IL-17 enhances chemokine gene expression through mRNA stabilization

Area of Science:

• Immunology
• Molecular Biology
• Gene Regulation

Background:

• Interleukin-17 (IL-17) is crucial for host defense and autoimmunity, inducing proinflammatory gene expression, often synergistically with Tumor Necrosis Factor-alpha (TNF-alpha).
• The precise molecular mechanisms underlying IL-17's regulation of gene expression remain incompletely understood.
• Understanding these mechanisms is key to deciphering inflammatory and immune responses.

Purpose of the Study:

• To investigate the molecular mechanisms of IL-17 in regulating gene expression, focusing on transcriptional and posttranscriptional events.
• To elucidate the role of IL-17, alone and with TNF-alpha, in controlling the expression of the mouse chemokine CXCL1 (KC) gene.
• To identify the specific pathways and proteins involved in IL-17-mediated gene regulation.

Main Methods:

• Utilized mouse embryonic fibroblasts and HeLa cells for gene expression analysis.
• Employed a tetracycline-regulated transgene to study mRNA stability.
• Investigated transcriptional and posttranscriptional regulation, including mRNA half-life and NF-kappaB activation.
• Examined the role of the activator of NF-kappaB1 protein (Act1) in IL-17 signaling.

Main Results:

• IL-17 alone had a modest effect on KC gene expression, but synergized strongly with TNF-alpha.
• IL-17 significantly extended the half-life of TNF-alpha-induced KC mRNA, indicating a major posttranscriptional role.
• IL-17 treatment promoted KC mRNA stabilization independently of TNF-alpha, primarily acting posttranscriptionally rather than on transcription or NF-kappaB activation.
• The adaptor protein Act1 was essential for IL-17-induced mRNA stabilization, with its overexpression sufficient to stabilize KC mRNA.

Conclusions:

• IL-17 primarily acts posttranscriptionally by stabilizing mRNA, a mechanism dependent on the Act1 protein.
• The synergy between IL-17 and TNF-alpha arises from their distinct roles: TNF-alpha initiates transcription via NF-kappaB, while IL-17 enhances mRNA stability via Act1.
• This mRNA stabilization mechanism is likely a common pathway for IL-17-mediated gene expression, impacting immune responses.