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IL-17 Enhances Chemokine Gene Expression through mRNA Stabilization¹

Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195

IL-17 plays an important role in host defense and autoimmunity via the induction of proinflammatory gene expression, particularly in combination with TNF-. The molecular mechanisms by which IL-17 regulates such expression are not well understood. Using the mouse chemokine CXCL1 (KC) gene as a model, we have examined the effects of IL-17 alone or in combination with TNF- on transcriptional and posttranscriptional events. Although treatment of mouse embryonic fibroblasts with IL-17 alone only modestly increased KC expression, the combination of IL-17 with TNF- induced a synergistic response. IL-17 treatment exerted a strong posttranscriptional effect by extending the t_1/2 of the highly unstable, TNF--induced KC mRNA. Using a tetracycline-regulated transgene in HeLa cells, we determined that IL-17 treatment alone promoted stabilization of KC mRNA in the absence of TNF-. IL-17 treatment exerted little effect on KC transcription or NF-B activation, suggesting that it primarily acts posttranscriptionally. We identified a number of other mRNAs whose t_1/2 are prolonged in response to IL-17, suggesting that this is a common mechanism by which IL-17 promotes enhanced gene expression. Finally, activator of NF-B1 protein (Act1), an adaptor protein recently implicated in IL-17 signaling, was necessary for IL-17-induced stabilization, and overexpression of Act1 resulted in stabilization of KC mRNA, indicating that events downstream of Act1 are sufficient to initiate this process. Thus, the synergy between TNF- and IL-17 reflects their independent actions on KC gene expression; TNF- serves as a stimulus to initiate transcription through activation of NF-B, whereas IL-17 drives mRNA stabilization through an Act1-dependent pathway.

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 U.S. Public Health Service Grants CA39621, AI50739, and T32 GM07250.

² Address correspondence and reprint requests to: Thomas Hamilton, Department of Immunology, NE40 Cleveland Clinic, 9500 Euclid, Cleveland, OH 44195. E-mail address: hamiltt{at}ccf.org

³ Abbreviations used in this paper: UTR, untranslated region; Act1, activator of NF-B1 protein; ActD, actinomycin D; Dox, doxycycline; IB SR, dominant-negative version of IB or IB superrepressor; KC, mouse chemokine CXCL1; MEF, mouse embryo fibroblast; TIR, Toll-IL-1 family receptor.

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