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The anti-proliferative effects of type I IFN involve STAT6-mediated regulation of SP1 and BCL6
Yu-An Hsu1, Chi-Chun Huang2, Yung-Jen Kung3
1Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan.
Abstract:
Type I IFN-induced STAT6 has been shown to have anti-proliferative effects in Daudi and B cells. IFN-sensitive (DS) and IFN-resistant (DR) subclones of Daudi cells were used to study the role of STAT6 in the anti-proliferative activities. Type I IFN significantly increased STAT6 mRNA and protein expression in DS but not DR cells. STAT6 knockdown significantly reduced the sensitivity to IFN in both cell lines. The molecular targets and functional importance of IFN-activated STAT6 were performed by chromatin immunoprecipitation-on-chip (ChIP-on-chip) experiments in type I IFN-treated Daudi cells. Two target genes (Sp1 and BCL6) were selected from the ChIP-on-chip data. IFN-induced STAT6 activation led to Sp1 upregulation and BCL6 downregulation in DS cells, with only minimal effects in DR cells. siRNA inhibition of STAT6 expression resulted in decreased Sp1 and BCL6 mRNA and protein levels in both DS and DR cells. IFN treatment did not increase Sp1 and BCL6 expression in a STAT2-deficient RST2 cell line, and this effect was mitigated by plasmid overexpression of STAT2, indicating that STAT2 is important for STAT6 activation. These results suggest that STAT6 plays an important role in regulating Sp1 and BCL6 through STAT2 to exert the anti-proliferative effects of type I IFN.
Insights
Type I Interferon (IFN) activates STAT6, a protein crucial for its anti-proliferative effects in B cells. STAT6 regulates Sp1 and BCL6 gene expression via STAT2, impacting cell growth.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Type I Interferon (IFN) signaling is vital for immune responses.
- STAT6 is implicated in the anti-proliferative actions of Type I IFN in B cells.
- Understanding the precise mechanisms of IFN resistance is critical.
Purpose of the Study:
- To elucidate the role of STAT6 in Type I IFN-induced anti-proliferative effects.
- To identify molecular targets regulated by IFN-activated STAT6.
- To investigate the involvement of STAT2 in STAT6-mediated IFN responses.
Main Methods:
- Utilized IFN-sensitive (DS) and IFN-resistant (DR) Daudi cell lines.
- Assessed STAT6 mRNA and protein expression following Type I IFN treatment.
- Performed STAT6 knockdown via siRNA.
- Conducted chromatin immunoprecipitation-on-chip (ChIP-on-chip) assays.
- Analyzed Sp1 and BCL6 gene expression.
- Investigated STAT2's role using a STAT2-deficient cell line.
Main Results:
- Type I IFN increased STAT6 expression in DS cells but not DR cells.
- STAT6 knockdown diminished IFN sensitivity in both cell lines.
- ChIP-on-chip identified Sp1 and BCL6 as STAT6 targets.
- IFN-induced STAT6 upregulated Sp1 and downregulated BCL6 in DS cells.
- STAT2 was essential for IFN-induced STAT6 activation and its downstream effects on Sp1 and BCL6.
Conclusions:
- STAT6 is a key mediator of Type I IFN's anti-proliferative effects.
- STAT6 regulates Sp1 and BCL6 expression, influencing cell proliferation.
- STAT2 is critical for STAT6 activation and function in response to Type I IFN.
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