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INFLAMMATION/IMMUNITY/MEDIATORS

Inflammatory gene expression by human colonic smooth muscle cells

Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada 89557-0270

Submitted 30 October 2003 ; accepted in final form 26 April 2004

ABSTRACT

Intestinal mucosal cells and invading leukocytes produce inappropriate levels of cytokines and chemokines in human colitis. However, smooth muscle cells of the airway and vasculature also synthesize cytokines and chemokines. To determine whether human colonic myocytes can synthesize proinflammatory mediators, strips of circular smooth muscle and smooth muscle cells were isolated from human colon. Myocytes and muscle strips were stimulated with 10 ng/ml of IL-1, TNF-, and IFN-, respectively. Expression of mRNA for IL-1, IL-6, IL-8, and cyclooxygenase-2 (COX-2) was induced within 2 h and continued to increase for 8–12 h. Regulated on activation, normal T cell-expressed and -secreted (RANTES) mRNA expression was slower, appearing at 8 h and increasing linearly through 20 h. Expression of all five mRNAs was inhibited by 0.1 µM MG-132, a proteosome inhibitor that blocks NF-B activation. Expression of IL-1, IL-6, IL-8, and COX-2 mRNA was reduced by 30 µM PP1, an Src family tyrosine kinase inhibitor, and by 25 µM SB-203580, a p38 MAPK inhibitor. MAPK/extracellular regulated kinase-1 inhibitor PD-98059 (25 µM) was much less effective. In conclusion, human colonic smooth muscle cells can synthesize and secrete interleukins (IL-1 and IL-6) and chemokines (IL-8 and RANTES) and upregulate expression of COX-2. Regulation of cytokine, chemokine, and COX-2 mRNA depends on multiple signaling pathways, including Src-family kinases, extracellular regulated kinase, p38 MAPKs, and NF-B. SB-203580 was a consistent, efficacious inhibitor of inflammatory gene expression, suggesting an important role of p38 MAPK in synthetic functions of human colonic smooth muscle.

cyclooxygenase; cytokine synthesis; mitogen-activated protein kinase-activated protein kinase; nuclear factor-B; p38 mitogen-activated protein kinase

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