Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 280, Issue 15, Pages 14981-14988Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M500966200
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Nuclear factor-kappa B (NF-kappa 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 I kappa B-dependent NF-kappa 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-kappa B activity. The molecular analysis of NF-kappa B activation revealed that Rip-like interacting caspase-like apoptosis-regulatory protein kinase (RICK), a key component of a pathway leading to NF-kappa B induction, is also strongly inhibited by SB203580. In contrast, SB203580 had no effect on the colitis-induced activation of other potential NF-kappa B-activating kinases such as protein kinase C theta (PKC theta), mixed lineage kinase 3, and the oncogene product Cot/TPL2. Thus, the inhibitory effect of SB203580 on NF-kappa 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.
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