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

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-1 beta-induced hBD-2 secretion and mRNA expression in keratinocytes. IL-1 beta- and IL-1 beta plus leptin-induced hBD-2 production both were suppressed by antisense oligonucleotides against nuclear factor-kappa B B (NF-kappa B) p50 and p65; the latter was also suppressed by antisense signal transducer and activator of transcription (STAT) 1 and STAT3. IL-1 beta enhanced the transcriptional activity of NF-kappa B, whereas leptin enhanced STAT1 and STAT3 activity. The p38 MAPK inhibitor SB202190 suppressed IL-1 beta- and IL-1 beta plus leptin-induced hBD-2 production, IL-1 beta-induced NF-kappa B activity, and leptin-induced STAT1 and STAT3 activity; contrastingly, the Janus kinase (JAK) 2 inhibitor AG490 suppressed IL-1 beta plus leptin-induced hBD-2 production and leptin-induced STAT1 and STAT3 activity. IL-1 induced serine phosphorylation of inhibitory kappa B alpha, 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-1 beta 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-kappa B, which is activated by IL-1 beta. Leptin may promote cutaneous antimicrobial defense, inflammation, and wound repair via hBD- 2.