Interleukin 33 and interleukin 4 regulate interleukin 31 gene expression and secretion from human laboratory of allergic diseases 2 mast cells stimulated by substance P and/or immunoglobulin E

Background: Cytokine interleukin (IL) 31 has emerged as an important component of allergic and inflammatory diseases associated with pruritus, such as atopic dermatitis (AD) and mastocytosis. Mast cells (MC) are stimulated by allergic and nonallergic triggers, and play a critical role in such diseases by secreting histamine and tryptase as well as cytokines and chemokines. IL-33 has been reported to augment MC responses, but its effect on secretion of IL-31 is not known. Objectives: To investigate whether IL-33 can stimulate the secretion of IL-31 from cultured human MCs and whether this response is augmented by either the neuropeptide substance P (SP) or immunoglobulin E (IgE) and anti-IgE in the absence or presence of IL-4. Methods: Laboratory of Allergic Diseases (LAD2) human MCs were cultured in StemProH-34 SFM medium supplemented by stem cell factor and were stimulated either with IL-33 (10 ng /mL) or SP (2 mu M), or preincubated with IgE (1 mu g/mL) overnight, and then stimulated with anti-IgE (1 mu g/mL) for 24 hours. IL-31 gene expression was measured by quantitative polymerase chain reaction, and protein was measured by enzyme-linked immunosorbent assay. Results: IL-33 (10 ng/mL) induces IL-31 gene expression, synthesis, and secretion from LAD2 cells in the absence of degranulation, whereas SP and IgE on their own have no effect. However, the effect of IL-33 is augmented by SP (2 mu M) and/or IgE and anti-IgE (1 mu g/mL both) and especially their combination. Moreover, this response is significantly further increased when LAD2 cells are cultured in the presence of IL-4. Conclusion: These findings provide evidence that IL-33 induced secretion of IL-31 from LAD2 MC, an action augmented by novel neuroimmune interactions that may help in the development of new treatments of allergic and inflammatory diseases, especially AD and mastocytosis.