Cmtm4 deficiency exacerbates colitis by inducing gut dysbiosis and S100a8/9 expression

The dysfunction of innate immunity components is one of the major drivers for ulcerative colitis(UC),and increasing reports indicate that the gut microbiome serves as an intermediate between genetic mutations and UC development.Here,we find that the IL-17 receptor subunit,CMTM4,is reduced in UC patients and dextran sulfate sodium(DSS)-induced colitis.The deletion of CMTM4(Cmtm4^(-/-))in mice leads to a higher susceptibility to DSS-induced colitis than in wild-type,and the gut microbiome significantly changes in composition.The causal role of the gut microbiome is confirmed with a cohousing experiment.We further identify that S100a8/9 is significantly up-regulated in Cmtm4^(-/-)colitis,with the block of its receptor RAGE that reverses the phenotype associated with the CMTM4 deficiency.CMTM4 deficiency rather suppresses S100a8/9 expression in vitro via the IL17 pathway,further supporting that the elevation of S100a8/9 in vivo is most likely a result of microbial dysbiosis.Taken together,the results suggest that CMTM4 is involved in the maintenance of intestinal homeostasis,suppression of S100a8/9,and prevention of colitis development.Our study further shows CMTM4 as a crucial innate immunity component,confirming its important role in UC development and providing insights into potential targets for the development of future therapies.

Potential of new anti-cancer agents targeting the nuclear translocation signaling of HB-EGF C-terminal fragments during the development of colitis-associated cancer

In inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn’s disease (CD), the duration and severity of inflammation are responsible for the development of colorectal cancer. Inflammatory cytokines such as interleukin (IL)-8 and tumor necrotic factor (TNF)-a, which are released by epithelial and immune cells, are involved in the pathogenesis of colitis-associated cancer. Current treatments for advanced colorectal cancers focus primarily on targeting epidermal growth factor receptor (EGFR) signaling. IL-8 (a G-protein coupled receptor (GPCR) agonist), which is involved in neutrophil recruitment and activation in persistent active colitis, also promotes cleavage of theproheparin-binding epidermal growth factor—like growth factor (proHB-EGF) through a disintegrin and metalloproteinase (ADAM), so that the resulting soluble HB-EGF activates EGFR. In parallel, the carboxy-terminal fragment of proHB-EGF (HB-EGF-CTF) translocates into the inner nuclear membrane, where HB-EGF-CTF binds the nuclear promyelocytic leukemia zinc finger (PLZF) protein, resulting in the nuclear export of the PLZF transcriptional repressor and thereby affecting cell proliferation. Screening for potent chemical inhibitors of the interactions between HB-EGF-CTF and PLZF identified telmisartan (and related compounds in corporating a biphenyl tetrazole moiety) as inhibitors of cell proliferation. Here we focus on the inhibitory effects of these compounds on cell proliferation, demonstrating the potential for targeting the nuclear translocation of HB-EGF-CTF in the treatment of colitis-associated cancer.

芪仙汤对溃疡性结肠炎患者血清TNF-α,IL-8的影响及疗效观察

目的:观察芪仙汤治疗溃疡性结肠炎的效果及探讨芪仙汤对溃疡性结肠炎患者的细胞因子的影响。方法:将50例溃疡性结肠炎患者随机分成治疗组、对照组。分别予芪仙汤煎剂口服灌肠、柳氮磺胺吡啶片口服,结合地塞米松灌肠治疗。观察临床疗效,并检测治疗前后及25例健康志愿者的血清肿瘤坏死因子(TNF-α),白细胞介素-8(IL-8)的含量。结果:治疗组疗效明显优于西药对照组(P<0.05),治疗组更能显著降低溃疡性结肠炎患者血清TNF-α,IL-8水平。结论:芪仙汤治疗溃疡性结肠炎疗效显著,可能通过调节溃疡性结肠炎患者细胞因子而达到治疗作用。