Interleukin-6 potentiates FcεRI-induced PGD2 biosynthesis and induces VEGF from human in situ-matured skin mast cells

Interleukin-6 is a gp130 utilizing cytokine that is consistently associated with allergic diseases like asthma and urticaria in humans where mast cells are known to play a critical role. However, the role of IL-6 in allergic disease in not known. IL-6 was reported to enhance degranulation of in vitro-derived mast cells, but the effect of IL-6 on mediator release from human in situ-matured tissue-isolated mast cells had not been reported. Human mature mast cells were isolated and purified from normal skin tissue from different donors. The expression of surface-expressed IL-6 receptors was demonstrated by flow cytometry. The effect of IL-6 on FcεRI-induced degranulation, PGD2 biosynthesis, and cytokine production was determined with β‑hexosaminidase release assay, Western blotting, quantitative real-time PCR, and ELISA. The small molecule inhibitor of STAT-3, C188-9, was used to demonstrate STAT3 dependency. Results: IL-6 significantly potentiated FcεRI-induced PGD2 biosynthesis, but had no effect on degranulation. IL-6 also induced VEGF gene expression and protein secretion, and enhanced FcεRI-induced IL-8 production. Mechanistically, IL-6 enhanced FcεRI-induced COX‑2 expression, PGD2 biosynthesis, and VEGF production in a STAT3 dependent manner. Here, we demonstrate that IL-6 is a potentiator of FcεRI-induced PGD2 biosynthesis, and can induce or enhance production of pro-angiogenesis factors VEGF and IL-8 from human in situ-matured skin mast cells. These findings from this study indicate that IL-6 contributes to human allergic disease by enhancing the production of inflammatory PGD2 from tissue-resident mast cells. Moreover, the data suggest a novel role for IL-6 in mast cell-mediated angiogenesis. •Human skin mast cells constitutively express membrane-bound IL-6Rα and gp130.•IL-6 potentiates FcεRI-induced PGD2 biosynthesis in human skin mast cells.•IL-6 enhances FcεRI-induced COX‑2 expression and PGD2 biosynthesis by a STAT3 dependent mechanism.•IL-6 induces de novo production of VEGF in human skin mast cells by a STAT3 dependent mechanism.•IL-6 enhances FcεRI-induced IL-8 production from human skin mast cells.