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Role of Phosphatidylinositol-3 Kinase in Transcriptional Regulation of TLR-Induced IL-12 and IL-10 by Fc Receptor Ligation in Murine Macrophages¹

Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, MD 21201

Ligation of FcR concurrent with LPS stimulation of murine macrophages results in decreased IL-12 and increased IL-10 production. Because PI3K deficiency has been associated with increased IL-12, we hypothesized that PI3K was central to the anti-inflammatory effect of FcR ligation on TLR-induced IL-12. FcR ligation of macrophages increased pAKT, a correlate of PI3K activity, above levels induced by TLR4 or TLR2 agonists. This increase was blocked by PI3K inhibitors, wortmannin or LY294002, as was the effect of FcR ligation on TLR-induced IL-12 and IL-10. LPS-induced binding of NF-B to the IL-12 p40 promoter NF-B-binding site was not affected by FcR ligation at 1 h; however, by 4 h, NF-B binding was markedly inhibited, confirmed in situ by chromatin immunoprecipitation analysis. This effect was wortmannin sensitive. Although TLR-induced IB degradation was not affected by FcR ligation, IB accumulated in the nuclei of cells treated with LPS and FcR ligation for 4 h, and was blocked by PI3K inhibitors. LPS-induced IFN regulatory factor-8/IFN consensus sequence-binding protein mRNA, and an IFN regulatory factor-8-dependent gene, Nos2, were inhibited by concurrent FcR ligation, and this was also reversed by wortmannin. Thus, FcR ligation modulates LPS-induced IL-12 via multiple PI3K-sensitive pathways that affect production, accumulation, and binding of key DNA-binding proteins required for IL-12 induction.

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 National Institutes of Health Grant AI18797 (to S.N.V.).

² S.K.P. and V.Y.T. contributed equally to the work in this article.

³ Address correspondence and reprint requests to Dr. Stefanie N. Vogel, Department of Microbiology and Immunology, School of Medicine, University of Maryland, Howard Hall Room 324, 660 West Redwood Street, Baltimore, MD 21201. E-mail address: svogel{at}som.umaryland.edu

⁴ Abbreviations used in this paper: PKB, protein kinase B; ChIP, chromatin immunoprecipitation; IRF-8, IFN regulatory factor-8; ICSBP, IFN consensus sequence-binding protein; P3C, S-[2,3-Bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-(R)-Cys-(S)-Ser-Lys4-OH trihydrochloride; iNOS, inducible NO synthase; GSK3, glycogen synthase kinase-3; MAST 205, microtubule-associated serine/threonine kinase 205 kDa.

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