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Endometrial Stromal Cells Undergoing Decidualization Down-Regulate Their Properties to Produce Proinflammatory Cytokines in Response to Interleukin-1ß via Reduced p38 Mitogen-Activated Protein Kinase Phosphorylation

Department of Obstetrics and Gynecology (O.Y., Y.O., Y.H., K.K., T.H., T.Y., T.A., O.T., Y.T.), Faculty of Medicine, 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: Yutaka Osuga, M.D., Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: yutakaos-tky{at}umin.ac.jp.

The decidualized endometrium plays a role in regulating trophoblast invasion for successful implantation and maintenance of pregnancy. IL-1ß, a proinflammatory cytokine, has been suggested to play a role in this process. Recently, several lines of evidence indicate the importance of p38 MAPK in various inflammatory responses. We investigated whether endometrial stromal cells (ESC) change their inflammatory responses to IL-1ß as related to p38 MAPK phosphorylation during the process of decidualization. ESC were decidualized by the treatment with progesterone for 9 d, as determined as such by an increase in the production of prolactin and cAMP by the cells. Whereas IL-1ß increased the production of IL-6, IL-8, and monocyte chemotactic protein-1, and expression of cyclooxygenase-2 mRNA in ESC cultured without treatment, the stimulatory effects of IL-1ß were reduced in the decidualized cells. Treatment with SB202190, a p38 MAPK inhibitor, also reduced the stimulatory effects of IL-1ß in nondecidualized ESC. P38 MAPK phosphorylation was increased by IL-1ß in nondecidualized ESC, whereas the IL-1ß-induced increase was suppressed in the decidualized cells. Treatment with 8-bromo-cAMP reduced IL-1ß-induced phosphorylation of p38 MAPK in nondecidualized ESC. In contrast, treatment with H89, a protein kinase A inhibitor, reversed a reduction in IL-1ß-induced p38 MAPK phosphorylation in the decidualized cells. In summary, decidualization seems to be a process during which endometrial cells diminish their response to IL-1ß, a known key factor for implantation, leading to the down-regulation of inflammation-like events, which may be relevant to controlled trophoblast invasion. The altered property of decidualized cells is thought to be caused by attenuation of IL-1ß-induced p38 MAPK phosphorylation in a way that involves the activation of the cAMP/protein kinase A pathway.

Abbreviations: COX, Cyclooxygenase; E, estradiol; EP, estradiol plus progesterone; ESC, endometrial stromal cells; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; MCP, monocyte chemotactic protein; P, progesterone; PKA, protein kinase A; PRL, prolactin.

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