Leptin-Induced Il-6 Production Is Mediated by Leptin Receptor, Irs-1, Pi3 K, Akt, Nf-κb and P300 Pathway in Microglia

Leptin, the adipocyte-secreted hormone that centrally regulates weight control, is known to function as an immunomodulatory regulator. We investigated the signaling pathway involved in IL-6 production caused by leptin in microglia. Microglia expressed the long (OBRl) and short ( OBRs) isoforms of the leptin receptor. Leptin caused concentration- and time- dependent increases in IL-6 production. Leptin-mediated IL-6 production was attenuated by OBRl receptor antisense oligonucleotide, PI3K inhibitor ( Ly294002 and wortmannin), Akt inhibitor (1L-6- pydroxymethyl-chiro- inositol-2-((R)-2-O-methyl- 3-O- octadecylcarbonate)), NF- dithiocarbamate ), I phenylenylethyl chloromethyl ketone), I inhibitor (Bay 117082), or NF - Transfection with insulin receptor substrate (IRS)-1 small- interference RNA or the dominant-negative mutant of p85 and Akt also inhibited the potentiating action of leptin. Stimulation of microglia with leptin activated I kinase, I phosphorylation at Ser276, p65 and p50 translocation from the cytosol to the nucleus, and Leptin- mediated an increase of I activity, the NF- and IRS-1 smallinterference RNA. The binding of p65 and p50 to the NF- and the enhancement of histone H3 and H4 acetylation on the IL-6 promoter was enhanced by leptin. Our results suggest that leptin increased IL-6 production in microglia via the leptin receptor/IRS-1/ PI3K /Akt/NF- Immunology, 2007, 179: 1292–1302