UMMS Affiliation

Department of Molecular, Cell and Cancer Biology; UMass Metabolic Network

Date

3-15-2016

Document Type

Article

Disciplines

Cell Biology | Digestive System Diseases | Immunopathology | Immunoprophylaxis and Therapy

Abstract

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.

Rights and Permissions

Citation: Immunity. 2016 Mar 15;44(3):553-67. doi: 10.1016/j.immuni.2016.02.020. Link to article on publisher's site

DOI of Published Version

10.1016/j.immuni.2016.02.020

Related Resources

Link to Article in PubMed

Journal Title

Immunity

PubMed ID

26982364

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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