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1 Department of Pharmacology, University of Nevada School of Medicine, Reno, NV, USA
* To whom correspondence should be addressed. E-mail: wtg{at}med.unr.edu.
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 [CAS2]10 ng/ml, interleukin-1
(IL-1), tumor necrosis
factor 
(TNF) and interferon 
(IFN). Expression of mRNA for IL-1, IL-6, IL-8 and
cyclooxygenase-2 (COX-2) was induced within 2 hr and continued to increase for 8-12
hr. Regulated on activation, normal T cell expressed and secreted (RANTES) mRNA
expression was slower, appearing at 8 hr and increasing linearly through 20 hr.
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, a Src-family tyrosine kinase inhibitor, and by 25 µM SB203580,
a p38 MAP kinase inhibitor. The MEK1 inhibitor, PD98059 (25 µM) was much less
effective. In conclusion, human colon smooth muscle cells can synthesize and secrete
interleukins (IL-1 and IL-6), 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, ERK, p38 MAP kinases
and NF-B. SB203580 was a consistent, efficacious inhibitor of inflammatory gene
expression, suggesting an important role of p38 MAP kinase in synthetic functions of
human colon smooth muscle.
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