Inflammatory signaling compromises cell responses to interferon alpha.

ABSTRACT: Interferon alpha (IFN?) is widely used for treatment of melanoma and certain other malignancies. This cytokine as well as the related IFN? exerts potent anti-tumorigenic effects; however, their efficacy in patients is often suboptimal. Here, we report that inflammatory signaling impedes the effects of IFN?/?. Melanoma cells can secrete pro-inflammatory cytokines that inhibit cellular responses to IFN?/? 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 IFN?/? 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 IFN?/? on cell viability and growth in vitro and in vivo. The roles of inflammation and p38 protein kinase in regulating cellular responses to IFN?/? in normal and tumor cells are discussed.

SUBMITTER: Huangfu WC 

PROVIDER: S-EPMC3175348 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature