Introduction IL-36γ (also designated as IL-1F9) has been recently identified and belongs to the IL-1 family of cytokines. Despite expression of IL-36γ at other mucosal sites, it has not previously been reported in the vaginal or cervical epithelium. Overall, there is a paucity of information regarding the induction and physiological function of IL-36γ.
Methods Utilising our human 3-D vaginal EC model, that more accurately recapitulates in vivo human vaginal tissue, we tested the hypothesis that IL-36γ induction in the vaginal epithelium is microbe-dependent by testing a panel of STI microbes and microbial products. To further investigate the induction and regulation of IL-36γ, 3-D vaginal EC were treated with poly (I:C), flagellin or FSL-1 for 24 h. Human 3-D cells were analysed by real-time qPCR analysis. Cell pellets and culture supernatants were also collected and analysed by IL-36γ ELISA, Western blot and cytometric bead array.
Results Following exposure to STI pathogens (herpes simplex virus and bacterial vaginosis (BV)-associated bacteria) and specific microbial products, IL-36γ expression was significantly increased relative to untreated and Lactobacilli spp. bacteria in the vaginal EC model. All microbial products tested significantly (p < 0.05) induced expression of IL-36γ in a dose- and TLR-dependent manner. Treatment with IL-36γ significantly (p < 0.05) induced proinflammatory cytokines and antimicrobial peptides (AMP). Recombinant IL-36γ treatment resulted in cytokine and AMP production, thereby promoting inflammation in the local microenvironment.
Conclusion We show that human 3-D vaginal EC express IL-36γ and this cytokine is elicited in a microbe-dependent manner at this mucosal site. Furthermore, we demonstrate that IL-36γ is an important driver for epithelial activation and inflammation following infection with STI-related pathogens and BV-associated bacteria, as such this novel cytokine may play an important role in host defense in the vaginal epithelium.
Disclosure of interest statement No pharmaceutical grants were received in the development of this study.
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