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IL-1ß Induction of RANTES (Regulated upon Activation, Normal T Cell Expressed and Secreted) Chemokine Gene Expression in Endometriotic Stromal Cells Depends on a Nuclear Factor-B Site in the Proximal Promoter

Reproductive Endocrinology Division, Department of Obstetrics and Gynecology, University of Michigan (D.I.L.), Ann Arbor, Michigan 48109-0276; Center for Reproductive Sciences, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California (V.A.C., J.-F.M., R.N.T.), San Francisco, California 94143-0556

Address all correspondence and requests for reprints to: Robert N. Taylor, M.D., Ph.D., Center for Reproductive Sciences, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, HSE 1689, Box 0556, San Francisco, California 94143-0556. E-mail: rtaylor{at}socrates.ucsf.edu

Abstract

A complex network of cytokines mediates immunoregulatory responses in the pathogenesis of endometriosis. RANTES (regulated upon activation, normal T cell expressed and secreted) is a chemoattractant for monocytes and T cells. Endometriotic lesions express RANTES, and its concentration in peritoneal fluid correlates with the severity of endometriosis. We investigated the influence of IL-1ß, a potent macrophage cytokine, on RANTES production in endometriotic stromal cells and determined the region of the RANTES promoter responsible for IL-1ß action. RANTES mRNA was induced 5-fold in endometriotic stromal cells, and the conditioned medium RANTES protein concentrations were 12-fold higher in IL-1ß-treated endometriotic stromal cells vs. untreated controls (P < 0.05). IL-1ß activated the full-length (-940 bp) RANTES promoter as well as a truncated 456-bp 5'-flanking construct by 2-fold. Mutagenesis of a nuclear factor-B response element at -30 bp abolished the IL-1ß effect, whereas mutation of a nearby TNF response element did not affect the IL-1ß induction. An IL-1ß time-course Western assay revealed a rapid diminution of IB (endogenous inhibitor of nuclear factor-B) in endometriotic stromal cells. Overexpression of IB in endometriotic stromal cells inhibited the IL-1ß response of the RANTES gene promoter. Transcription of RANTES mRNA is up-regulated by IL-1ß via a nuclear factor-B response element in the proximal RANTES gene promoter. These results demonstrate a feed-forward regulatory loop in the pathogenesis of endometriosis by which IL-1ß produced from activated macrophages can lead to further macrophage recruitment via RANTES production in endometriotic stromal cells.

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