Raf kinase inhibitor protein mediates intestinal epithelial cell apoptosis and promotes IBDs in humans and mice

Lin, Wenlong; Ma, Chunmei; Su, Fasheng; Jiang, Yu; Lai, Rongrong; Zhang, Ting; Sun, Kai; Fan, Liping; Cai, Zijian; Li, Zhongqi; Huang, He; Li, Jun; Wang, Xiaojian

doi:10.1136/gutjnl-2015-310096

Cited by 57 publications

(58 citation statements)

References 43 publications

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“…These results are concordant with a recent study that suggested positive correlation between RKIP (a kinase upstream to TAK1) activation and disease severity in IBD patients, as well as between RKIP and TAK1 phosphorylation in DSS and TNBS models of colitis (Lin et al. ). Our immunofluorescence studies indicated elevated p‐TAK1 expression, prominently in nonepithelial cells (Fig.…”

Section: Discussionsupporting

confidence: 93%

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Activation of TGF-β activated kinase 1 promotes colon mucosal pathogenesis in inflammatory bowel disease

et al. 2017

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The etiology and mechanisms for inflammatory bowel disease (IBD) are incompletely known. Determination of new, clinically important mechanisms for intestinal inflammation is imperative for developing effective therapies to treat IBD. We sought to define a widespread mechanism for colon mucosal inflammation via the activation of TGF‐β activated Kinase 1 (TAK1), a central regulator of cellular inflammatory actions. Activation of TAK1 and the downstream inflammatory signaling mediators was determined in pediatric patients with ulcerative colitis (UC) or Crohn's disease (CD) as well as in DSS‐induced and spontaneous IBD in mice. The role of TAK1 in facilitating intestinal inflammation in murine models of IBD was investigated by using (5Z)‐7‐Oxozeaenol, a highly selective pharmacological inhibitor of TAK1. We found hyper‐activation of TAK1 in patients with UC or CD and in murine models of IBD. Pharmacological inhibition of TAK1 prevented loss in body weight, disease activity, microscopic histopathology, infiltration of inflammatory cells in the colon mucosa, and elevated proinflammatory cytokine production in two murine models of IBD. We demonstrated that at the early phase of the disease activation of TAK1 is restricted in the epithelial cells. However, at a more advanced stage of the disease, TAK1 activation predominantly occurs in nonepithelial cells, especially in macrophages. These findings elucidate the activation of TAK1 as crucial in promoting intestinal inflammation. Thus, the TAK1 activation pathway may represent a suitable target to design new therapies for treating IBD in humans.

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Section: Discussionsupporting

confidence: 93%

“…Raf kinase inhibitor protein (RKIP) promoted intestinal epithelial cell apoptosis in human and mouse IBD via interaction with TAK1 (Lin et al. ). Also, a recent GWAS study suggested association of TAB 2, a TAK1‐binding protein with IBD (Liu et al.…”

Section: Introductionmentioning

confidence: 99%

Activation of TGF-β activated kinase 1 promotes colon mucosal pathogenesis in inflammatory bowel disease

et al. 2017

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“…We next asked whether CD177 + neutrophils could maintain intestinal barrier integrity. WT and CD177 −/− mice were fed with fluorescein isothiocyanate (FITC)-dextran (500 mg/kg) 4 hours before anesthetisation on day 10 as described previously,39 40 and the levels of FITC-dextran in sera were detected by ELISA. As shown in figure 6G, CD177 −/− mice displayed significantly higher serum levels of FITC-dextran compared with WT mice after DSS exposure.…”

Section: Resultsmentioning

confidence: 99%

CD177⁺neutrophils as functionally activated neutrophils negatively regulate IBD

Zhou

Lin

Fang

et al. 2017

Gut

175

149

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“…This response is characterized by the recruitment of immune cells and the production of proinflammatory cytokines via the activation of transcription factors, such as NF-κB (5,6). These cytokines typically clear invading bacteria and protect the body from infection; however, under pathogenic conditions, they induce IEC death and further impair epithelial integrity, thereby creating a vicious cycle and eventually leading to IBD (3,(7)(8)(9). Among the cytokines implicated in colitis, TNFα is the best studied, and its overproduction is a hallmark of IBD.…”

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confidence: 99%

Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNFα-mediated inflammation and apoptosis

Liu

Peng

Sun

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Epithelial barrier disruption is a major cause of inflammatory bowel disease (IBD); however, the mechanism through which epigenetic regulation modulates intestinal epithelial integrity remains largely undefined. Here we show that EZH2, the catalytic subunit of polycomb repressive complex (PRC2), is indispensable for maintaining epithelial cell barrier integrity and homeostasis under inflammatory conditions. In accordance with reduced EZH2 expression in patients, the inactivation of EZH2 in IECs sensitizes mice to DSS-and TNBSinduced experimental colitis. Conversely, EZH2 overexpression in the intestinal epithelium renders mice more resistant to colitis. Mechanistically, the genes encoding TRAF2/5 are held in a finely tuned bivalent status under inflammatory conditions. EZH2 deficiency potentiates the expression of these genes to enhance TNFα-induced NF-κB signaling, thereby leading to uncontrolled inflammation. More importantly, we show that EZH2 depletion compromises the protective role of NF-κB signaling in cell survival by directly up-regulating ITCH, a well-known E3 ligase that degrades the c-FLIP protein. Thus, our findings highlight an epigenetic mechanism by which EZH2 integrates the multifaceted effects of TNFα signaling to promote the inflammatory response and apoptosis in colitis.colitis | EZH2 | TNFα | NF-κB | ITCH

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Raf kinase inhibitor protein mediates intestinal epithelial cell apoptosis and promotes IBDs in humans and mice

Abstract: RKIP contributes to colitis development by promoting inflammation and mediating IEC apoptosis and might represent a therapeutic target of IBD.

Cited by 57 publications

References 43 publications

Activation of TGF-β activated kinase 1 promotes colon mucosal pathogenesis in inflammatory bowel disease

Activation of TGF-β activated kinase 1 promotes colon mucosal pathogenesis in inflammatory bowel disease

CD177⁺neutrophils as functionally activated neutrophils negatively regulate IBD

Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNFα-mediated inflammation and apoptosis

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Raf kinase inhibitor protein mediates intestinal epithelial cell apoptosis and promotes IBDs in humans and mice

Abstract: RKIP contributes to colitis development by promoting inflammation and mediating IEC apoptosis and might represent a therapeutic target of IBD.

Cited by 57 publications

References 43 publications

Activation of TGF-β activated kinase 1 promotes colon mucosal pathogenesis in inflammatory bowel disease

Activation of TGF-β activated kinase 1 promotes colon mucosal pathogenesis in inflammatory bowel disease

CD177+neutrophils as functionally activated neutrophils negatively regulate IBD

Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNFα-mediated inflammation and apoptosis

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Product

Resources

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CD177⁺neutrophils as functionally activated neutrophils negatively regulate IBD