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J. Biol. Chem., Vol. 283, Issue 38, 25900-25912, September 19, 2008

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Interleukin (IL) 1β Induction of IL-6 Is Mediated by a Novel Phosphatidylinositol 3-Kinase-dependent AKT/IB Kinase Pathway Targeting Activator Protein-1^*

From the Neurochemistry Laboratory, Department of Psychiatry-Neuroscience and Genetics and Aging Research Unit, Massachusetts General Hospital (East), Charlestown, Massachusetts 02129

Here we describe a novel role for the phosphatidylinositol 3-kinase/AKT pathway in mediating induction of interleukin-6 (IL-6) in response to IL-1. Pharmacological inhibition of phosphatidylinositol 3-kinase (PI3K) inhibited IL-6 mRNA and protein production. Overexpression of either dominant-negative AKT or IB kinase mutant, IKKT23A, containing a mutation in a functional AKT phosphorylation site, shown previously to be important for NFB activation, completely abrogated IL-6 promoter activation in response to IL-1. However, mutation of the consensus NFB site on the IL-6 promoter did not abrogate promoter activation by IL-1 in contrast to the AP-1 site mutation. IL-1 induces phosphorylation of IKK on the NFB inducing kinase (NIK) phosphorylation sites Ser¹⁷⁶/Ser¹⁸⁰ and on the Thr²³ site, and although phosphorylation of IKKT23 is inhibited both by LY294002 and wortmannin, phosphorylation of Ser¹⁷⁶/Ser¹⁸⁰ is not. Neither inhibition of PI 3-kinase/AKT nor IKKT23A overexpression affected IB degradation in response to IL-1. Only partial inhibition by dominant-negative AKT and no inhibitory effect of IKKT23A was observed on an IL-6 promoter-specific NFB site in contrast to significant inhibitory effects on the AP-1 site. Taken together, we have discovered a novel PI 3-kinase/AKT-dependent pathway in response to IL-1, encompassing PI 3-kinase/AKT/IKKT23 upstream of AP-1. This novel pathway is a parallel pathway to the PI 3-kinase/AKT upstream of NFB and both are involved in IL-6 gene transcription in response to IL-1.

Received for publication, September 13, 2007 , and in revised form, April 28, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant R01 AG20181. 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 To whom correspondence should be addressed: CNY 149, Rm. 2510, MA General Hospital, 13th St., Charlestown, MA 02129. Tel.: 617-775-5524; Fax: 617-726-4078; E-mail: ccahill{at}rics.bwh.harvard.edu.

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