title: Inflammatory signaling compromises cell responses to interferon alpha.
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.
authors.affiliation: Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: W-C
authors.initials: WC
authors.lastname: Huangfu
authors.forename: J
authors.initials: J
authors.lastname: Qian
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: A E
authors.initials: AE
authors.lastname: Lokshin
authors.forename: D P
authors.initials: DP
authors.lastname: Baker
authors.forename: H
authors.initials: H
authors.lastname: Rui
authors.forename: S Y
authors.initials: SY
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000502:physiology; D016898:Interferon-alpha / Q000502:physiology*; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D016898:Interferon-alpha; D048051:p38 Mitogen-Activated Protein Kinases