Interferon-gamma expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway

Rincón, Mercedes; Enslen, Hervé; Raingeaud, Joël; Recht, Michael; Zapton, Tyler; Su, Michael; Penix, Laurie; Davis, Roger J.; Flavell, Richard A.

doi:10.1093/emboj/17.10.2817

Cited by 389 publications

(382 citation statements)

References 79 publications

(152 reference statements)

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“…In T cells, IFN-␥ expression is dependent on p38 MAPK, a key pathway activated by DDR1. 20,27,34 Alternatively to a role of DDR1 in macrophage migration, but not exclusively, the proinflammatory chemotactic environment may consequently be influenced by DDR1 expression in resident and/or infiltrating cells in UUO.…”

Section: Discussionmentioning

confidence: 99%

Discoidin Domain Receptor 1 Is a Major Mediator of Inflammation and Fibrosis in Obstructive Nephropathy

Guerrot

Kerroch

Placier

et al. 2011

The American Journal of Pathology

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The interactions between tubulointerstitial infiltrating cells and the extracellular matrix play an important role in regulating renal fibrosis. Discoidin domain receptor 1 (DDR1) is a nonintegrin tyrosine kinase receptor for collagen implicated in cell adhesion, proliferation, and extracellular matrix remodeling. We have previously demonstrated that transgenic mice lacking DDR1 are protected from hypertension-associated renal fibrosis. The purpose of this study was to determine the role of DDR1 in renal inflammation and fibrosis related to primitive tubulointerstitial injury. After 12 days of unilateral ureteral obstruction (UUO), kidney histopathologic and real-time quantitative PCR analyses were performed in DDR1 ؊/؊ and wild-type mice. DDR1 expression was strongly increased in the obstructed kidney. Wild-type mice developed important perivascular and interstitial inflammation and fibrosis. In comparison, DDR1 ؊/؊ mice displayed reduced accumulation of fibrillar collagen and transforming growth factor ␤ expression. F4/80 ؉ cell count and proinflammatory cytokines were remarkably blunted in DDR1 ؊/؊ obstructed kidneys. Leukocyte rolling and adhesion evaluated by intravital microscopy were not different between DDR1 ؊/؊ and wild-type mice. Importantly, macrophages isolated from DDR1 ؊/؊ mice presented similar M1/M2 polarization but displayed impaired migration in response to monocyte chemoattractant protein-1. Together, these data suggest that DDR1 plays an important role in the pathogenesis of renal disease via enhanced inflammation. Inhibition of DDR1 expression or activity may represent a novel therapeutic target against the progression of renal diseases. Renal fibrosis is the consequence of the accumulation of extracellular matrix (ECM) components, including collagen, in the kidney. In chronic kidney diseases, irrespective of the initiating cause, fibrotic lesions autoaggravate, leading to a progressive decrease in renal function. Despite growing interest, the pathophysiologic pathways responsible for the progression of renal fibrosis remain elusive. A better understanding of specific mechanisms that promote inflammation and ECM synthesis is of critical importance in this setting because such pathways are susceptible to being at the cornerstone of the initiation and the progression of fibrogenesis.Discoidin domain receptor 1 (DDR1) is a tyrosine kinase transmembrane receptor for collagen constitutively expressed in several cell types and organs, including the gastrointestinal tract, lung, and kidney. 1 In the mammalian kidney, DDR1 is predominantly expressed by vascular smooth muscle cells, mesangial cells, and epithelial cells in normal conditions. 2,3 On activation by binding to collagen I to VI and VIII, DDR1 regulates cell differentiation, adhesion, proliferation, and ECM remodeling. 4 -6 A number of studies have shown that DDR1 is implicated in carcinogenesis, inflammation, atherosclerosis, and fibrogenesis. [7][8][9][10][11][12] Consistent with an important pathogenetic role in vascular diseases, 8,[1...

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Section: Discussionmentioning

confidence: 99%

Discoidin Domain Receptor 1 Is a Major Mediator of Inflammation and Fibrosis in Obstructive Nephropathy

Guerrot

Kerroch

Placier

et al. 2011

The American Journal of Pathology

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“…However, the role of p38 in Th1 development is not entirely clear. In vitro polarized Th1 cells expressing constitutively active MAP kinase kinase (MKK) 6, an upstream activator of p38, displayed increased IFN-␥ production, whereas expression of a dominant negative form of p38 or treatment with the p38 inhibitor SB203580 decreased IFN-␥ expression by Th1 effectors (4,5). Recently, however, p38␣ Ϫ/Ϫ T and B cells were found to develop normally (7), and p38␣-deficient CD4 ϩ T cells expressed normal levels of IFN-␥ when differentiated in vitro under Th1-polarizing conditions (8).…”

Section: Gadd45␣ Regulates P38-dependent Dendritic Cell Cytokinementioning

confidence: 99%

Gadd45α Regulates p38-Dependent Dendritic Cell Cytokine Production and Th1 Differentiation

Jirmanova

Janković

Fornace

et al. 2007

The Journal of Immunology

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Gadd45α inhibits the activation of p38 by the T cell alternative pathway involving phosphorylation of p38 Tyr323. Given that T cell p38 may play a role in Th1 development, the response to Th-skewing Ags was analyzed in Gadd45α−/− mice. Despite constitutively increased p38 activity in Gadd45α−/− T cells, the Th1 immune response to Toxoplasma gondii Ag (STAg), was diminished. In contrast to T cells, dendritic cells (DC) lacked the alternative p38 activation pathway. Gadd45α−/− DCs responded to STAg with low levels of MAP kinase cascade-dependent p38 activation, IL-12 production, and CD40 expression. Wild-type T cells transferred into Gadd45α−/− recipients had a diminished Th1 response to STAg, whereas Gadd45α−/− T cells transferred into wild-type hosts behaved normally. Therefore, Gadd45α has tissue-specific and opposing functions on p38 activity, and Gadd45α-regulated p38 activation in DCs is a critical event in Th1 polarization in vivo.

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“…The consequence of chemokine activation of p38 MAPK in T cells has not been determined. Certainly, p38 activation is necessary for the transcriptional activation of IL-2 in Jurkat T cells and interferon-␥ in Th1 cells [87][88][89]. Given that Th1 cells express CCR5, p38 activation by CCL5 may determine the transcriptional activation of specific cytokine genes.…”

Section: Maps Kinases and Chemokine Signalingmentioning

confidence: 99%

Chemokines: attractive mediators of the immune response

Wong

Fish

2003

Seminars in Immunology

227

186

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Interferon-gamma expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway

Cited by 389 publications

References 79 publications

Discoidin Domain Receptor 1 Is a Major Mediator of Inflammation and Fibrosis in Obstructive Nephropathy

Discoidin Domain Receptor 1 Is a Major Mediator of Inflammation and Fibrosis in Obstructive Nephropathy

Gadd45α Regulates p38-Dependent Dendritic Cell Cytokine Production and Th1 Differentiation

Chemokines: attractive mediators of the immune response

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