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J Immunol. 2009 Feb 1;182(3):1660-6.

IL-17 signaling for mRNA stabilization does not require TNF receptor-associated factor 6.

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1
Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.

Abstract

IL-17 alone is a relatively weak inducer of gene expression, but cooperates with other cytokines, including TNF-alpha, 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-kappaB, it does not stabilize transfected KC mRNA. Furthermore, a dominant-negative TRAF6 abrogates NF-kappaB activation, but does not block IL-17-induced chemokine mRNA stabilization. IL-17 can stabilize KC and MIP-2 mRNAs comparably in TNF-alpha-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-alpha-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-alpha, these findings suggest that this pathway is a major contributing mechanism for response to IL-17.

PMID:
19155515
PMCID:
PMC2665037
[Indexed for MEDLINE]
Free PMC Article

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