TY - JOUR
T1 - IL-17 enhances chemokine gene expression through mRNA stabilization
AU - Hartupee, Justin
AU - Liu, Caini
AU - Novotny, Michael
AU - Li, Xiaoxia
AU - Hamilton, Thomas
PY - 2007/9/15
Y1 - 2007/9/15
N2 - IL-17 plays an important role in host defense and autoimmunity via the induction of proinflammatory gene expression, particularly in combination with TNF-α. 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-α 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-α induced a synergistic response. IL-17 treatment exerted a strong posttranscriptional effect by extending the t 1/2 of the highly unstable, TNF-α-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-α. IL-17 treatment exerted little effect on KC transcription or NF-κB 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-κB1 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-α and IL-17 reflects their independent actions on KC gene expression; TNF-α serves as a stimulus to initiate transcription through activation of NF-κB, whereas IL-17 drives mRNA stabilization through an Act1-dependent pathway.
AB - IL-17 plays an important role in host defense and autoimmunity via the induction of proinflammatory gene expression, particularly in combination with TNF-α. 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-α 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-α induced a synergistic response. IL-17 treatment exerted a strong posttranscriptional effect by extending the t 1/2 of the highly unstable, TNF-α-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-α. IL-17 treatment exerted little effect on KC transcription or NF-κB 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-κB1 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-α and IL-17 reflects their independent actions on KC gene expression; TNF-α serves as a stimulus to initiate transcription through activation of NF-κB, whereas IL-17 drives mRNA stabilization through an Act1-dependent pathway.
UR - http://www.scopus.com/inward/record.url?scp=35748973565&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.179.6.4135
DO - 10.4049/jimmunol.179.6.4135
M3 - Article
C2 - 17785852
AN - SCOPUS:35748973565
SN - 0022-1767
VL - 179
SP - 4135
EP - 4141
JO - Journal of Immunology
JF - Journal of Immunology
IS - 6
ER -