Requirement for endogenous heat shock factor 1 in inducible nitric oxide synthase induction in murine microglia

Journal of Neuroinflammation

Rongrong Yang¹  Bo Jiang²  Wei Zhang²  Jili Wang²  Lijuan Tong²  Xu Lu²  Chao Huang² 

[1] Department of Anesthesiology, Affiliated Hospital of Nantong University, Jiangsu Province, #20Xisi Road, Nantong 226001, Jiangsu Province, China;Key Laboratory of Inflammation and Molecular Drug Targets of Jiangsu Province, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu Province, China

关键词: Signal transducer and activator of transcription 1;    Nuclear factor-κB;    Inducible nitric oxide synthase;    Interferon-γ;    Lipopolysaccharide;    Heat shock factor 1;   

Others  :  1228646
DOI  :  10.1186/s12974-015-0406-5

 received in 2015-06-18, accepted in 2015-09-28,  发布年份 2015

【 摘 要 】

Background

Inducible nitric oxide synthase (iNOS) makes a great contribution to host defense and inflammation. In many settings, lipopolysaccharide (LPS) induces iNOS expression through activation of the inhibitor of κB-α (IκB-α)-nuclear factor-κB (NF-κB) cascade, whereas interferon-γ (IFN-γ) acts through Janus kinase (JAK)-signal transducer and activator of transcription 1 (STAT1) signals. Heat shock factor 1 (HSF1), a major regulator of heat shock protein transcription, has been shown to regulate the production of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), but it remains obscure whether and how HSF1 affects iNOS induction.

Methods

Western blot was used to measure the protein expression. The mRNA level was measured by real-time PCR. Silence of HSF1 was achieved by small interfering RNA. Nitric oxide (NO) content and NF-κB binding activity were assayed by commercial kits. Chromatin immunoprecipitation (ChIP) was used to measure the binding activity of NF-κB and STAT1 to iNOS promoters.

Results

HSF1 inhibition or knockdown prevented the LPS- and/or IFN-γ-stimulated iNOS protein expression in cultured microglia. HSF1 inhibition blocked iNOS mRNA transcription. These inhibitory effects of HSF1 inhibition on iNOS expression were confirmed in brain tissues from endotoxemic mice. Further analysis showed that HSF1 inhibition had no effect on IκB-α degradation and NF-κB or STAT1 phosphorylation in LPS/IFN-γ-stimulated cells. The nuclear transport of active NF-κB or STAT1 was also not affected by HSF1 inhibition, but HSF1 inhibition reduced the binding of NF-κB and STAT1 to their DNA elements. In addition, HSF1 inhibition reduced NF-κB and STAT1 bindings to iNOS promoter inside the LPS/IFN-γ-stimulated cells.

Conclusions

This preventing effect of HSF1 inhibition on iNOS mRNA transcription presents the necessary role of HSF1 in iNOS induction.

【 授权许可】

   
2015 Huang et al.

【 图 表 】

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