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Possible Roles of Thrombin-Induced Activation of Protease-Activated Receptor 1 in Human Luteinized Granulosa Cells

Department of Obstetrics and Gynecology (Y.H., Y.O., O.Y., K.K., T.Y., T.H., E.N., T.A., A.N., O.T., Y.T.), University of Tokyo, Tokyo 113-8655; Department of Obstetrics and Gynecology (T.A.), Teikyo University, Tokyo 173-8605; and CREST (O.T.), Japan Science and Technology, Kawaguchi 332-0012, Japan

Address all correspondence and requests for reprints to: Dr. Yutaka Osuga, Department of Obstetrics and Gynecology, University of Tokyo, Tokyo 113-8655, Japan. E-mail: yutakaos-tky{at}umin.ac.jp.

The presence of thrombin and its receptor, protease-activated receptor 1 (PAR 1), in the ovary suggests that thrombin may regulate ovarian function. In particular, to address the possible role of thrombin in ovulation, a phenomenon displaying mimicry of inflammation, we investigated the effects of thrombin and PAR 1 on the production of inflammation-related substances in human luteinized granulosa cells (LGC). Thrombin stimulated the production of IL-8 and monocyte chemoattractant protein-1 by cultured LGC. The stimulatory effects of thrombin were inhibited by both inhibitors of thrombin (hirudin and PPACK) and a protein kinase C inhibitor (calphostin C). The PAR 1 agonist, SFLLRN, also stimulated the production of IL-8 and monocyte chemoattractant protein-1. Thrombin and SFLLRN stimulated the geletinase activities of LGC, the effect of both being inhibited by hirudin and PPACK. Immunocytochemical study showed that thrombin and SFLLRN induced translocation of nuclear factor B to the nucleus from the cytoplasm in LGC. Expression of PAR 1 mRNA was detected in LGC by RT-PCR analysis. These findings suggest that thrombin plays physiological roles in ovulation by enhancing the production of chemoattractive and gelatinolytic substances by granulosa cells by a mechanism involving PAR 1.

Abbreviations: FBS, Fetal bovine serum; GAPDH, glycerinaldehyde dehydrogenase; LGC, luteinized granulosa cell(s); MCP, macrophage chemoattractant protein; MMP, matrix metalloproteinase; NFB, nuclear factor B; PAR, protease-activated receptor; PKC, protein kinase C.

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