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IL-17 Signaling for mRNA Stabilization Does Not Require TNF Receptor-Associated Factor 6¹

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

IL-17 alone is a relatively weak inducer of gene expression, but cooperates with other cytokines, including TNF-, to generate a strong response in part via prolongation of mRNA t_1/2. Because TNFR-associated factor 6 (TRAF6) has been reported to be essential for signaling by IL-17, we examined its involvement in IL-17-mediated mRNA stabilization. Although overexpression of TRAF6 in HeLa cells activates NF-B, it does not stabilize transfected KC mRNA. Furthermore, a dominant-negative TRAF6 abrogates NF-B activation, but does not block IL-17-induced chemokine mRNA stabilization. IL-17 can stabilize KC and MIP-2 mRNAs comparably in TNF--treated mouse embryo fibroblasts from TRAF6^+/+ and TRAF6^–/– mice. TRAF6 is known to couple upstream signals with activation of p38 MAPK and mitogen activated protein kinase activated protein kinase 2, both of which have been shown to be important for Toll/IL-1R-mediated mRNA stabilization in various cell types. Inhibition of p38 MAPK, however, does not block IL-17-induced KC mRNA stabilization, and IL-17 can stabilize KC mRNA equally in mouse embryo fibroblasts from both wild-type and mitogen activated protein kinase activated protein kinase 2/3 doubly-deficient mice. Finally, IL-17 can amplify the levels of multiple TNF--stimulated mRNAs in wild-type and TRAF6-deficient cells, but not in cells from Act1^–/– mice. Collectively, these findings demonstrate the existence of a TRAF6/p38 MAPK-independent pathway that couples the IL-17R with enhanced mRNA stability. Because the most potent effects of IL-17 on gene expression are obtained in cooperation with other cytokines such as TNF-, these findings suggest that this pathway is a major contributing mechanism for response to IL-17.

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 and CA62220.

² Address correspondence and reprint requests to Dr. Thomas A. Hamilton, Department of Immunology, Lerner Research Institute, 9500 Euclid Ave., Cleveland, OH 44195. E-mail address: hamiltt{at}ccf.org

³ Abbreviations used in this paper: MK, mitogen activated protein kinase activated protein kinase; Act1, NF-B activator 1; ActD, actinomycin D; dn, dominant negative; dox, doxycycline; Lcn2, lipocalin 2; MEF, mouse embryo fibroblast; tet, tetracycline; TRAF6, TNFR-associated factor 6; UTR, untranslated region.