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CD40 Expression in Uterine Tissues: A Key Regulator of Cytokine Expression by Fibroblasts¹

Medical Research Council Reproductive Biology Unit (A.E.K., R.W.K.) and Department of Obstetrics and Gynecology (H.O.D.C.), University of Edinburgh, Center for Reproductive Biology, Edinburgh, United Kingdom EH3 9ET; Department of Cell and Molecular Biology, Lund University (A.M.), S-221 00, Lund, Sweden; Department of Obstetrics and Gynecology, Karolinska Hospital (M.S.), S-171 76, Stockholm, Sweden; and University of Rochester Cancer Center (R.P.P.), Rochester, New York 14642

Address all correspondence and requests for reprints to: Dr. Anne King, Medical Research Council Reproductive Biology Unit, University of Edinburgh, Center for Reproductive Biology, Edinburgh, United Kingdom EH3 9ET. E-mail: a.e.king-1{at}sms.ed.ac.uk

CD40 is a cell surface receptor initially discovered on cells of the hemopoietic lineage. Its primary role on immune cells is to enhance their activation and hence their production of cytokines and immunomodulatory molecules. Recently, CD40 has also been detected on human fibroblasts. An emerging view of the fibroblast is that it is far more than a structural cell, being capable of intimate interaction with cells of the immune system. In fibroblasts from several tissues, the engagement of CD40 with its ligand (CD40L) resulted in the secretion of proinflammatory molecules such as interleukin-6 (IL-6) and IL-8. Currently, there are few data about the presence of the CD40-CD40L system in female reproductive tissues. This study investigates the expression of CD40 by human endometrium, myometrium, and cervix both in situ and in tissue explant-derived fibroblasts. CD40 was detected mainly in the perivascular region of endometrium, myometrium, and cervix. Light staining for CD40 was observed in stromal elements. Additionally, the basal epithelium of cervix expressed CD40. Fibroblastic cells derived from all three sources express low levels of CD40, and this is up-regulated with interferon- treatment (500 U/mL; 72 h). When activated with interferon- and CD40L, the fibroblasts secreted increased amounts of IL-6, IL-8, and MCP-1. These data suggest that the CD40-CD40L system may provide a link between the resident structural cells of these reproductive tissues and the infiltrating immune cells or activated platelets that may express CD40L. The possible interaction of CD40 with CD40L may be particularly important during events such as menstruation and cervical ripening, where up-regulation of the proinflammatory molecules IL-6 and IL-8 is viewed as critical for these processes. In addition, dysregulation of this system may be a contributory factor to problems such as menstrual dysfunction and preterm labor.

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