TGF-β Mediates Proinflammatory Seminal Fluid Signaling in Human Cervical Epithelial Cells

The cervix is central to the female genital tract immune response to pathogens and foreign male Ags introduced at coitus. Seminal fluid profoundly influences cervical immune function, inducing proinflammatory cytokine synthesis and leukocyte recruitment. In this study, human Ect1 cervical epithelial cells and primary cervical cells were used to investigate agents in human seminal plasma that induce a proinflammatory response. TGF-beta 1, TGF-beta 2, and TGF-beta 3 are abundant in seminal plasma, and Affymetrix microarray revealed that TGF-beta 3 elicits changes in Ect1 cell expression of several proinflammatory cytokine and chemokine genes, replicating principal aspects of the Ect1 response to seminal plasma. The differentially expressed genes included several induced in the physiological response of the cervix to seminal fluid in vivo. Notably, all three TGF-beta isoforms showed comparable ability to induce Ect1 cell expression of mRNA and protein for GM-CSF and IL-6, and TGF-beta induced a similar IL-6 and GM-CSF response in primary cervical epithelial cells. TGF-beta neutralizing Abs, receptor antagonists, and signaling inhibitors ablated seminal plasma induction of GM-CSF and IL-6, but did not alter IL-8, CCL2 (MCP-1), CCL20 (MIP-3 alpha), or IL-1 alpha production. Several other cytokines present in seminal plasma did not elicit Ect1 cell responses. These data identify all three TGF-beta isoforms as key agents in seminal plasma that signal induction of proinflammatory cytokine synthesis in cervical cells. Our findings suggest that TGF-beta in the male partner's seminal fluid may influence cervical immune function after coitus in women, and potentially be a determinant of fertility, as well as defense from infection. The Journal of Immunology, 2012, 189: 1024-1035.