Histamine enhances the production of human beta-defensin-2 in human keratinocytes.
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.
Kanda
Naoko
N
Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan.
Watanabe
Shinichi
S
D002478:Cells, Cultured; D006632:Histamine / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D015603:Keratinocytes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D023083:beta-Defensins / Q000096:biosynthesis*
C106641:DEFB4A protein, human; D016328:NF-kappa B; D011969:Receptors, Histamine H1; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D023083:beta-Defensins; D006632:Histamine; D007371:Interferon-gamma