Universität zu Köln

Wong, Jerry, Garcia-Carbonell, Ricard, Zelic, Matija, Ho, Samuel B., Boland, Brigid S., Yao, Shih-Jing, Desai, Shalin A., Das, Soumita, Planell, Nuria, Harris, Philip A., Font-Burgada, Joan, Taniguchi, Koji, Bertin, John, Salas, Azucena, Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Gough, Pete J., Kelliher, Michelle, Karin, Michael and Guma, Monica (2020). RIPK1 Mediates TNF-Induced Intestinal Crypt Apoptosis During Chronic NF-kappa B Activation. Cell. Mol. Gastroenterol. Hepatol., 9 (2). S. 295 - 313. SAN DIEGO: ELSEVIER INC. ISSN 2352-345X

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Abstract

BACKGROUND AND AIMS: Tumor necrosis factor (TNF) is a major pathogenic effector and a therapeutic target in inflammatory bowel disease (IBD), yet the basis for TNF-induced intestinal epithelial cell (IEC) death is unknown, because TNF does not kill normal IECs. Here, we investigated how chronic nuclear factor (NF)-kappa B activation, which occurs in human IBD, promotes TNF-dependent IEC death in mice. METHODS: Human IBD specimens were stained for p65 and cleaved caspase-3. C57BL/6mice with constitutively active IKK beta in IEC (Ikk beta(EE)(IEC)), Ripk1(D138N/D138N) knockinmice, and Ripk3(-/-) mice were injected with TNF or lipopolysaccharide. Enteroids were also isolated from these mice and challenged with TNF with or without RIPK1 and RIPK3 inhibitors or butylated hydroxyanisole. Ripoptosome-mediated caspase-8 activation was assessed by immunoprecipitation. RESULTS: NF-kappa B activation in human IBD correlated with appearance of cleaved caspase-3. Congruently, unlike normal mouse IECs that are TNF-resistant, IECs in Ikk beta(EE)(IEC) mice and enteroids were susceptible to TNF-dependent apoptosis, which depended on the protein kinase function of RIPK1. Constitutively active IKK beta facilitated ripoptosome formation, a RIPK1 signaling complex that mediates caspase-8 activation by TNF. Butylated hydroxyanisole treatment and RIPK1 inhibitors attenuated TNF-induced and ripoptosome-mediated caspase-8 activation and IEC death in vitro and in vivo. CONCLUSIONS: Contrary to common expectations, chronic NF-kappa B activation induced intestinal crypt apoptosis after TNF stimulation, resulting in severe mucosal erosion. RIPK1 kinase inhibitors selectively inhibited TNF destructive properties while preserving its survival and proliferative properties, which do not require RIPK1 kinase activity. RIPK1 kinase inhibition could be a potential treatment for IBD.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Wong, Jerry UNSPECIFIED UNSPECIFIED UNSPECIFIED Garcia-Carbonell, Ricard UNSPECIFIED UNSPECIFIED UNSPECIFIED Zelic, Matija UNSPECIFIED UNSPECIFIED UNSPECIFIED Ho, Samuel B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boland, Brigid S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Yao, Shih-Jing UNSPECIFIED UNSPECIFIED UNSPECIFIED Desai, Shalin A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Das, Soumita UNSPECIFIED UNSPECIFIED UNSPECIFIED Planell, Nuria UNSPECIFIED UNSPECIFIED UNSPECIFIED Harris, Philip A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Font-Burgada, Joan UNSPECIFIED UNSPECIFIED UNSPECIFIED Taniguchi, Koji UNSPECIFIED UNSPECIFIED UNSPECIFIED Bertin, John UNSPECIFIED UNSPECIFIED UNSPECIFIED Salas, Azucena UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Gough, Pete J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kelliher, Michelle UNSPECIFIED UNSPECIFIED UNSPECIFIED Karin, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Guma, Monica UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-351710
DOI:	10.1016/j.jcmgh.2019.10.002
Journal or Publication Title:	Cell. Mol. Gastroenterol. Hepatol.
Volume:	9
Number:	2
Page Range:	S. 295 - 313
Date:	2020
Publisher:	ELSEVIER INC
Place of Publication:	SAN DIEGO
ISSN:	2352-345X
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CROHNS-DISEASE; ULCERATIVE-COLITIS; OXIDATIVE STRESS; EPITHELIAL-CELLS; IN-VITRO; 2 FACES; KINASE; NECROPTOSIS; INFLAMMATION; NECROSIS Multiple languages Gastroenterology & Hepatology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/35171