Stimulation of histamine H4 receptors increases the production of IL-9 in Th9 polarized cells.

Th9 cells represent a recently defined subset of CD4+ T-helper cells, characterized by a high production of IL-9. They are found at increased frequency in lesions of atopic dermatitis, where IL-9 is also elevated. As histamine is up-regulated in lesions of inflammatory skin diseases, we investigated the expression profile of histamine receptors and their functional role on Th9 cells. Naïve CD4+ T-cells were purified from human peripheral blood mononuclear cells, using magnetic beads and further differentiated into Th9 cells. During differentiation, cells were additionally stimulated with histamine receptor agonists or left untreated. Histamine receptor expression as well as IL-9 production was measured. As proof of a successful differentiation, IL-9 production was measured at mRNA and protein level. Expression of mRNA for histamine H1 , H2 and H4 receptors were up-regulated in differentiated Th9 cells compared to Th0 cells, while no mRNA for the H3 receptor was detectable. Stimulation of Th9 cells with histamine significantly up-regulated expression of mRNA and protein for IL-9 . Experiments with specific histamine receptor agonists and antagonists revealed that this up-regulation was mediated by H4 receptors. In summary, our study demonstrates a functional role for histamine H4 receptors on Th9 cells, which might amplify the pro-inflammatory potency of these cells. Together with earlier studies on Th2 and Th17 cells, this study underlines the promising approach for the use of H4 receptor antagonists in inflammatory and allergic diseases such as atopic dermatitis. This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.