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J. Biol. Chem., Vol. 283, Issue 23, 15689-15693, June 6, 2008

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Interleukin 1-induced NFB Activation and Chemokine mRNA Stabilization Diverge at IRAK1^*

From the Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195

Interleukin 1 (IL-1) is capable of driving pro-inflammatory gene expression through both the initiation of transcription and by prolonging the half-life of short-lived mRNAs. Although the signaling events linking the IL-1 receptor to the activation of NFB and the initiation of transcription have been well characterized, less is known about the signaling events linking to mRNA stabilization. As a model to study the control of mRNA stability we have used the mouse chemokine KC, expression of which requires both NFB-driven transcription and stabilization of the constitutively unstable mRNA. We have evaluated the role of signaling adaptors known to play a role in IL-1-driven NFB activation in the generation of mRNA stability. Surprisingly, although TRAF6 is essential for NFB activation, it is not required for IL-1-induced mRNA stabilization. IRAK1, which is recognized to function upstream of TRAF6, is required for both mRNA stabilization and activation of NFB. Consistent with the previous findings, the TRAF6 interaction sites in IRAK1 are required for NFB activation but do not play a role in mRNA stabilization. These findings indicate that signals from the IL-1 receptor segregate into at least two separate pathways at the level of IRAK1; one couples through TRAF6 to NFB activation while a second utilizes a TRAF6-independent pathway that is responsible for mRNA stabilization.

Received for publication, February 20, 2008 , and in revised form, April 9, 2008.

^* This work was supported by United States Public Health Service Grants CA39621 and T32GM007250. 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: Dept. of Immunology, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. Tel.: 216-444-6246; Fax: 216-444-9329; E-mail: hamiltt{at}ccf.org.

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