p38 Mitogen-Activated Protein Kinase Is Activated and Linked to TNF-α Signaling in Inflammatory Bowel Disease

Abstract Inflammatory bowel diseases (IBD)—Crohn’s disease and ulcerative colitis—are relapsing chronic inflammatory disorders which involve genetic, immunological, and environmental factors. The regulation of TNF-α, a key mediator in the inflammatory process in IBD, is interconnected with mitogen-activated protein kinase pathways. The aim of this study was to characterize the activity and expression of the four p38 subtypes (p38α–δ), c-Jun N-terminal kinases (JNKs), and the extracellular signal-regulated kinases (ERK)1/2 in the inflamed intestinal mucosa. Western blot analysis revealed that p38α, JNKs, and ERK1/2 were significantly activated in IBD, with p38α showing the most pronounced increase in kinase activity. Protein expression of p38 and JNK was only moderately altered in IBD patients compared with normal controls, whereas ERK1/2 protein was significantly down-regulated. Immunohistochemical analysis of inflamed mucosal biopsies localized the main expression of p38α to lamina propria macrophages and neutrophils. ELISA screening of the supernatants of Crohn’s disease mucosal biopsy cultures showed that incubation with the p38 inhibitor SB 203580 significantly reduced secretion of TNF-α. In vivo inhibition of TNF-α by a single infusion of anti-TNF-α Ab (infliximab) resulted in a highly significant transient increase of p38α activity during the first 48 h after infusion. A significant infliximab-dependent p38α activation was also observed in THP-1 myelomonocytic cells. In human monocytes, infliximab enhanced TNF-α gene expression, which could be inhibited by SB 203580. In conclusion, p38α signaling is involved in the pathophysiology of IBD.