Inflammatory signaling compromises cell responses to interferon alpha

W. C. Huangfu, J. Qian, C. Liu, J. Liu, A. E. Lokshin, D. P. Baker, H. Rui, S. Y. Fuchs

Research output: Contribution to journalArticle

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Abstract

Interferon alpha (IFNα) is widely used for treatment of melanoma and certain other malignancies. This cytokine as well as the related IFNΒ exerts potent anti-tumorigenic effects; however, their efficacy in patients is often suboptimal. Here, we report that inflammatory signaling impedes the effects of IFNα/Β. Melanoma cells can secrete pro-inflammatory cytokines that inhibit cellular responses to IFNα/Β via activating the ligand-independent pathway for the phosphorylation and subsequent ubiquitination and accelerated degradation of the IFNAR1 chain of type I IFN receptor. Catalytic activity of the p38 protein kinase was required for IFNAR1 downregulation and inhibition of IFNα/Β signaling induced by proinflammatory cytokines such as interleukin 1 (IL-1). Activation of p38 kinase inversely correlated with protein levels of IFNAR1 in clinical melanoma specimens. Inhibition of p38 kinase augmented the inhibitory effects of IFNα/Β on cell viability and growth in vitro and in vivo. The roles of inflammation and p38 protein kinase in regulating cellular responses to IFNα/Β in normal and tumor cells are discussed.

Original languageEnglish
Pages (from-to)161-172
Number of pages12
JournalOncogene
Volume31
Issue number2
DOIs
Publication statusPublished - Jan 12 2012
Externally publishedYes

Fingerprint

Interferon-alpha
Interferon alpha-beta Receptor
Melanoma
p38 Mitogen-Activated Protein Kinases
Cytokines
Phosphotransferases
Ubiquitination
Interleukin-1
Neoplasms
Cell Survival
Down-Regulation
Phosphorylation
Ligands
Inflammation
Growth
Proteins

Keywords

  • cancer
  • inflammation
  • interferon
  • melanoma
  • receptor
  • ubiquitin

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Huangfu, W. C., Qian, J., Liu, C., Liu, J., Lokshin, A. E., Baker, D. P., ... Fuchs, S. Y. (2012). Inflammatory signaling compromises cell responses to interferon alpha. Oncogene, 31(2), 161-172. https://doi.org/10.1038/onc.2011.221

Inflammatory signaling compromises cell responses to interferon alpha. / Huangfu, W. C.; Qian, J.; Liu, C.; Liu, J.; Lokshin, A. E.; Baker, D. P.; Rui, H.; Fuchs, S. Y.

In: Oncogene, Vol. 31, No. 2, 12.01.2012, p. 161-172.

Research output: Contribution to journalArticle

Huangfu, WC, Qian, J, Liu, C, Liu, J, Lokshin, AE, Baker, DP, Rui, H & Fuchs, SY 2012, 'Inflammatory signaling compromises cell responses to interferon alpha', Oncogene, vol. 31, no. 2, pp. 161-172. https://doi.org/10.1038/onc.2011.221
Huangfu WC, Qian J, Liu C, Liu J, Lokshin AE, Baker DP et al. Inflammatory signaling compromises cell responses to interferon alpha. Oncogene. 2012 Jan 12;31(2):161-172. https://doi.org/10.1038/onc.2011.221
Huangfu, W. C. ; Qian, J. ; Liu, C. ; Liu, J. ; Lokshin, A. E. ; Baker, D. P. ; Rui, H. ; Fuchs, S. Y. / Inflammatory signaling compromises cell responses to interferon alpha. In: Oncogene. 2012 ; Vol. 31, No. 2. pp. 161-172.
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