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Oncogene. 2012 Jan 12;31(2):161-72. doi: 10.1038/onc.2011.221. Epub 2011 Jun 13.

Inflammatory signaling compromises cell responses to interferon alpha.

Author information

1
Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

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.

PMID:
21666722
PMCID:
PMC3175348
DOI:
10.1038/onc.2011.221
[Indexed for MEDLINE]
Free PMC Article

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