Down-regulation of p38 mitogen-activated protein kinase activation and proinflammatory cytokine production by mitogen-activated protein kinase inhibitors in inflammatory bowel disease

Abstract

SummaryCrohn's disease and ulcerative colitis are inflammatory bowel diseases (IBD) characterized by chronic relapsing mucosal inflammation. Tumour necrosis factor (TNF)-a, a known agonist of the mitogen-activated protein kinase (MAPK) pathway, is a key cytokine in this process. We aimed first to determine whether p38 MAPK is activated in IBD inflamed mucosa, and then studied the effect of four different p38a inhibitory compounds on MAPK phosphorylation and secretion of proinflammatory cytokines by IBD lamina propria mononuclear cells (LPMCs) and organ culture biopsies. In vivo phospho-p38a and p38a expression was evaluated by immunoblotting on intestinal biopsies from inflamed areas of patients affected by Crohn's disease and ulcerative colitis, and from normal mucosa of sex-and age-matched control subjects. Both mucosal biopsies and isolated LPMCs were incubated with four different p38a selective inhibitory drugs. TNF-a, interleukin (IL)-1b and IL-6 were measured in the organ and cell culture supernatants by enzyme-linked immunosorbent assay. We found higher levels of phosphop38a in the inflamed mucosa of IBD patients in comparison to controls. All the p38a inhibitory drugs inhibited p38a phosphorylation and secretion of TNF-a, IL-1b and IL-6 from IBD LPMCs and biopsies. Activated p38a MAPK is up-regulated in the inflamed mucosa of patients with IBD. Additionally, all the p38a selective inhibitory drugs significantly down-regulated the activation of the MAPK pathway and the secretion of proinflammatory cytokines.

Influence of extra virgin olive oil diet enriched with hydroxytyrosol in a chronic DSS colitis model

“…Recent experiments have evidenced the importance of p38 MAPK in UC, since they have demonstrated the use of p38 MAPK inhibitors for abrogated colitis [13,35,36]. MAPKs regulate cytokine production in response to a variety of stimuli [37] and upregulate COX-2 and iNOS expression in intestinal Fig.…”

Mechanism of IL-1β Modulation of Intestinal Epithelial Barrier Involves p38 Kinase and Activating Transcription Factor-2 Activation

“…The p38 kinase pathway is known to regulate wide-ranging proinflammatory responses, including stimulation of proinflammatory genes (36,37), induction of COX-2 (38), increases in iNOS expression (39), increases in adhesion molecule expression (40)(41)(42), and proliferation of inflammatory cells (43)(44)(45)(46). The p38 kinase is both upregulated and activated in intestinal tissue of patients with IBD, and inhibition of p38 kinase inhibits the secretion of inflammatory cytokines in intestinal tissue and in lamina propria mononuclear cells isolated from IBD patients (47,48). Previous studies have suggested that p38 kinase may also be involved in TJ barrier regulation (49).…”

Pro-Oncogenic Role of Alternative p38 Mitogen-Activated Protein Kinases p38γ and p38δ, Linking Inflammation and Cancer in Colitis-Associated Colon Cancer

“…Studies using tissue-specific conditional knockouts of p38a mice showed the importance of this isoform in the inflammatory response, both in cultured macrophages in vitro (8) and for development of skin and gut inflammation in vivo (9,10). p38a also mediates inflammation in IBD; it is highly phosphorylated and active in the inflamed intestinal mucosa of patients with IBD (11,12). The role of p38a in colitis was confirmed in experimental mouse models, and p38a/bMAPK inhibitors have been tested in clinical trials (10,(13)(14)(15)(16).…”