Role of the Guanosine Triphosphatase Rac2 in T Helper 1 Cell Differentiation

Li, Baiyong; Yu, Hong; Zheng, Weiping; Voll, Reinhard; Na, Songqing; Roberts, Andrew W.; Williams, David A.; Davis, Roger J.; Ghosh, Sankar; Flavell, Richard A.

doi:10.1126/science.288.5474.2219

Cited by 155 publications

(139 citation statements)

References 22 publications

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“…At the current time it is unknown whether the predominant effect of Rac2 deficiency on the respiratory burst reflects its function in the NADPH oxidase complex itself or in the preceding steps leading to enzyme assembly. However, since multiple functional abnormalities in other BMderived cells have been identified in rac2 Ϫ/Ϫ mice (11,29,30), we speculate that defects in intracellular signaling pathways account for at least some of the observed decrease in superoxide production in response to specific agonists. Why Rac1 is unable to substitute for Rac2 in superoxide production, chemotaxis, and other functional responses that are impaired in Rac2-deficient blood cells also remains to be defined.…”

Section: Discussionmentioning

confidence: 99%

“…Genetic deficiency of Rac2, a hematopoietic-specific Rho GTPase, is associated with a variety of functional defects in murine BMderived cells due to abnormalities in intracellular signaling pathways (11,29,30) despite the presence of the highly homologous Rac1 (Fig. 1) and, probably, Rac3 (18).…”

Section: Discussionmentioning

confidence: 99%

“…Taken together, these findings suggested that Rac2 regulates multiple cellular functions in neutrophils. Additional studies in mast cells (29) and T cells (30) have demonstrated a variety of functional abnormalities associated with intracellular signaling defects. These include reduced chemotaxis and growth factor-induced survival in mast cells, with impaired activation of Akt (29).…”

Section: T He Phagocyte Nadph Oxidase (Respiratory Burst Oxidase)mentioning

confidence: 99%

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Rac2 Is an Essential Regulator of Neutrophil Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activation in Response to Specific Signaling Pathways

Kim

Dinauer

2001

The Journal of Immunology

183

173

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Rac2 is a hematopoietic-specific Rho family GTPase implicated as an important constituent of the NADPH oxidase complex and shares 92% amino acid identity with the ubiquitously expressed Rac1. In bone marrow (BM) neutrophils isolated from rac2−/− mice generated by gene targeting, we previously reported that PMA-induced superoxide production was reduced by about 4-fold, which was partially corrected in TNF-α-primed BM neutrophils and in peritoneal exudate neutrophils. We investigated receptor-mediated activation of the NADPH oxidase in the current study, finding that superoxide production in rac2−/− BM and peritoneal exudate neutrophils was normal in response to opsonized zymosan, reduced to 22% of wild type in response to IgG-coated SRBC, and almost absent in response to fMLP. In wild-type murine BM neutrophils, phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and Akt was induced by PMA or fMLP, which was decreased in rac2−/− neutrophils for ERK1/2 and p38. Activation of p38 by either opsonized zymosan or IgG-coated SRBC was similar in wild-type and rac2−/− cells. Inhibition of ERK1/2 or p38 activation using either PD98059 or SB203580, respectively, had only a modest effect on fMLP-elicited superoxide production and no effect on the PMA-induced response. These data provide genetic evidence supporting an important role for Rac2 in regulating neutrophil NADPH oxidase activation downstream of chemoattractant and Fcγ receptors. The effect of Rac2 deficiency on superoxide production is probably exerted through multiple pathways, including those independent of mitogen-activated protein kinase activation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: T He Phagocyte Nadph Oxidase (Respiratory Burst Oxidase)mentioning

confidence: 99%

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Rac2 Is an Essential Regulator of Neutrophil Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activation in Response to Specific Signaling Pathways

Kim

Dinauer

2001

The Journal of Immunology

183

173

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“…This highlights the importance of NF‐κB signaling in the pathogenesis of JIA, as has been established in RA 32. NF‐κB is a major inflammatory regulator and has a role in activation and proliferation of RA FLS and the development of the Th1 helper subset 32, 33, 34. TNF has been shown to induce a TNFR2/NF‐κB‐dependent proinflammatory program in Tregs derived from JIA synovial fluid 35, but ours is the first work to show the activity of NF‐κB signaling in JIA FLS.…”

Section: Resultsmentioning

confidence: 73%

Secretion of pro‐inflammatory cytokines and chemokines and loss of regulatory signals by fibroblast‐like synoviocytes in juvenile idiopathic arthritis

Brescia

Simonds

Sullivan

et al. 2017

Proteomics Clinical Apps

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PurposeThe goal is to investigate the specific contribution of fibroblast‐like synoviocytes (FLS) to the inflammatory milieu of the synovium in juvenile idiopathic arthritis (JIA) through detection of secreted proteins.Experimental designExpression of 89 cytokines and chemokines is determined on unprocessed synovial fluid from controls and JIA patients using antibody arrays. Supernatants from pure cell cultures of FLS grown from synovial fluids or tissues from JIA and controls are also examined for protein expression. Ingenuity Pathway Analysis (IPA) is revealed top pathways and upstream regulators of significant proteins.ResultsProtein studies is revealed that JIA FLS release pro‐inflammatory cytokines and chemokines, including IL‐4, IL‐6, IL‐17, CXCL1, and CXCL6, and lose expression of important regulator signals, such as IL‐10 and TIMP2. Of the 84 proteins differentially expressed between controls and JIA in the synovial fluid, 1/3 (29 proteins) are differentially expressed in the cell culture supernatants of JIA and control FLS. ELISA of cell culture supernatants and synovial fluid confirmed seven key proteins.Conclusion and clinical relevanceJIA FLS are central to perpetuation of inflammation in JIA, including trafficking of inflammatory cells and effects on the extracellular matrix. These cells express key disease‐specific chemokines that, with further refinement, may allow us to tailor therapy appropriately.

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“…It is reasonable to hypothesize that increased Rac2 expression is one of the factors involved in corneal graft failure as Rac2 had been demonstrated to play a central role in T helper 1 (Th1), cell differentiation, and cytokine production. 17 Evidence from studies in mouse and rat models have shown the predominance of Th1 cytokine expression in cells infiltrating the graft during corneal allograft rejection. [18][19][20] The Th1 cytokine, interferon-g, as well as other cytokines, such as IL-1b, IL-2, IL-12, have also been shown to compromise ocular immune privilege, and their upregulation may contribute to graft rejection.…”

Section: Discussionmentioning

confidence: 99%

Increased Rac2 mRNA expression in peripheral blood during human corneal graft rejection

Huang

Tullo

Hillarby

2008

Eye

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Purpose Allograft rejection is the main cause of graft failure in human corneal transplantation, for which underlying pathomechanism is not yet clear. We compared gene expression in the peripheral blood of patients who after undergoing corneal transplantation experienced graft rejection with those patients who accepted grafts. Methods Sixty-six patients who underwent corneal transplantation were studied including 18 patients who suffered subsequent graft rejection. cDNA array technology was used to survey and quantify transcript expression . A semiquantitative reverse transcriptase-PCR (RT-PCR) was used to confirm the gene expression pattern measured by a cDNA array of selected genes. Results Among 265 genes present on the array, eight genes were found to be differentially expressed. Four genes (Rac 2, RhoA, paxillin, and CD18) were further analysed by semiquantitative RT-PCR, and significant differences in mRNA expression levels in the rejection group were confirmed. Conclusions Our study demonstrated that the expression of Rac2 mRNA was upregulated in the peripheral blood of patients experiencing corneal transplantation rejection compared to those patients who had no rejection episodes. In addition, three genes, RhoA, paxillin, and CD18, showed decreased expression in rejecting patients. cDNA array technology provides a potentially useful approach to identify novel genes that might participate in pathogenic pathways during corneal graft rejection.

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Role of the Guanosine Triphosphatase Rac2 in T Helper 1 Cell Differentiation

Cited by 155 publications

References 22 publications

Rac2 Is an Essential Regulator of Neutrophil Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activation in Response to Specific Signaling Pathways

Rac2 Is an Essential Regulator of Neutrophil Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activation in Response to Specific Signaling Pathways

Secretion of pro‐inflammatory cytokines and chemokines and loss of regulatory signals by fibroblast‐like synoviocytes in juvenile idiopathic arthritis

Increased Rac2 mRNA expression in peripheral blood during human corneal graft rejection

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