Differential responses to IFN-alpha subtypes in human T cells and dendritic cells.
Type I IFNs (IFN-alphabeta) constitute a family of cytokines that have important antiviral and immunoregulatory properties and have been successfully used in the treatment of a wide variety of diseases. There are 12 functional human IFN-alpha subtypes and one IFN-beta subtype that signal through the common cell surface IFN-alphabetaR. To date, virtually no information is available on the specificity of IFN-alpha responses in immune cells. In this study, Janus kinase/STAT signaling and transcriptional responses to selected IFN-alpha subtypes in human T cells and dendritic cells were analyzed. Evidence for IFN-alpha subtype and cell type specificity was found. Also, differences between kinetics of expression of IFN-stimulated genes (ISGs) and in the requirements of individual ISGs for additional signaling pathways were observed. In particular, IFN-gamma-inducible protein-10 (IP-10), a key chemokine in Th1-type inflammatory diseases, was differentially regulated. In dendritic cells, it was highly induced by IFN-alpha2 and IFN-alpha21 but much less efficiently by IFN-alpha1. It was only marginally induced by these subtypes in T cells. In marked contrast to other ISGs analyzed, optimum induction of IP-10 was dependent on activation of p38 kinase(s). The observed variations (subtype-, cell type-, and ISG-related differentials) provide further insight into the complexity and plasticity of the IFN-alphabeta response. Furthermore, the novel observation that IFN-alpha1 poorly induces IP-10 is potentially of clinical importance, because this subtype may be more beneficial in cases where Th1-mediated side effects (e.g., exacerbation of autoimmune diseases) are not desirable.
Hilkens
Catharien M U
CM
Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, London, United Kingdom.
Schlaak
Jörg F
JF
Kerr
Ian M
IM
D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D020869:Gene Expression Profiling; D006801:Humans; D016898:Interferon-alpha / Q000145:classification* / Q000494:pharmacology*; D007700:Kinetics; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D053707:Receptors, Interleukin-12; D050794:STAT1 Transcription Factor; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases