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RECEPTORS AND SIGNAL TRANSDUCTION

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

Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan

Submitted 9 July 2007 ; accepted in final form 5 October 2007

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-- or IFN--induced hBD-2 secretion and mRNA expression. Histamine alone enhanced transcriptional activities of NF-B and activator protein-1 (AP-1) and potentiated TNF--induced NF-B and AP-1 activities or IFN--induced NF-B and STAT1 activities. Antisense oligonucleotides against NF-B 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- or IFN-. Antisense oligonucleotide against STAT1 only suppressed hBD-2 production induced by histamine plus IFN-. Histamine induced serine phosphorylation of inhibitory NF-B (IB) alone or together with TNF- or 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 TNF-- or IFN--induced hBD-2 production dependent on NF-B, AP-1, or STAT1 in human keratinocytes. Histamine may potentiate anti-microbial defense, skin inflammation, and wound repair via the induction of hBD-2.

NF-B; activator protein-1; STAT1; TNF-; IFN-