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Peritoneal Macrophages Induce RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted) Chemokine Gene Transcription in Endometrial Stromal Cells

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

Address all correspondence and requests for reprints to: Dr. Dan I. Lebovic, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan 48109-0276. E-mail: lebovic{at}umich.edu.

Peritoneal fluid macrophages (PFM) are activated in women with endometriosis, in whom they are thought to mediate or exacerbate inflammation. The effect of PFM on endometrial stromal cells (ESC) was studied using a coculture model to evaluate the influence of IL-1ß and other macrophage-derived cytokines on the transcriptional activation of the human RANTES (regulated on activation, normal T cell expressed and secreted) gene. Normal endometrial biopsies from four patients were used to prepare stromal cell cultures, and pelvic fluid was collected to isolate peritoneal macrophages. A full length (-940 bp) human RANTES promoter construct provided an indicator of transcriptional activation in luciferase reporter transfection assays. Without lipopolysaccharide (LPS), cocultures with PFM had no effect on ESC RANTES gene expression. However, when PFM were treated with LPS within the coculture apparati, ESC RANTES promoter activity was increased more than 2-fold (P < 0.05). The addition of IL-1 receptor antagonist abrogated activation of the RANTES luciferase transgene by LPS-induced PFM products (P < 0.05). We identified IL-1 from PFM as a major stimulus to initiate ESC RANTES gene expression in cocultures. We postulate that PFM stimulation of RANTES production by ESC could lead to a self-propagating recruitment of inflammatory cells that contribute to the development and progression of endometriotic lesions.

This work was supported by the following NIH grants and fellowships: HD-08517 (to D.I.L.) and HD-37321 (to D.I.L. and R.N.T.), through the Specialized Cooperative Centers Program in Reproductive Research.

Abbreviations: ESC, Endometriotic stromal cells; FBS, fetal bovine serum; IL-1ra, IL-1 receptor antagonist; LPS, lipopolysaccharide; PFM, peritoneal fluid macrophages; RANTES, regulated on activation, normal T cell expressed and secreted.

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