Estradiol‐regulated innate antiviral responses of human endometrial stromal fibroblasts

Problem The contribution of fibroblasts to innate immune protection of the human female reproductive tract ( FRT ) against viral pathogens is relatively unknown. Method of Study Endometrial ( EM ), endocervical (Cx) and ectocervical ( EC x) fibroblasts were isolated from hysterectomy patients and grown in vitro. Fibroblasts were treated with the viral mimic poly (I:C) in the presence or absence of the sex hormone estradiol ( E 2 ), with gene expression measured by real‐time RT ‐ PCR and protein secretion by ELISA . Results Poly (I:C) induced the expression of the interferon‐stimulated genes ( ISG ) MxA, OAS 2 and APOBEC 3G, and the cytokines MCP ‐1, IL ‐8, IL ‐6, CCL 20, IFN β and RANTES by fibroblasts from all three sites. ISG upregulation was dependent upon Type I IFN signaling. E 2 inhibited the poly (I:C)‐induced upregulation of MxA and OAS 2 in EM fibroblasts, but not Cx or EC x fibroblasts. E 2 upregulated SDF ‐1α by EM fibroblasts but had no effect on secretion of other cytokines either alone or in the presence of poly (I:C). Conditioned media ( CM ) from poly (I:C)‐treated or E 2 ‐treated fibroblasts significantly reduced HIV infection of CD 4+ T cells. Conclusion Stromal fibroblasts represent a level of innate immune protection against viral pathogens in the FRT beyond that seen with epithelial cells and immune cells. Our findings indicate that fibroblasts FRT are selectively responsive to E 2 , capable of initiating an antiviral response against viral pathogens and may play a role in preventing HIV infection of CD 4+ T cells.