Aberrant integrin activation induces p38 MAPK phosphorylation resulting in suppressed Fas-mediated apoptosis in T cells: Implications for rheumatoid arthritis

Yu, Lin; Su, Chung Chen; Huang, Jyun Yuan; Lin, Huan Chin; Cheng, Yu Jung; Liu, Ming Fei; Yang, Bei

doi:10.1016/j.molimm.2009.07.021

Cited by 18 publications

(19 citation statements)

References 36 publications

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“…Inhibition of apoptosis is a hallmark in autoimmune disease and RA. We and others have previously demonstrated that a2b1 integrin engagement with collagen inhibits Fas-induced apoptosis of effector T cells (19,22), suggesting the possibility that a2b1 integrin could promote Th17 cell survival in the arthritic joint tissue. Finally, a2b1 integrin could also costimulate Th17 cells; thus, its blockade could lead to the reduction of IL-17 levels observed in anti-a2b1 mAb-treated animals.…”

Section: Discussionmentioning

confidence: 85%

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α2β1 Integrin Regulates Th17 Cell Activity and Its Neutralization Decreases the Severity of Collagen-Induced Arthritis

Azreq

Boisvert

Césaro

et al. 2013

The Journal of Immunology

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Th17 cells play a critical role in the pathogenesis of rheumatoid arthritis (RA), but the mechanisms by which these cells regulate the development of RA are not fully understood. We have recently shown that α2β1 integrin, the receptor of type I collagen, is the major collagen-binding integrin expressed by human Th17 cells. In this study, we examined the role of α2β1 integrin in Th17-mediated destructive arthritis in the murine model of collagen-induced arthritis (CIA). We found that α2β1 integrin is expressed on synovial Th17 cells from CIA mice and its neutralization with a specific mAb significantly reduced inflammation and cartilage degradation, and protected the mice from bone erosion. Blockade of α2β1 integrin led to a decrease in the number of Th17 cells in the joints and to a reduction of IL-17 levels in CIA mice. This was associated with an inhibition of receptor activator of NF-κB ligand levels and osteoclast numbers, and reduction of bone loss. We further show that α2β1 integrin is expressed on synovial Th17 cells from RA patients, and that its ligation with collagen costimulated the production of IL-17 by polarized human Th17 cells by enhancing the expression of retinoic acid receptor–related orphan receptor C through ERK and PI3K/AKT. Our findings provide the first evidence, to our knowledge, that α2β1 integrin is an important pathway in Th17 cell activation in the pathogenesis of CIA, suggesting that its blockade can be beneficial for the treatment of RA and other Th17-associated autoimmune diseases.

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Section: Discussionmentioning

confidence: 85%

“…We and others have found that a2b1 integrin protects human effector T cells from Fas-mediated apoptosis (19,22). In addition, we have recently reported that a2b1, but not a1b1, integrin is the major collagen-binding integrin expressed by human Th17 cells (23).…”

mentioning

confidence: 91%

α2β1 Integrin Regulates Th17 Cell Activity and Its Neutralization Decreases the Severity of Collagen-Induced Arthritis

Azreq

Boisvert

Césaro

et al. 2013

The Journal of Immunology

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“…Fas-mediated apoptosis is also regulated by the mitogen-activated protein kinase pathway (34). When activated by phosphorylation, p38 kinase inhibits the activation (auto-cleavage) of caspase-3 and caspase-8 (35). Multiple stimuli induce p38 activation, including transforming growth factor beta (TGF-␤ (36)), which directly downregulates Fas-mediated apoptosis (37).…”

Section: Discussionmentioning

confidence: 99%

Proteomic Pathway Analysis Reveals Inflammation Increases Myeloid-Derived Suppressor Cell Resistance to Apoptosis

Chornoguz

Grmai

Sinha

et al. 2011

Molecular & Cellular Proteomics

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Myeloid-derived suppressor cells (MDSC) accumulate in patients and animals with cancer where they mediate systemic immune suppression and obstruct immunebased cancer therapies. We have previously demonstrated that inflammation, which frequently accompanies tumor onset and progression, increases the rate of accumulation and the suppressive potency of MDSC. To determine how inflammation enhances MDSC levels and activity we used mass spectrometry to identify proteins produced by MDSC induced in highly inflammatory settings. Proteomic pathway analysis identified the Fas pathway and caspase network proteins, leading us to hypothesize that inflammation enhances MDSC accumulation by increasing MDSC resistance to Fas-mediated apoptosis. Immunotherapies aimed at activating the host's immune system are promising strategies for the treatment of cancer because of their potential for minimal toxicity to healthy cells and their ability to induce immune memory that may protect against metastatic disease (1). Disappointingly, clinical trials of most cancer vaccines or other active T-cell mediated immunotherapies have not yielded significant patient responses (2). Because most cancer patients are immune suppressed, these failures are most likely because of the inability of cancer patients to immunologically respond to the immunotherapy agents. Although multiple mechanisms contribute to immune suppression in individuals with cancer (3), myeloid-derived suppressor cells (MDSC) 1 accumulate in virtually all cancer patients and are a major cause of tumor-induced immune suppression because of their inhibition of both adaptive and innate immunity (4). Because of their widespread presence and potent immune suppressive effects, identifying the cellular and molecular mechanisms responsible for MDSC accumulation and suppressive activity may facilitate the development of effective immunotherapy strategies.Chronic inflammation frequently precedes tumor onset (5) and many cancer cells produce pro-inflammatory mediators, suggesting that chronic inflammation contributes to tumorigenesis and tumor progression (6). We and others have previously demonstrated that inflammation via the proinflammatory molecules interleukin (IL)-1␤ (7, 8), toll-like receptor 4 (TLR4) (9), IL-6 (10), prostaglandin E2 (11, 12), and S100A8/A9 proteins (13, 14) increases either the number or the suppressive potency of MDSC, or both. This causative relationship between inflammation and MDSC induction led us to hypothesize that MDSC not only are an obstacle to immunotherapy, but also contribute to the onset and progression of tumors by inhibiting immune surveillance of newly transformed cells and by blocking natural immunity to established tumors (15).We are studying the effects of inflammation on tumor progression and MDSC development using the mouse BALB/cderived, spontaneously metastatic 4T1 mammary carcinoma (16) transfected with the IL-1␤ gene (4T1/IL-1␤) (7). When 1 The abbreviations used are: MDSC, myeloid-derived suppressor cells; DAPI, 4Ј,6-diamidino-2-phenylin...

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“…pathway (34). When activated by phosphorylation, p38 kinase inhibits the activation (auto-cleavage) of caspase-3 and caspase-8 (35). Multiple stimuli induce p38 activation, including transforming growth factor beta (TGF-β (36)), which directly down-regulates Fas-mediated apoptosis (37).…”

Section: Discussionmentioning

confidence: 99%

Breast Cancer Vaccines That Overcome Tolerance and Immune Suppression

Chornoguz¹

2011

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Aberrant integrin activation induces p38 MAPK phosphorylation resulting in suppressed Fas-mediated apoptosis in T cells: Implications for rheumatoid arthritis

Cited by 18 publications

References 36 publications

α2β1 Integrin Regulates Th17 Cell Activity and Its Neutralization Decreases the Severity of Collagen-Induced Arthritis

α2β1 Integrin Regulates Th17 Cell Activity and Its Neutralization Decreases the Severity of Collagen-Induced Arthritis

Proteomic Pathway Analysis Reveals Inflammation Increases Myeloid-Derived Suppressor Cell Resistance to Apoptosis

Breast Cancer Vaccines That Overcome Tolerance and Immune Suppression

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