It has been shown that the addition of erythrocytes to cultured slanDC blocks their capacity

to produce IL-12 and TNF-α via the interaction of CD47 on erythrocytes and the corresponding ligand signal regulatory protein α on slanDC.4 After slanDC leave the bloodstream and infiltrate the tissue, as it was shown in inflamed skin of AD lesions, the control by erythrocytes is lost. Our study suggests that histamine might take over this control function in the tissue because we could show that histamine reduces the highly pro-inflammatory capacity of slanDC, particularly via activation of the H4R. To be sure that histamine stimulation does not reduce cytokine production in general, we investigated IL-10 as a SCH727965 research buy cytokine DAPT in vitro that is associated with anti-inflammatory actions. Interleukin-10 reduces the production of IL-2, TNF-α, IFN-γ and co-stimulatory molecules and was shown to counteract the inflammatory response in allergic contact dermatitis.24 In our study we could not observe a significant effect of histamine receptor activation on the release of IL-10. As a result, it can be assumed that H4R and H2R stimulation on slanDC specifically down-regulate the production of the pro-inflammatory mediators TNF-α and IL-12, whereas the level of the anti-inflammatory mediator IL-10 is not affected. The differential regulation of cytokine release by histamine might

be explained by varying signalling processes involved. For example, it was shown that the activation of mitogen-activated protein kinase signalling mediates histamine-induced down-regulation of IL-12p70 in monocytes,15 but on the other hand induces IL-10 production in monocytes.25 Our observations fit the current understanding

of the role of the H4R on antigen-presenting cells. Several studies have shown that the H4R on DC has an anti-inflammatory role: on MoDC, monocytes and inflammatory dendritic epidermal cells the production of IL-12 and CCL2 was down-regulated after H4R activation.15–17 In response to the reduced presence of these mediators, Histamine H2 receptor Th1 polarization is impaired and a lower number of macrophages and T cells is attracted to the site of the immune response, respectively. We can draw the conclusion that the stimulation of the H4R on DC, and as shown here in particular on slanDC, could greatly reduce the inflammatory responses taking place in the course of inflammatory skin diseases like AD and H4R agonists therefore might represent potential therapeutic tools in these kinds of diseases. This study was supported by grants from the Deutsche Forschungsgemeinschaft DFG: Gu434/5-1 and GRK1441/1 and the European Community (COST action BM0806). Maria Gschwandtner was supported by a grant from the Hannover Biomedical Research School. The authors declare no conflict of interest.