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Leptin-Induced IL-6 Production Is Mediated by Leptin Receptor, Insulin Receptor Substrate-1, Phosphatidylinositol 3-Kinase, Akt, NF-B, and p300 Pathway in Microglia¹

Chih-Hsin Tang^2,*, Da-Yuu Lu^2,, Rong-Sen Yang^2,, Huei-Yann Tsai^*, Ming-Ching Kao, Wen-Mei Fu^3, and Yuh-Fung Chen^3,*

^* Department of Pharmacology, Graduate Institute of Medical Science, College of Medicine, China Medical University, Taichung, Taiwan; and Department of Pharmacology and Department of Orthopaedics, College of Medicine, National Taiwan University, Taipei, Taiwan

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-hydroxymethyl-chiro-inositol-2-((R)-2-O-methyl-3-O-octadecylcarbonate)), NF-B inhibitor (pyrrolidine dithiocarbamate), IB protease inhibitor (L-1-tosylamido-2-phenylenylethyl chloromethyl ketone), IB phosphorylation inhibitor (Bay 117082), or NF-B inhibitor peptide. 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 IB kinase /IB kinase , IB phosphorylation, IB degradation, p65 phosphorylation at Ser²⁷⁶, p65 and p50 translocation from the cytosol to the nucleus, and B-luciferase activity. Leptin-mediated an increase of IB kinase /IB kinase activity, B-luciferase activity, and p65 and p50 binding to the NF-B element was inhibited by wortmannin, Akt inhibitor, and IRS-1 small-interference RNA. The binding of p65 and p50 to the NF-B elements, as well as the recruitment of p300 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-B and p300 signaling pathway.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Science Council of Taiwan (NSC 95-2314-B-039-045) and China Medical University (CMU 95-208).

² C.-H.T., D.-Y.L., and R.-S.Y. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Chen Yuh-Fung, Department of Pharmacology, College of Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung, Taiwan; E-mail address: yfchen{at}mail.cmu.edu.tw or Dr. Fu Wen-Mei, Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; E-mail address: wenmei{at}ntu.edu.tw

⁴ Abbreviations used in this paper: OBR, lectin receptor; IRS-1, insulin receptor substrate-1; IKK, IB kinase; siRNA, small-interference RNA; ODN, oligonucleotide; DAPA, DNA affinity protein-binding assay; ChIP, chromatin immunoprecipitation; AS, antisense; MM, missense; PDTC, pyrrolidine dithiocarbamate; TPCK, L-1-tosylamido-2-phenylenylethyl chloromethyl ketone.

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