Histamine H4 receptor activation enhances LPS-induced IL-6 production in mast cells via ERK and PI3K activation

The histamine H-4 receptor (H4R) has been implicated in numerous inflammatory functions. Here it is shown that the receptor can mediate cytokine production from mast cells. Histamine and an H4R agonist, JNJ 28610244, induced the production of IL-6 in mouse bone marrow (BM)-derived mast cells. This effect was blocked by two different H4R antagonists and was not present in H4R-deficient cells. In addition, histamine acting via the H4R potentiated LPS-induced IL-6 production. Histamine-induced IL-6 production could be blocked by inhibitors of ERK and phosphoinositide 3-kinase gamma (PI3K gamma) pathways. Furthermore, it was shown that H4R activation can induce phosphorylation of ERK, MEK and AKT. H4R activation led to a rapid and transient phosphorylation of these kinases, whereas with LPS the activation occurred at later time points. When both histamine and LPS were added, the phosphorylation was evident at 5 min and persisted for at least 60 min suggesting that changes in the kinetics of kinase activation may be one mechanism driving the signaling interaction between the H4R and toll-like receptors. These observations suggest that the H4R can synergize with other inflammatory signals to potentiate cytokine production and provides mechanistic information on the role of the H4R in inflammation.