Histamine induces human beta-defensin-3 production in human keratinocytes

Takeko Ishikawa, Naoko Kanda, Carren S Hau, Yayoi Tada, Shinichi Watanabe
Journal of Dermatological Science 2009, 56 (2): 121-7

BACKGROUND: The antimicrobial peptide human beta-defensin-3 (hBD-3) is produced by epidermal keratinocytes, and promotes cutaneous antimicrobial defense, inflammation, and wound repair. hBD-3 induces histamine release from mast cells. We previously showed that histamine enhanced transcriptional activity of activator protein-1 (AP-1) in human keratinocytes by inducing the expression of AP-1 component c-Fos via the activation of extracellular signal-regulated kinase (ERK) through H1 receptors.

OBJECTIVE: To examine in vitro effects of histamine on hBD-3 production in normal human keratinocytes.

METHODS: The hBD-3 production was examined by enzyme-linked immunosorbent assays and reverse transcription-polymerase chain reaction. The transcriptional activities were analyzed by dual luciferase assays. The phosphorylation of proteins was examined by Western blotting.

RESULTS: Histamine enhanced hBD-3 secretion and mRNA expression in keratinocytes. The histamine-induced hBD-3 production was suppressed by H1 antagonist pyrilamine and antisense oligonucleotides against signal transducer and activator of transcription 3 (STAT3) and AP-1 components c-Jun and c-Fos. Histamine enhanced STAT3 transcriptional activity and induced tyrosine and serine phosphorylation of STAT3. The former was suppressed by Janus kinase 2 (JAK2) inhibitor AG490, while the latter was suppressed by mitogen-activated protein kinase kinase (MEK) inhibitor PD98059; both were suppressed by pyrilamine. AG490 and PD98059 suppressed histamine-induced hBD-3 production and STAT3 activity. Histamine induced tyrosine phosphorylation of JAK2, and pyrilamine suppressed the phosphorylation.

CONCLUSION: It is suggested that histamine induces hBD-3 production in human keratinocytes through H1 receptors by activating STAT3 and AP-1 via JAK2 and MEK/ERK. Histamine may promote cutaneous antimicrobial defense, inflammation, and wound repair through hBD-3.

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