IL-17 enhances chemokine gene expression through mRNA stabilization.
IL-17 plays an important role in host defense and autoimmunity via the induction of proinflammatory gene expression, particularly in combination with TNF-alpha. 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-alpha 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-alpha induced a synergistic response. IL-17 treatment exerted a strong posttranscriptional effect by extending the t1/2 of the highly unstable, TNF-alpha-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-alpha. IL-17 treatment exerted little effect on KC transcription or NF-kappaB activation, suggesting that it primarily acts posttranscriptionally. We identified a number of other mRNAs whose t1/2 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-kappaB1 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-alpha and IL-17 reflects their independent actions on KC gene expression; TNF-alpha serves as a stimulus to initiate transcription through activation of NF-kappaB, whereas IL-17 drives mRNA stabilization through an Act1-dependent pathway.
Hartupee
Justin
J
Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Liu
Caini
C
Novotny
Michael
M
Li
Xiaoxia
X
Hamilton
Thomas
T
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000818:Animals; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D006207:Half-Life; D006367:HeLa Cells; D006801:Humans; D020381:Interleukin-17 / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D020871:RNA Stability / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology