Docena, G.,Rovedatti, L.,Kruidenier, L.,Fanning, A.,Leakey, N. A.,Knowles, C. H.,Lee, K.,Shanahan, F.,Nally, K.,McLean, P. G.,Di Sabatino, A.,MacDonald, T. T.

2010

October

Clin Exp Immunolclin Exp Immunol

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

Validated

()

162

11

108

115

Crohn's disease and ulcerative colitis are inflammatory bowel diseases (IBD) characterized by chronic relapsing mucosal inflammation. Tumour necrosis factor (TNF)-alpha, 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 p38alpha inhibitory compounds on MAPK phosphorylation and secretion of proinflammatory cytokines by IBD lamina propria mononuclear cells (LPMCs) and organ culture biopsies. In vivo phospho-p38alpha and p38alpha 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 p38alpha selective inhibitory drugs. TNF-alpha, interleukin (IL)-1beta and IL-6 were measured in the organ and cell culture supernatants by enzyme-linked immunosorbent assay. We found higher levels of phospho-p38alpha in the inflamed mucosa of IBD patients in comparison to controls. All the p38alpha inhibitory drugs inhibited p38alpha phosphorylation and secretion of TNF-alpha, IL-1beta and IL-6 from IBD LPMCs and biopsies. Activated p38alpha MAPK is up-regulated in the inflamed mucosa of patients with IBD. Additionally, all the p38alpha selective inhibitory drugs significantly down-regulated the activation of the MAPK pathway and the secretion of proinflammatory cytokines.Crohn's disease and ulcerative colitis are inflammatory bowel diseases (IBD) characterized by chronic relapsing mucosal inflammation. Tumour necrosis factor (TNF)-alpha, 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 p38alpha inhibitory compounds on MAPK phosphorylation and secretion of proinflammatory cytokines by IBD lamina propria mononuclear cells (LPMCs) and organ culture biopsies. In vivo phospho-p38alpha and p38alpha 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 p38alpha selective inhibitory drugs. TNF-alpha, interleukin (IL)-1beta and IL-6 were measured in the organ and cell culture supernatants by enzyme-linked immunosorbent assay. We found higher levels of phospho-p38alpha in the inflamed mucosa of IBD patients in comparison to controls. All the p38alpha inhibitory drugs inhibited p38alpha phosphorylation and secretion of TNF-alpha, IL-1beta and IL-6 from IBD LPMCs and biopsies. Activated p38alpha MAPK is up-regulated in the inflamed mucosa of patients with IBD. Additionally, all the p38alpha selective inhibitory drugs significantly down-regulated the activation of the MAPK pathway and the secretion of proinflammatory cytokines.

1365-2249 (Electronic)00

http://www.ncbi.nlm.nih.gov/pubmed/20731675http://www.ncbi.nlm.nih.gov/pubmed/20731675