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Tumor Necrosis Factor Alpha Stimulates Adenylyl Cyclase Activity in Human Myometrial Cells¹

^a Departments of Anesthesiology, College of Physicians & Surgeons, Columbia University, New York, New York 10032 ^b Universitätsklinikum Münster, 48129 Münster, Germany ^c The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287

Cytokines such as tumor necrosis factor (TNF) have been implicated in amniotic fluid infections and preterm and term labor. The underlying mechanisms are incompletely understood. In some smooth muscle cells, TNF affects function of the ß-adrenergic/adenylyl cyclase pathway. The present study was performed to examine the effects of chronic TNF exposure on adenylyl cyclase activity in cell cultures of human myometrium. Chronic TNF exposure led to a dose- and time-dependent increase in basal-, GTP-, NaF-, and forskolin-stimulated adenylyl cyclase (AC) activity. The increase in AC activity was not mediated by changes in the expression of the heterotrimeric G proteins G_s or G_i as determined by immunoblotting. In addition, increases in AC activity occurred in the presence of indomethacin, indicating that these changes were not provoked by TNF-induced changes in prostaglandin production. The present results suggest that TNF-induced increases in AC activity in human myometrial cells obtained from the lower uterine segment occur at the level of G-protein/AC interaction or at the level of the AC enzyme itself.

¹ Supported in part by the National Institutes of Health NHLBI RO1 HL 62340 and R29 HD 34782. W.G. is a postdoctoral fellow supported by the Innovative Medizinische Forschung, Germany.

² Correspondence: Charles W. Emala, Department of Anesthesiology, College of Physicians & Surgeons of Columbia University, P & S Box 46, 630 West 168th Street, New York, NY 10032. FAX: 212 305 8287; e-mail: cwe5{at}columbia.edu

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