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J. Biol. Chem., Vol. 279, Issue 24, 25189-25195, June 11, 2004

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Dual Receptors and Distinct Pathways Mediate Interleukin-1 Receptor-associated Kinase Degradation in Response to Lipopolysaccharide

INVOLVEMENT OF CD14/TLR4, CR3, AND PHOSPHATIDYLINOSITOL 3-KINASE^*

Sanaâ Noubir, Zakaria Hmama, and Neil E. Reiner¶||

From the Department of Medicine, Division of Infectious Diseases, and the ^¶Department of Microbiology and Immunology, University of British Columbia Faculties of Medicine and Science and Vancouver Coastal Health Research Institute, Vancouver, British Columbia V5Z 3J5, Canada

Lipopolysaccharide (LPS) signaling leading to nuclear factor-B activation in mononuclear phagocytes involves interleukin-1 receptor-associated kinase (IRAK), which is rapidly activated after exposure to agonist. Although it is known that IRAK also undergoes rapid inactivation/degradation in response to LPS, providing negative feedback leading to LPS tolerance, mechanisms governing IRAK degradation are not fully understood. In the present study, examination of LPS signaling showed that IRAK degradation was bimodal and involved dual receptors and distinct pathways. Rapid degradation of IRAK, occurring within 30 min of exposure to agonist, was shown to signal through CD14/TLR4 and was regulated by phosphatidylinositol 3-kinase. A second delayed wave of IRAK degradation occurred 2 h after exposure to LPS and was mediated by CR3 independently of phosphatidylinositol 3-kinase. Thus, multiple independent mechanisms have evolved to regulate IRAK degradation, likely reflecting the importance of limiting cellular responses to LPS. Recognition of a CR3-dependent, CD14/TLR4-independent pathway leading to IRAK degradation has implications for understanding modulation of LPS responses by cells with important immunoregulatory function such as dendritic cells that are CD14^–.

Received for publication, November 13, 2003 , and in revised form, April 5, 2004.

^* This work was supported in part by Canadian Institutes of Health Research Operating Grants MOP-8633 (to N. E. R.) and MOP-43891 (to Z. H.) and by Michael Smith Foundation for Health Research Establishment Grant CI-SCH-26 (to Z. H.). 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.

Supported by Scholar Awards from the Canadian Institutes of Health Research and the Michael Smith Foundation for Health Research.

^|| To whom correspondence should be addressed: Division of Infectious Diseases, Dept. of Medicine, University of British Columbia, Rm. 452D, 2733 Heather St., Vancouver, BC V5Z 3J5, Canada. Tel.: 604-875-4347; Fax: 604-875-4013; E-mail: ethan{at}interchange.ubc.ca.

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