Inflammatory signaling compromises cell responses to interferon alpha. Oncogene 2012 Jan 12;31(2):161-72
Date
06/15/2011Pubmed ID
21666722Pubmed Central ID
PMC3175348DOI
10.1038/onc.2011.221Scopus ID
2-s2.0-84855769864 (requires institutional sign-in at Scopus site) 59 CitationsAbstract
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.
Author List
Huangfu WC, Qian J, Liu C, Liu J, Lokshin AE, Baker DP, Rui H, Fuchs SYMESH terms used to index this publication - Major topics in bold
AnimalsCell Line, Tumor
Cytokines
Humans
Inflammation
Inflammation Mediators
Interferon-alpha
Melanoma
Mice
Mice, SCID
Signal Transduction
p38 Mitogen-Activated Protein Kinases
