Human skin mast cells constitutively express gp130 and functional IL-6 receptor

Abstract

Mast cells, the effector cell type of allergic reactions, have been implicated in numerous traditionally non-allergic diseases including cancer, diabetes, and obesity. Interleukin-6 (IL-6) is a pleiotropic cytokine involved in many of these pathologies suggesting that IL-6 could be the link that connects mast cells to these disease states. However, it had not been formally demonstrated that human primary mast cells express a functional IL-6 surface receptor. In this study, we show that human skin mast cells (hSMCs) constitutively express IL-6Ra and gp130, a common signal transducing chain shared by members of the IL-6 cytokine family that includes leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, IL-11, cardiotrophin 1, IL-35 and IL-27. Whereas previous studies with mouse bone marrow-derived mast cells showed that IL-10 was required for surface expression of gp130, we found that IL-10 did not enhance expression on hSMCs although gp130 mRNA was increased. IL-6R functionality is demonstrated by the IL-6-induced phosphorylation of STAT3, and increased expression of SOCS3 mRNA. Interestingly, IL-6 gene expression was enhanced with IL-6 itself suggesting a positive feedback mechanism. Similar results were obtained with IL-27, which also utilizes gp130 together with WSX-1 for signaling. Mast cell degranulation was not induced with IL-6 or IL-27 alone, and neither cytokine affected FcɛRI-induced release of β-hexoaminidase. However, IgE-dependent TNF production was enhanced with IL-27. These data demonstrate that human mast cells can be directly activated by IL-6 or other gp130-utilizing cytokines, and support the notion that IL-6 could be a link that connects mast cells to non-allergic disease.