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

DOCENA G; ROVEDATTI L; KRUIDENIER L; FANNING A; LEAKY NA; KNOWLES CH; LEE K; SHANAHAN F; NALLY K; MCLEAN PG; DI SABATINO A,; MACDONALD T

Clinical & Experimental Immunology

Wiley-Blackwell

Año: 2010 vol. 162 p. 108 - 115

0009-9104

Crohn’s disease and ulcerative colitis are inflammatory bowel diseases (IBD) characterized by chronic relapsing mucosal inflammation. Tumor necrosis factor (TNF)-a, a known agonist of the mitogen-activated protein kinase (MAPK) pathway, is a key cytokine in this process. We firstly aimed 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 pro-inflammatory cytokines by IBD lamina propria monuclear cells and organ culture biopsies. Methods: 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 lamina propria mononuclear cells were incubated with four different p38a selective inhibitory drugs. TNF-a, interleukin (IL)-1â and IL-6 were measured in the organ and cell culture supernatants by ELISA. Results: We found higher levels of phospho-p38á 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-1â and IL-6 from IBD lamina propria mononuclear cells and biopsies. Conclusions: Activated p38á 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 pro-inflammatory cytokines.