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(American Journal of Pathology. 2002;160:1495-1502.)
© 2002 American Society for Investigative Pathology

Regular Articles

Induction of the Hyaluronic Acid-Binding Protein, Tumor Necrosis Factor-Stimulated Gene-6, in Cervical Smooth Muscle Cells by Tumor Necrosis Factor- and Prostaglandin E₂

Toshio Fujimoto^*, Rashmin C. Savani^*, Michiko Watari^*, Anthony J. Day and Jerome F. Strauss, III^*

From the Center for Research on Reproduction and Women’sHealth,^* University of Pennsylvania Medical Center,Philadelphia, Pennsylvania; and the Department ofBiochemistry, MRC Immunochemistry Unit,University of Oxford, Oxford, United Kingdom

Immediately before parturition the cervix undergoes striking changes in structure (ripening) that facilitate dilatation and effacement. Cervical ripening shares many features in common with inflammation-associated tissue remodeling, making it a valuable process to explore with respect to the biochemical events in extracellular matrix restructuring. Cervical ripening can be pharmacologically induced with prostaglandin E₂ (PGE₂). Among the biochemical changes in the cervix at parturition is a marked increase in the hyaluronic acid (HA) content. HA and HA-binding proteins have been implicated in tissue hydration, release of collagenase, and leukocyte migration, but their roles in cervical ripening have not been explored. In the present study we examined the ability of PGE₂ to induce expression of the HA-binding protein, tumor necrosis factor-stimulated gene (TSG)-6, in human cervical smooth muscle cells (hCSMCs) and compared the PGE₂ response to that of tumor necrosis factor- (TNF-), an established inducer of TSG-6. TNF- stimulated TSG-6 mRNA accumulation in a dose- and time-dependent manner, with the maximal response observed at 10 ng/ml after 6 hours of incubation. PGE₂ stimulated TSG-6 mRNA expression, but the magnitude of response was substantially less than that produced by TNF-, and it was maximal only after 24 hours of incubation. Quantitative real-time polymerase chain reaction was performed to assess the induction of TSG-6 mRNA and nascent transcripts at 24 hours of treatment. Induction of TSG-6 mRNA and nascent transcripts in response to 10 µmol/L of PGE₂ was 5.7-fold and 6.3-fold greater than control values, respectively, whereas TNF- (10 ng/ml) induced TSG-6 mRNA and nascent transcripts by 80-fold and 134-fold, respectively. TNF- and PGE₂ stimulated secretion of TSG-6 into the culture medium as detected by Western blotting. The effects of PGE₂ on secretion of TSG-6 were delayed compared to TNF-. A 1.3-kb fragment of the human TSG-6 proximal promoter drove luciferase expression in transfected hCSMCs. PGE₂ increased TSG-6 promoter activity 1.75-fold. Paradoxically, TNF- reduced TSG-6 promoter activity by 50%. We conclude that hCSMCs express the hyaladherin TSG-6; that TSG-6 expression in these cells is regulated by PGE₂ as well as proinflammatory cytokines; responses of hCSMCs to TNF- and PGE₂ are distinct in terms of magnitude and the time course; and PGE₂ and TNF- exert different effects on the TSG-6 proximal promoter.

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