Histamine enhances the production of human -defensin-2 in human keratinocytes

Kanda N, Watanabe S. Histamine enhances the production of human -defensin-2 in human keratinocytes. Am J Physiol Cell Physiol 293: C1916–C1923, 2007. First published October 10, 2007; doi:10.1152/ajpcell.00293.2007.—The anti-microbial peptide human -defensin-2 (hBD-2), produced by epidermal keratinocytes, plays pivotal roles in anti-microbial defense, inflammatory dermatoses, and wound repair. hBD-2 induces histamine release from mast cells. We examined the in vitro effects of histamine on hBD-2 production in normal human keratinocytes. Histamine enhanced TNFor IFNinduced hBD-2 secretion and mRNA expression. Histamine alone enhanced transcriptional activities of NFB and activator protein-1 (AP-1) and potentiated TNF-induced NFB and AP-1 activities or IFN-induced NFB and STAT1 activities. Antisense oligonucleotides against NFB components p50 and p65, AP-1 components c-Jun and c-Fos, or H1 antagonist pyrilamine suppressed hBD-2 production induced by histamine plus TNFor IFN. Antisense oligonucleotide against STAT1 only suppressed hBD-2 production induced by histamine plus IFN. Histamine induced serine phosphorylation of inhibitory NFB (I B ) alone or together with TNFor IFN. Histamine induced c-Fos mRNA expression alone or together with TNF, whereas it did not further increase c-Jun mRNA levels enhanced by TNF. Histamine induced serine phosphorylation of STAT1 alone or together with IFN, whereas it did not further enhance IFN-induced tyrosine phosphorylation of STAT1. The histamine-induced serine phosphorylation of STAT1 was suppressed by MAPKK (MEK) inhibitor PD98059. These results suggest that histamine stimulates H1 receptor and potentiates TNFor IFNinduced hBD-2 production dependent on NFB, AP-1, or STAT1 in human keratinocytes. Histamine may potentiate anti-microbial defense, skin inflammation, and wound repair via the induction of hBD-2.