Department of Molecular, Cell and Cancer Biology; UMass Metabolic Network
Cell Biology | Digestive System Diseases | Immunopathology | Immunoprophylaxis and Therapy
Intestinal epithelial cells (IECs) regulate gut immune homeostasis, and impaired epithelial responses are implicated in the pathogenesis of inflammatory bowel diseases (IBD). IEC-specific ablation of nuclear factor kappaB (NF-kappaB) essential modulator (NEMO) caused Paneth cell apoptosis and impaired antimicrobial factor expression in the ileum, as well as colonocyte apoptosis and microbiota-driven chronic inflammation in the colon. Combined RelA, c-Rel, and RelB deficiency in IECs caused Paneth cell apoptosis but not colitis, suggesting that NEMO prevents colon inflammation by NF-kappaB-independent functions. Inhibition of receptor-interacting protein kinase 1 (RIPK1) kinase activity or combined deficiency of Fas-associated via death domain protein (FADD) and RIPK3 prevented epithelial cell death, Paneth cell loss, and colitis development in mice with epithelial NEMO deficiency. Therefore, NEMO prevents intestinal inflammation by inhibiting RIPK1 kinase activity-mediated IEC death, suggesting that RIPK1 inhibitors could be effective in the treatment of colitis in patients with NEMO mutations and possibly in IBD.
DOI of Published Version
Immunity. 2016 Mar 15;44(3):553-67. doi: 10.1016/j.immuni.2016.02.020. Link to article on publisher's site
Vlantis, Katerina; Wullaert, Andy; Polykratis, Apostolos; Kondylis, Vangelis; Dannappel, Marius; Schwarzer, Robin; Welz, Patrick; Corona, Teresa; Walczak, Henning; Weih, Falk; Klein, Ulf; Kelliher, Michelle; and Pasparakis, Manolis, "NEMO Prevents RIP Kinase 1-Mediated Epithelial Cell Death and Chronic Intestinal Inflammation by NF-kappaB-Dependent and -Independent Functions" (2016). Open Access Articles. 2883.
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