IL-27 Expression and Responsiveness in Human Uterine Epithelial Cells and Fibroblasts In Vitro and the Role of Estradiol.

Interleukin (IL)-27 is a pleiotropic cytokine that regulates multiple aspects of innate and adaptive immunity, but whose role in immune protection of the female reproductive tract is unknown. Although not constitutively expressed by human uterine epithelial cells and fibroblasts in culture, IL-27 secretion was upregulated after treatment with the viral ligand poly (I:C) in a type I interferon (IFN)-dependent manner, with higher levels measured in fibroblasts than epithelial cells. Estradiol increased poly (I:C)-induced IL-27 production by fibroblasts, but not epithelial cells. While both cell types expressed the IL-27 receptor, only fibroblasts responded to recombinant IL-27 with increased expression of the antiviral genes, APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G) and MxA, and the tryptophan-catabolizing enzyme, indoleamine 2,3-dioxygenase (IDO). Estradiol inhibited IL-27-mediated induction of IDO in fibroblasts through estrogen receptor alpha, but had no effect on APOBEC3G. IL-27 pretreatment also potentiated poly (I:C) upregulation of the antiviral genes, OAS2 and APOBEC3G, in fibroblasts. Thus, IL-27 is part of the antiviral response by uterine cells against potential pathogens. The effect of estradiol on IL-27 production and sensitivity by fibroblasts demonstrates a selective hormone action on individual cell types in the uterus and suggests that IL-27 may have differential effects during the menstrual cycle.