STAT3 in immune responses and inflammatory bowel diseases

Fu, Xin

doi:10.1038/sj.cr.7310029

Cited by 76 publications

(51 citation statements)

References 84 publications

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“…STAT3 is a transcription factor that requires phosphorylation for activation and plays an important role in Th17 differentiation (63)(64)(65)(66). Our results demonstrate that mucosal STAT3 activation is greater in the mice receiving WT T cells than in the mice receiving MyD88 Ϫ/Ϫ T cells.…”

Section: Cd45rbsupporting

confidence: 55%

The Myeloid Differentiation Factor 88 (MyD88) Is Required for CD4+ T Cell Effector Function in a Murine Model of Inflammatory Bowel Disease

Fukata¹,

Breglio²,

Chen³

et al. 2008

The Journal of Immunology

121

108

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Abnormal T cell responses to commensal bacteria are involved in the pathogenesis of inflammatory bowel disease. MyD88 is an essential signal transducer for TLRs in response to the microflora. We hypothesized that TLR signaling via MyD88 was important for effector T cell responses in the intestine. TLR expression on murine T cells was examined by flow cytometry. CD4+CD45Rbhigh T cells and/or CD4+CD45RblowCD25+ regulatory T cells were isolated and adoptively transferred to RAG1−/− mice. Colitis was assessed by changes in body weight and histology score. Cytokine production was assessed by ELISA. In vitro proliferation of T cells was assessed by [3H]thymidine assay. In vivo proliferation of T cells was assessed by BrdU and CFSE labeling. CD4+CD45Rbhigh T cells expressed TLR2, TLR4, TLR9, and TLR3, and TLR ligands could act as costimulatory molecules. MyD88−/− CD4+ T cells showed decreased proliferation compared with WT CD4+ T cells both in vivo and in vitro. CD4+CD45Rbhigh T cells from MyD88−/− mice did not induce wasting disease when transferred into RAG1−/− recipients. Lamina propria CD4+ T cell expression of IL-2 and IL-17 and colonic expression of IL-6 and IL-23 were significantly lower in mice receiving MyD88−/− cells than mice receiving WT cells. In vitro, MyD88−/− T cells were blunted in their ability to secrete IL-17 but not IFN-γ. Absence of MyD88 in CD4+CD45Rbhigh cells results in defective T cell function, especially Th17 differentiation. These results suggest a role for TLR signaling by T cells in the development of inflammatory bowel disease.

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Section: Cd45rbsupporting

confidence: 55%

The Myeloid Differentiation Factor 88 (MyD88) Is Required for CD4+ T Cell Effector Function in a Murine Model of Inflammatory Bowel Disease

Fukata¹,

Breglio²,

Chen³

et al. 2008

The Journal of Immunology

121

108

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“…Specific STAT3 ablation in intestinal epithelial cells interferes with tumor formation and growth in CAC (7,8). The possible role of STAT3 in the development of inflammation related colon cancer has been suggested by the findings that the activation of STAT3 signaling is persistently present in patients with IBD and colorectal cancer (32,33). Thus, the intervention of IL-6/STAT3 signaling holds a preventive and therapeutic potential for CAC.…”

Section: Discussionmentioning

confidence: 99%

Embelin Reduces Colitis-Associated Tumorigenesis through Limiting IL-6/STAT3 Signaling

Dai

Jiao

Teng

et al. 2014

Molecular Cancer Therapeutics

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The interleukin-6 (IL-6)/STAT3 signaling regulates survival and proliferation of intestinal epithelial cells and plays an important role in the pathogenesis of inflammatory bowel disease and colorectal cancer. Embelin is a small molecule inhibitor of X-linked inhibitor of apoptosis protein (XIAP), with antioxidant, anti-inflammatory, and antitumor activities. We previously showed that embelin inhibits the growth of colon cancer cells in vitro, and effectively suppresses 1,2-dimethylhydrazine dihydrochloride-induced colon carcinogenesis in mice. Here, we explored the antitumor effects and mechanisms of embelin on colitis-associated cancer (CAC) using the azoxymethane/dextran sulfate sodium (AOM/DSS) model, with a particular focus on whether embelin exerts its effect through the IL-6/STAT3 pathway. We found that embelin significantly reduced incidence and tumor size in CAC-bearing mice. In addition to inhibiting proliferation of tumor epithelial cells, embelin suppressed colonic IL-6 expression and secretion, and subsequently STAT3 activation in vivo. Importantly, in vitro studies have revealed that in colon cancer cells, embelin diminished both the constitutive and IL-6-induced STAT3 activation by stimulating Src homology domain 2-containing protein tyrosine phosphatase (SHP2) activity. Moreover, embelin protected mice from AOM/DSS-induced colitis before tumor development. Embelin decreased IL-1b, IL-17a, and IL-23a expression as well as the number of CD4 þ T cells and macrophages infiltrating the colonic tissues. Thus, our findings demonstrated that embelin suppresses CAC tumorigenesis, and its antitumor effect is partly mediated by limiting IL-6/STAT3 activation and Th17 immune response. Embelin may be a potential agent in the prevention and treatment of CAC. Mol Cancer Ther; 13(5); 1206-16. Ó2014 AACR.

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“…10 Several lines of evidence, including a recent genome-wide association study, 38,39 suggest that Stat3 plays an important role in human IBD and inflammation-associated colorectal cancers. 40,41 Similar to mice with IL-10 depletion, 9 mice in which Stat3 was depleted in myeloid cells via LysM-or Mx1 promoterdriven Cre expression develop colonic inflammation, 11,42 indicating that IL-10 plays a critical role in regulating mucosal immunity in colon and IL-10 exerts its action through Stat3 expressed in myeloid cells. Mice with Stat3 inactivation in myeloid cells had enhanced Th1 activity and were highly susceptible to endotoxin shock, with increased production of inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

A Novel Mouse Model of Inflammatory Bowel Disease Links Mammalian Target of Rapamycin-Dependent Hyperproliferation of Colonic Epithelium to Inflammation-Associated Tumorigenesis

Deng

Zhou

Sellers

et al. 2010

The American Journal of Pathology

195

158

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STAT3 in immune responses and inflammatory bowel diseases

Cited by 76 publications

References 84 publications

The Myeloid Differentiation Factor 88 (MyD88) Is Required for CD4+ T Cell Effector Function in a Murine Model of Inflammatory Bowel Disease

The Myeloid Differentiation Factor 88 (MyD88) Is Required for CD4+ T Cell Effector Function in a Murine Model of Inflammatory Bowel Disease

Embelin Reduces Colitis-Associated Tumorigenesis through Limiting IL-6/STAT3 Signaling

A Novel Mouse Model of Inflammatory Bowel Disease Links Mammalian Target of Rapamycin-Dependent Hyperproliferation of Colonic Epithelium to Inflammation-Associated Tumorigenesis

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