Phosphatidylinositol 3-Kinase in Interleukin 1 Signaling
PHYSICAL INTERACTION WITH THE INTERLEUKIN 1 RECEPTOR AND REQUIREMENT IN NFκB AND AP-1 ACTIVATION*
- From the Department of Biochemistry and Molecular Biology, Box 117, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
Abstract
The signaling mechanisms utilized by the proinflammatory cytokine interleukin-1 (IL-1) to activate the transcription factors NFκB and activator protein-1 (AP-1) are poorly defined. We present evidence here that IL-1 not only stimulates a dramatic increase in phosphatidylinositol 3-kinase (PI 3-kinase) activity but also induces the physical interaction of its type I receptor with the p85 regulatory subunit of PI 3-kinase. Furthermore, two PI 3-kinase-specific inhibitors, wortmannin and a dominant-negative mutant of the p85 subunit, inhibited IL-1-induced activation of both NFκB and AP-1. Transient transfection experiments indicated that whereas overexpression of PI 3-kinase may be sufficient to induce AP-1 and increase nuclear c-Fos protein levels, PI 3-kinase may need to cooperate with other IL-1-inducible signals to fully activate NFκB-dependent gene expression. In this regard, cotransfection studies suggested that PI 3-kinase may functionally interact with the recently-identified IL-1-receptor-associated kinase to activate NFκB. Our results thus indicate that PI 3-kinase is a novel signal transducer in IL-1 signaling and that it may differentially mediate the activation of NFκB and AP-1.
Footnotes
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↵* This work is supported by National Institutes of Health Grant AR38858 (to W. S.-L. L).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ Supported by a postdoctoral training grant from the National Institute of Child Health and Human Development.
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↵§ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Box 117, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-792-2556; Fax: 713-790-0329; E-mail: wliao{at}odin.mdacc.tmc.edu.
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↵1 The abbreviations used are: AP-1, activator protein 1; IL-1, interleukin 1; IL-1RI, type I IL-1 receptor; TNF, tumor necrosis factor; IRAK, IL-1 receptor-associated protein kinase; TRAF, TNF receptor-associated factor; PI 3-kinase, phosphatidylinositol 3-kinase; CAT, chloramphenicol acetyltransferase; PKC, protein kinase C.
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- Received July 29, 1997.
