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

The anti-microbial peptide human β-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 TNF-α- or IFN-γ-induced hBD-2 secretion and mRNA expression. Histamine alone enhanced transcriptional activities of NF-κB and activator protein-1 (AP-1) and potentiated TNF-α-induced NF-κB and AP-1 activities or IFN-γ-induced NF-κB and STAT1 activities. Antisense oligonucleotides against NF-κB components p50 and p65, AP-1 components c-Jun and c-Fos, or H1 antagonist pyrilamine suppressed hBD-2 production induced by histamine plus TNF-α or IFN-γ. Antisense oligonucleotide against STAT1 only suppressed hBD-2 production induced by histamine plus IFN-γ. Histamine induced serine phosphorylation of inhibitory NF-κBα (IκBα) alone or together with TNF-α or IFN-γ. Histamine induced c-Fos mRNA expression alone or together with TNF-α, whereas it did not further increase c-Jun mRNA levels enhanced by TNF-α. Histamine induced serine phosphorylation of STAT1 alone or together with IFN-γ, whereas it did not further enhance IFN-γ-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 TNF-α- or IFN-γ-induced hBD-2 production dependent on NF-κB, AP-1, or STAT1 in human keratinocytes. Histamine may potentiate anti-microbial defense, skin inflammation, and wound repair via the induction of hBD-2.