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J. Biol. Chem., Vol. 280, Issue 15, 14981-14988, April 15, 2005

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Inhibition of RICK/Nuclear Factor-B and p38 Signaling Attenuates the Inflammatory Response in a Murine Model of Crohn Disease^*

Eike Hollenbach, Michael Vieth¶, Albert Roessner¶, Manfred Neumann||, Peter Malfertheiner||, and Michael Naumann||**

From the Institute of Experimental Internal Medicine, Department of Gastroenterology, Hepatology and Infectiology, and the ^¶Institute of Pathology, Otto-von-Guericke-University, Magdeburg D-39120, Germany

Nuclear factor-B (NF-B) is the main target of anti-inflammatory therapies in human chronic inflammatory bowel diseases (IBD), Crohn disease, and ulcerative colitis. This study investigates the molecular anti-inflammatory mechanisms of SB203580, an inhibitor of the mitogen-activated protein kinase p38. The murine trinitrobenzene sulfonic acid (TNBS)-induced colitis was used as an established model of human Crohn disease. Here we show that SB203580 improved the clinical condition, reduced intestinal inflammation, and suppressed mRNA levels of pro-inflammatory cytokines elevated upon induction of colitis. Besides p38 kinase activity, the "classical" IB-dependent NF-B pathway was strongly up-regulated during colitis induction, whereas the "alternative" was not. SB203580 treatment resulted in a drastic down-regulation of p38 and NF-B activity. The molecular analysis of NF-B activation revealed that Rip-like interacting caspase-like apoptosis-regulatory protein kinase (RICK), a key component of a pathway leading to NF-B induction, is also strongly inhibited by SB203580. In contrast, SB203580 had no effect on the colitis-induced activation of other potential NF-B-activating kinases such as protein kinase C (PKC), mixed lineage kinase 3, and the oncogene product Cot/TPL2. Thus, the inhibitory effect of SB203580 on NF-B activation is to a large extent mediated by RICK inhibition. RICK is the effector kinase of the intracellular receptor of bacterial peptidoglycan NOD. Because bacterial products are suggested to be the key pathogenic agents triggering IBD, inhibition of the NOD/RICK pathway may serve as a novel target of future therapies in human IBD.

Received for publication, January 26, 2005

^* The work was supported by Deutsche Forschungsgemeinschaft Grant NA 292/5-3 (to M. N.), the "Magdeburger Forschungsverbund (NBL3)" founded by the Bundesministerium für Bildung und Forschung with grants from "Spitzenbonusprojekt" (to M. N.) and "Rotationsstelle" (to E. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| These authors should be considered senior authors.

^** To whom correspondence should be addressed: Institute of Experimental Internal Medicine, Otto-von-Guericke-University, Leipziger Str. 44, D-39120 Magdeburg, Germany. Tel.: 49-391-6713227; Fax: 49-391-67190160; E-mail: Naumann{at}medizin.uni-magdeburg.de.

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