CD40 expression in uterine tissues: A key regulator of cytokine expression by fibroblasts

Abstract

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 cenix 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 cenix expressed CD40. Fibroblastic cells derived from all three sources express low levels of CD40, and this is up-regulated with interferon-gamma treatment (500 U/mL; 72 h). When activated with interferon-gamma 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