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Background Epidermal hyperproliferation resulting in acanthosis is an important clinical observation in patients with atopic dermatitis, and its underlying mechanisms are not completely understood. Objective Because increased levels of histamine are present in lesional skin, we investigated the effect of histamine, especially with regard to histamine 4 receptor (H4R) activation, on the proliferation of human and murine keratinocytes. Methods The expression of H4R on human and murine keratinocytes was detected by using real-time PCR. Keratinocyte proliferation was evaluated by using different in vitro cell proliferation assays, scratch assays, and measurement of the epidermal thickness of murine skin. Results We detected H4R mRNA on foreskin keratinocytes and on outer root sheath keratinocytes; H4R mRNA was more abundant in keratinocytes from patients with atopic dermatitis compared with those from nonatopic donors. Stimulation of foreskin keratinocytes, atopic dermatitis outer root sheath keratinocytes, and H4R-transfected HaCaT cells with histamine and H4R agonist resulted in an increase in proliferation, which was blocked with the H4R-specific antagonist JNJ7777120. Abdominal epidermis of H4R-deficient mice was significantly thinner, and the in vitro proliferation of keratinocytes derived from H4R-deficient mice was lower compared with that seen in control mice. Interestingly, we only detected H4R expression on murine keratinocytes after stimulation with LPS and peptidoglycan. Conclusion H4R is highly expressed on keratinocytes from patients with atopic dermatitis, and its stimulation induces keratinocyte proliferation. This might represent a mechanism that contributes to the epidermal hyperplasia observed in patients with atopic dermatitis.

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.