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

ArticleinAJP Cell Physiology 293(6):C1916-23 · January 2008with9 Reads
Impact Factor: 3.78 · DOI: 10.1152/ajpcell.00293.2007 · Source: PubMed

    Abstract

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