Histamine downregulates the Th1-associated chemokine IP-10 in monocytes and myeloid dendritic cells.

BACKGROUND: Histamine is an important mediator of allergic diseases. It modulates the cytokine expression of various subtypes of antigen-presenting cells by four known receptors, H1R-H4R. The effects of histamine on myeloid dendritic cells (mDC) are unclear. METHODS: Monocytes and mDC were isolated from human PBMC. Histamine receptor expression was evaluated by real-time PCR. Cells were stimulated with histamine and histamine receptor ligands, and restimulated with polyinosinic-polycytidylic acid (poly I:C), and supernatants were analyzed by protein array and ELISA. RESULTS: Monocytes and mDC express H1R and H2R without significant differences between the two cell types, whereas H4R mRNA was significantly higher in mDC compared with monocytes and H3R mRNA was not detected in any cell type. Prestimulation with histamine caused a significant decrease in poly I:C-induced expression of interferon-γ-induced protein (IP-10) in mDC and monocytes. Stimulation with specific H1R, H2R and H4R agonists and antagonists showed that the observed effect was mediated via H2R and H4R in monocytes and mDC. CONCLUSION: Monocytes and mDC have similar histamine receptor repertoires with regard to H1R, H2R and H3R, but H4R expression is higher on mDC. Histamine stimulation shows similar functional effects on both cell types, i.e., downregulation of TLR3-induced IP-10 production. This might be a new mechanism how histamine fosters a Th2 milieu.

Histamine induces proliferation in keratinocytes from patients with atopic dermatitis through the histamine 4 receptor.

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.