The histamine H4 receptor is functionally expressed on T(H)2 cells

Background Histamine influences T-cell reactions via histamine receptors 1 and 2. The histamine receptor 4 (H 4 R) is the most recently identified histamine receptor and is also expressed on human CD4 + T cells; however, its regulation and function are unclear. Objective To investigate expression, regulation, and function of the H 4 R on human CD4 + T cells. Methods Histamine receptor 4 expression was studied by real-time quantitative RT-PCR and by flow cytometry. Effects of H 4 R stimulation on induction of the signal transduction molecules activator protein 1 (AP-1) and nuclear factor-κB (NF-κB) were determined by electrophoretic mobility shift assay and on cytokine production by RT-PCR and ELISA. Results Histamine receptor 4 mRNA and protein were expressed by CD4 + T cells and upregulated by IL-4. Its expression was higher on T H 2 cells than T H 1 cells and naive T-cells. H 4 R agonists (clobenpropit and 4-methylhistamine) induced AP-1 in T H 2 cells but not in T H 1 cells. This effect was blocked by the H 4 R antagonist JNJ7777120. H 4 R agonists upregulated IL-31 mRNA in PBMCs and T H 2 cells, a cytokine that has been associated with T H 2 cells and the induction of pruritus. IL-31 mRNA induction by H 4 R stimulation was pronounced in PBMCs from patients with atopic dermatitis. Expression of IL-4, IL-5, and IL-13 was not altered by the H 4 R. Conclusion Human CD4 + T cells express a functional H 4 R. The receptor is upregulated under T H 2 conditions, and its stimulation leads to induction of AP-1 and IL-31.