JOURNAL ARTICLE

Leptin enhances human beta-defensin-2 production in human keratinocytes

Naoko Kanda, Shinichi Watanabe
Endocrinology 2008, 149 (10): 5189-98
18556347
Leptin, an adipocyte-derived cytokine/hormone, modulates innate and adaptive immunity. Human beta-defensin-2 (hBD-2) produced by epidermal keratinocytes promotes cutaneous antimicrobial defense, inflammation, and wound repair. We examined the in vitro effects of leptin on hBD-2 production in human keratinocytes. hBD-2 secretion and mRNA expression were analyzed by ELISA and RT-PCR, respectively. Although leptin alone was ineffective, it enhanced IL-1beta-induced hBD-2 secretion and mRNA expression in keratinocytes. IL-1beta- and IL-1beta plus leptin-induced hBD-2 production both were suppressed by antisense oligonucleotides against nuclear factor-kappaB (NF-kappaB) p50 and p65; the latter was also suppressed by antisense signal transducer and activator of transcription (STAT)1 and STAT3. IL-1beta enhanced the transcriptional activity of NF-kappaB, whereas leptin enhanced STAT1 and STAT3 activity. The p38 MAPK inhibitor SB202190 suppressed IL-1beta- and IL-1beta plus leptin-induced hBD-2 production, IL-1beta-induced NF-kappaB activity, and leptin-induced STAT1 and STAT3 activity; contrastingly, the Janus kinase (JAK) 2 inhibitor AG490 suppressed IL-1beta plus leptin-induced hBD-2 production and leptin-induced STAT1 and STAT3 activity. IL-1beta induced serine phosphorylation of inhibitory kappaBalpha, STAT1, and STAT3. Leptin induced tyrosine and serine phosphorylation of STAT1 and STAT3, both of which were suppressed by AG490, and serine phosphorylation was also suppressed by SB202190. IL-1beta or leptin individually induced threonine/tyrosine phosphorylation of p38 MAPK, whereas only leptin induced tyrosine phosphorylation of JAK2, suggesting that leptin may enhance hBD-2 production in keratinocytes by activating STAT1 and STAT3 via JAK2 and p38 MAPK in cooperation with NF-kappaB, which is activated by IL-1beta. Leptin may promote cutaneous antimicrobial defense, inflammation, and wound repair via hBD-2.

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