epithelial EGFr expression without increasing its phosphorylation. Conversely, IFN-γ caused a significant decrease in EGF-stimulated phosphorylation of specific EGFr tyrosine residues and activation of ERK but not Akt-1. In IFNγ-pretreated cells, the inhibitory effect of EGF on carbachol-stimulated K(+) channel activity was lost. In inflamed colonic tissues, EGFr expression was significantly increased, whereas ERK phosphorylation was reduced. Thus, although it up-regulates EGFr expression, IFN-γ causes defective EGFr activation in colonic epithelial cells via reduced phosphorylation of specific EGFr tyrosine residues. This probably accounts for altered downstream signaling consequences. These observations were corroborated in the setting of colitis. IFN-γ also abrogates the ability of EGF to inhibit carbachol-stimulated basolateral K(+) currents. Our data suggest that, in the setting of inflammation, the biological effect of EGF, including the inhibitory effect of EGF on Ca(2+)-dependent ion transport, is altered, perhaps contributing to diarrheal and other symptoms in vivo.
Collapse
Affiliation(s)
- Gisela Paul
- Division of Gastroenterology, University of California, San Diego, School of Medicine, La Jolla, California 92093, USA
| | | | | | | |
Collapse
|
|
34
|
Protein tyrosine phosphatases as drug targets: strategies and challenges of inhibitor development. Future Med Chem 2011; 2:1563-76. [PMID: 21426149 DOI: 10.4155/fmc.10.241] [Citation(s) in RCA: 213] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Several 'classical' protein tyrosine phosphatases are attractive therapeutic targets, including PTP1B for obesity and Type II diabetes; SHP2 for cancer and Lyp for rheumatoid arthritis. Progress has been made in identifying a broad range of chemically distinct inhibitors; however, developing selective and cell-permeable clinically useful compounds has proved challenging. Here the ongoing challenges and recent significant advances in the field are reviewed. Key novel compounds are highlighted and a perspective on the future of phosphatase inhibitor development is presented.
Collapse
|
|
35
|
Khor B, Gardet A, Xavier RJ, Stange DE, Vries RG, van den Born M, Barker N, Shroyer NF, van de Wetering M, Clevers H. Genetics and pathogenesis of inflammatory bowel disease. Nature 2011. [PMID: 21677747 DOI: 10.1038/nature] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Recent advances have provided substantial insight into the maintenance of mucosal immunity and the pathogenesis of inflammatory bowel disease. Cellular programs responsible for intestinal homeostasis use diverse intracellular and intercellular networks to promote immune tolerance, inflammation or epithelial restitution. Complex interfaces integrate local host and microbial signals to activate appropriate effector programs selectively and even drive plasticity between these programs. In addition, genetic studies and mouse models have emphasized the role of genetic predispositions and how they affect interactions with microbial and environmental factors, leading to pro-colitogenic perturbations of the host-commensal relationship.
Collapse
Affiliation(s)
- Bernard Khor
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Abstract
Recent advances have provided substantial insight into the maintenance of mucosal immunity and the pathogenesis of inflammatory bowel disease. Cellular programs responsible for intestinal homeostasis use diverse intracellular and intercellular networks to promote immune tolerance, inflammation or epithelial restitution. Complex interfaces integrate local host and microbial signals to activate appropriate effector programs selectively and even drive plasticity between these programs. In addition, genetic studies and mouse models have emphasized the role of genetic predispositions and how they affect interactions with microbial and environmental factors, leading to pro-colitogenic perturbations of the host-commensal relationship.
Collapse
Affiliation(s)
- Bernard Khor
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
| | | | | |
Collapse
|
|
37
|
Genetics and pathogenesis of inflammatory bowel disease. Nature 2011. [DOI: 10.1038/nature10209 order by 1-- -] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
|
|
38
|
Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature 2011. [DOI: 10.1038/nature10209 order by 8029-- #] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
|
|
39
|
Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature 2011. [DOI: 10.1038/nature10209 order by 8029-- -] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
|
|
40
|
Genetics and pathogenesis of inflammatory bowel disease. Nature 2011. [DOI: 10.1038/nature10209 and 1880=1880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
|
|
41
|
Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature 2011. [DOI: 10.1038/nature10209 order by 1-- #] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
|
|
42
|
Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature 2011. [DOI: 10.1038/nature10209 order by 1-- gadu] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
|
|
43
|
Genetics and pathogenesis of inflammatory bowel disease. Nature 2011. [DOI: 10.1038/nature10209 order by 8029-- awyx] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
|
|
44
|
Han X, Mann E, Gilbert S, Guan Y, Steinbrecher KA, Montrose MH, Cohen MB. Loss of guanylyl cyclase C (GCC) signaling leads to dysfunctional intestinal barrier. PLoS One 2011; 6:e16139. [PMID: 21305056 PMCID: PMC3031533 DOI: 10.1371/journal.pone.0016139] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2010] [Accepted: 12/11/2010] [Indexed: 12/12/2022] Open
Abstract
Background Guanylyl Cyclase C (GCC) signaling via uroguanylin (UGN) and guanylin activation is a critical mediator of intestinal fluid homeostasis, intestinal cell proliferation/apoptosis, and tumorigenesis. As a mechanism for some of these effects, we hypothesized that GCC signaling mediates regulation of intestinal barrier function. Methodology/Principal Findings Paracellular permeability of intestinal segments was assessed in wild type (WT) and GCC deficient (GCC−/−) mice with and without lipopolysaccharide (LPS) challenge, as well as in UGN deficient (UGN−/−) mice. IFNγ and myosin light chain kinase (MLCK) levels were determined by real time PCR. Expression of tight junction proteins (TJPs), phosphorylation of myosin II regulatory light chain (MLC), and STAT1 activation were examined in intestinal epithelial cells (IECs) and intestinal mucosa. The permeability of Caco-2 and HT-29 IEC monolayers, grown on Transwell filters was determined in the absence and presence of GCC RNA interference (RNAi). We found that intestinal permeability was increased in GCC−/− and UGN−/− mice compared to WT, accompanied by increased IFNγ levels, MLCK and STAT1 activation in IECs. LPS challenge promotes greater IFNγ and STAT1 activation in IECs of GCC−/− mice compared to WT mice. Claudin-2 and JAM-A expression were reduced in GCC deficient intestine; the level of phosphorylated MLC in IECs was significantly increased in GCC−/− and UGN−/− mice compared to WT. GCC knockdown induced MLC phosphorylation, increased permeability in IEC monolayers under basal conditions, and enhanced TNFα and IFNγ-induced monolayer hyperpermeability. Conclusions/Significance GCC signaling plays a protective role in the integrity of the intestinal mucosal barrier by regulating MLCK activation and TJ disassembly. GCC signaling activation may therefore represent a novel mechanism in maintaining the small bowel barrier in response to injury.
Collapse
Affiliation(s)
- Xiaonan Han
- Division of Gastroenterology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
| | | | | | | | | | | | | |
Collapse
|
|
45
|
Henderson P, van Limbergen JE, Schwarze J, Wilson DC. Function of the intestinal epithelium and its dysregulation in inflammatory bowel disease. Inflamm Bowel Dis 2011; 17:382-95. [PMID: 20645321 DOI: 10.1002/ibd.21379] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The intestinal epithelium not only acts as a physical barrier to commensal bacteria and foreign antigens but is also actively involved in antigen processing and immune cell regulation. The inflammatory bowel diseases (IBDs) are characterized by inflammation at this mucosal surface with well-recognized defects in barrier and secretory function. In addition to this, defects in intraepithelial lymphocytes, chemokine receptors, and pattern recognition receptors promote an abnormal immune response, with increased differentiation of proinflammatory cells and a dysregulated relationship with professional antigen-presenting cells. This review focuses on recent developments in the structure of the epithelium, including a detailed account of the apical junctional complex in addition to the role of the enterocyte in antigen recognition, uptake, processing, and presentation. Recently described cytokines such as interleukin-22 and interleukin-31 are highlighted as is the dysregulation of chemokines and secretory IgA in IBD. Finally, the effect of the intestinal epithelial cell on T effector cell proliferation and differentiation are examined in the context of IBD with particular focus on T regulatory cells and the two-way interaction between the intestinal epithelial cell and certain immune cell populations.
Collapse
Affiliation(s)
- Paul Henderson
- Department of Child Life and Health, University of Edinburgh, Edinburgh, UK.
| | | | | | | |
Collapse
|