The histamine H4 receptor is functionally expressed on TH2 cells

Background: Histamine influences T-cell reactions via histamine receptors I and 2. The histamine receptor 4 (H4R) 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 H4R on human CD4(+) T cells. Methods: Histamine receptor 4 expression was studied by real-time quantitative RT-PCR and by flow cytometry. Effects of H4R stimulation on induction of the signal transduction molecules activator protein 1 (AP-1) and nuclear factor-kappa B (NF-kappa B) 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. H4R 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 H4R antagonist JNJ7777120. H4R 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 H4R stimulation was pronounced in PBMCs from patients with atopic dermatitis. Expression of IL-4, IL-5, and IL-13 was not altered by the H4R. Conclusion: Human CD4(+) T cells express a functional H4R. The receptor is upregulated under T(H)2 conditions, and its stimulation leads to induction of AP-1 and IL-31. (J Allergy Clin Immunol 2009;123:619-25.)