Inhibition of p38 MAP kinase‐and RICK/NF‐κB‐signaling suppresses inflammatory bowel disease

Abstract

Ulcerative colitis and Crohn's disease are the two entities of chronic inflammatory bowel diseases (IBD). One of the main pathogenic mechanisms is probably a dysregulated immune response triggered by products of the enteric bacterial flora. The goal of this study was to evaluate the effects of the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 on inflammatory responses using the DSS-induced experimental colitis model in mice reflecting human IBD. We found that SB203580 improved the clinical score, ameliorates the histological alterations, and reduces the mRNA levels of proinflammatory cytokines. In addition to p38 kinase activity, the "classical" and the "alternative" NF-kappaB pathways were also strongly activated during colitis induction. All three pathways were drastically down-regulated by SB203580 treatment. An analysis of the molecular basis of NF-kappaB activation revealed that Rip-like interacting caspase-like apoptosis-regulatory protein kinase (RICK), a key component of a pathway leading to NF-kappaB induction, is also strongly inhibited by SB203580. Since RICK is an effector kinase of NOD2, an intracellular receptor of bacterial peptidoglycan, these results support the notion that NOD signaling could play a pivotal role in the IBD pathogenesis. Thus, RICK could represent a novel target for future therapies in human IBD.

Mitogen activated protein kinases: a role in inflammatory bowel disease?

“…Several studies using the p38 inhibitor, SB203580, have indicated that p38 phosphorylation is increased significantly in IBD tissue [28,29]. This finding is substantiated further by an in vitro study, indicating that inhibition of p38 using the natural IL-1 receptor antagonist, in a colonocyte cell line, leads to reduced IL-6 and -8 production, and an in vivo study using a murine model of IBD, where inhibition of p38 reduced significantly cytokine mRNA and NFkB activation [35,36].…”

“…Even preclinical studies with MAPK inhibitors have demonstrated significant efficacy repeatedly in experimental colitis models [36,52,[65][66][67], and it can be concluded that progress in identifying safe and effective MAPK inhibitors for clinical use has been slow. Therefore, more randomized controlled trials are needed to assess the importance of MAPK inhibitors in IBD.…”

“…Further studies using induction of IBD or infection with a nematode to induce an inflammatory response have substantiated a role in p38 regulating genes involved in the innate immune response by the gastrointestinal tract [43,44]. Similarly, indirect phopshorylation of various proteins can affect the activation of transcription factors, arguably one of the most important being NFkB, which was shown in an in vivo mouse model simulating IBD, to be subject to regulation via p38 [36]. This potent transcription factor is a central regulator of intestinal inflammation, mediating the transcription of not only many proinflammatory cytokines including TNF-a and ILs, but also proinflammatory proteins such as COX-2 [45].…”

Activation and signaling of the p38 MAP kinase pathway

“…Rheumatoid arthritis, Alzheimer's disease and inflammatory bowel disease are all postulated to be regulated in part by the p38 pathway [87][88][89]. The activation of the p38 pathway plays essential roles in the production of proinflammatory cytokines (IL-1β, TNF-α and IL-6) [90]; induction of enzymes such as COX-2 which controls connective tissue remodeling in pathological conditions [91]; expression of intracellular enzymes such as iNOS, a regulator of oxidation [92,93]; induction of VCAM-1 and other adherent proteins along with other inflammatory related molecules [18].…”

Role of mitogen-activated protein kinase kinase kinases in signal integration

“…MAPKs contribute to the cellular response to diverse stimuli, including growth factors, cytokines, and stresses such as toxins, numerous drugs, changes in cell adherence, osmolarity, oxygen radicals, ultraviolet light and temperature . It is therefore not unexpected that dysregulated MAPK activity is associated with a variety of pathological states, including those arising from inflammation, such as arthritis and inflammatory bowel disease (Johnson and Lapadat, 2002;Hollenbach et al, 2004), as well as syndromes that include the uncontrolled cellular proliferation and tissue remodeling characteristic of cancer (Gollob et al, 2006).…”