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(American Journal of Pathology. 1999;154:1755-1762.)
© 1999 American Society for Investigative Pathology

Regular Articles

Pro-Inflammatory Cytokines Induce Expression of Matrix-Metabolizing Enzymes in Human Cervical Smooth Muscle Cells

Michiko Watari*, Hidemichi Watari*, Michael E. DiSanto{dagger}, Samuel Chacko{dagger}, Guo-Ping Shi§ and Jerome F. Strauss, III*

From the Center for Research on Reproduction and Women's Health*
and the Department of Urology,{dagger}
University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, and the Division of Pulmonary and Critical Care Medicine,§
Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

The process of cervical ripening has been likened to an inflammatory reaction associated with the catabolism of cervical extracellular matrix by enzymes released from infiltrating leukocytes. We hypothesized that smooth muscle cells in the cervix also participate in this process and that pro-inflammatory cytokines act on cervical smooth muscle cells (CSMC) to provoke the expression of matrix-degrading enzymes. We treated primary cultures of human CSMC with tumor necrosis factor-{alpha} (TNF-{alpha}) and examined expression of the elastinolytic enzyme, cathepsin S, the collagen metabolizing matrix metalloproteinases (MMP)-1, -3, -9, and the tissue inhibitor of metalloproteinase (TIMP)-1 and -2. A time course analysis revealed that 10 ng/ml of TNF-{alpha} induced cathepsin S, MMP-1, -3, and -9 mRNA expression with the maximal response observed after 24–48 hours. TNF-{alpha} induced cathepsin S, MMP-1, -3, and -9 mRNA expression in a dose-dependent manner: the maximal effect was observed at a concentration of 10 ng/ml, with appreciable increases observed at concentrations of 0.1 to 1.0 ng/ml. In contrast, TIMP-1 and -2 mRNAs were not significantly increased by TNF-{alpha} treatment. Interleukin-1ß produced a pattern of gene expression in the CSMC similar to that observed following TNF-{alpha} treatment. Western blot analysis and zymography confirmed the induction of proMMP-1, -3, and -9 in response to TNF-{alpha}, but MMP-2 immunoreactivity and zymographic activity were unaffected. TNF-{alpha} increased secretion of procathepsin S, but did not affect TIMP-1 and reduced TIMP-2 production. We conclude that CSMC are targets of pro-inflammatory cytokines, which induce a repertoire of enzymes capable of degrading the cervical extracellular matrix. The induction of these enzymes may facilitate the normal ripening of the cervix at term and participate in the premature cervical changes associated with preterm labor.




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