Histamine H-4 receptor activation on human slan-dendritic cells down-regulates their pro-inflammatory capacity

P>6-Sulpho LacNAc dendritic cells (slanDC) are a major population of human blood DC that are highly pro-inflammatory, as characterized by their outstanding capacity to produce tumour necrosis factor-alpha and interleukin-12 (IL-12) and to prime antigen-specific T-cell responses. SlanDC were found to be present in inflamed tissue such as atopic dermatitis, where high levels of histamine are also present. As histamine is an important regulator of allergic inflammation we investigated the role of histamine receptors, particularly the most recently identified histamine H-4 receptor (H4R), in modulating the pro-inflammatory function of slanDC. The expression of H4R was evaluated by real-time PCR and flow cytometry. Cytokine production in response to H4R stimulation was assessed by intracellular flow cytometric staining and enzyme-linked immunosorbent assay. We show that slanDC express the H1R, H2R and H4R on mRNA and the H4R on protein level. No differences were observed in basal H4R expression in patients with atopic dermatitis and psoriasis, but in atopic dermatitis patients the H4R was up-regulated by interferon-gamma. When stimulated with lipopolysaccharide in the presence of histamine, slanDC produced substantially lower levels of the pro-inflammatory cytokines tumour necrosis factor-alpha and IL-12, mediated solely via the H4R and via the combined action of H2R and H4R, respectively. In contrast, the production of IL-10 was not affected by histamine receptor activation on slanDC. The slanDC express the H4R and its stimulation leads to reduced pro-inflammatory capacity of slanDC. Hence, H4R agonists might have therapeutic potential to down-regulate immune reactions, e.g. in allergic inflammatory skin diseases.