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IL-17 intensifies IFN-γ-induced NOS2 upregulation in RAW 264.7 cells by further activating STAT1 and NF-κB

  • Authors:
    • Qiyue Gao
    • Yang Liu
    • Yan Wu
    • Qiang Zhao
    • Lijun Wang
    • Shanshan Gao
    • Wen Wen
    • Weiping Zhang
    • Ning Guo
    • Juan Zhou
    • Zuyi Yuan

  • View Affiliations

  • Published online on: December 11, 2015     https://doi.org/10.3892/ijmm.2015.2433
  • Pages: 347-358

  • Copyright: © Gao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Interleukin-17 (IL-17) is a signature cytokine of Th17 cells. Previous research has indicated that IL-17 plays a proinflammatory role by exacerbating interferon-γ (IFN-γ)-induced inflammation. However, prior to this study, it was not known whether inducible nitric oxide synthase (iNOS or NOS2), a signature molecule of inflammation, could be intensified by IL-17 when combined with IFN-γ. Thus, we explored the roles and underlying mechanisms of IL-17 and IFN-γ in the regulation of NOS2 expression in RAW 264.7 cells using qPCR, western blot analysis, colorimetric analysis, ChIP assay and statistical analysis. Although IL-17 alone did not induce NOS2 expression or nitric oxide (NO) production, as shown by western blot analysis and colorimetric analysis, it intensified IFN-γ-induced NOS2 upregulation and NO production in RAW 264.7 cells. The alteration of relevant transcription factors demonstrated that a combination of IFN-γ and IL-17 enhanced Tyr701-phosphorylated signal transducer and activator of transcription 1 [p-STAT1(Y701)] and nuclear factor-κB (NF-κB) activation, nuclear translocations and their binding to the NOS2 promoter, compared with IFN-γ alone, as illustrated by the results of the western blot analysis and ChIP assay. Also, using the corresponding inhibitors of STAT1 and NF-κB, we noted downregulation of the expression of NOS2 induced by IFN-γ alone or in combination with IL-17, respectively. In addition, IFN-γ increased phosphorylated (p-)p38 mitogen-activated protein kinase (MAPK), and accelerated the activation of the NF-κB pathway and the expression of NOS2, but phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) was reduced by treatment with IFN-γ and IL-17. IL-17 intensified the activation of the NF-κB pathway and NOS2 upregulation induced by IFN-γ by increasing the phosphorylation of p38 MAPK and limiting the phosphorylation of ERK1/2. Taken together, these results suggest that IL-17 intensified IFN-γ-induced NOS2 upregulation and NO production by increasing the transcription activity of p-STAT1(Y701) and NF-κB in RAW 264.7 cells. Further activation of the NF-κB pathway induced by IL-17 relied on enhanced phosphorylation of p38 MAPK and decreased phosphorylation of ERK1/2. The mechanism suggested in this study provides novel information which may be used for anti-inflammatory therapy with IL-17.
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February-2016
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Spandidos Publications style
Gao Q, Liu Y, Wu Y, Zhao Q, Wang L, Gao S, Wen W, Zhang W, Guo N, Zhou J, Zhou J, et al: IL-17 intensifies IFN-γ-induced NOS2 upregulation in RAW 264.7 cells by further activating STAT1 and NF-κB. Int J Mol Med 37: 347-358, 2016.
APA
Gao, Q., Liu, Y., Wu, Y., Zhao, Q., Wang, L., Gao, S. ... Yuan, Z. (2016). IL-17 intensifies IFN-γ-induced NOS2 upregulation in RAW 264.7 cells by further activating STAT1 and NF-κB. International Journal of Molecular Medicine, 37, 347-358. https://doi.org/10.3892/ijmm.2015.2433
MLA
Gao, Q., Liu, Y., Wu, Y., Zhao, Q., Wang, L., Gao, S., Wen, W., Zhang, W., Guo, N., Zhou, J., Yuan, Z."IL-17 intensifies IFN-γ-induced NOS2 upregulation in RAW 264.7 cells by further activating STAT1 and NF-κB". International Journal of Molecular Medicine 37.2 (2016): 347-358.
Chicago
Gao, Q., Liu, Y., Wu, Y., Zhao, Q., Wang, L., Gao, S., Wen, W., Zhang, W., Guo, N., Zhou, J., Yuan, Z."IL-17 intensifies IFN-γ-induced NOS2 upregulation in RAW 264.7 cells by further activating STAT1 and NF-κB". International Journal of Molecular Medicine 37, no. 2 (2016): 347-358. https://doi.org/10.3892/ijmm.2015.2433