Submitted on November 12, 2004
Accepted on March 10, 2005
TRANSCRIPTIONAL REGULATION OF INFLAMMATORY MEDIATORS SECRETED BY HUMAN COLONIC CIRCULAR SMOOTH MUSCLE CELLS
Xuan-Zheng Shi1 and Sushil K. Sarna2*
1 Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology, Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA
2 Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology, Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA; Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology, Department of Neuroscience and Cell Biology, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA
* To whom correspondence should be addressed. E-mail: sksarna{at}utmb.edu.
Background & Aims: We investigated the transcriptional regulation of secretion of pro- and
anti-inflammatory mediators by human colonic circular smooth muscle cells (HCCSMC) in
response to TNF
. Results: Gene chip array analysis indicated that HCCSMC express a
specific panel of 11 cytokines, chemokines, and cell adhesion molecules in a time-dependent
manner in response to TNF. The chip array data were supported by
quantitative analysis of mRNA and protein expressions of IL-6, IL-8, ICAM-1 and IL-11. The
pro-inflammatory mediators were expressed early, whereas the anti-inflammatory cytokine
IL-11 was expressed late after TNF -treatment. The expression of ICAM-1 on HCCSMC
increased lymphocyte adhesion to these cells, which was blocked by pre-treatment with
antibody to ICAM-1. TNF acted on both R1 and R2 receptors to induce the expression of
ICAM-1. Pre-treatment of HCCSMC with antisense oligonucleotides to p65 NF-
B blocked
the expression of ICAM-1, while pre-treatment with antisense oligonucleotides to p50 NF-
B had little effect. The over expression of p65 NF-B enhanced the constitutive
expression of ICAM-1 and TNF-treatment had no further effect. The delayed expression of
endogenous IL-11 limited the expression of ICAM-1 and pre-treatment of HCCSMC with
antisense oligonucleotides to IL-11 enhanced it. Conclusion: TNF induces gene
expression in HCCSMC for programmed synthesis and release of pro- and anti-inflammatory
mediators.
