title: IFNα converts IL-22 into a cytokine efficiently activating STAT1 and its downstream targets.
abstract: Besides their antiviral activity, type I Interferons (IFN) display context-specific immunomodulation. In contrast to long-known IFNα/β, Interleukin (IL)-22 is an anti-bacterial, largely tissue protective cytokine that recently gained attention. Herein, cellular IFNα/IL-22 interactions are investigated. We report that pre-conditioning of epithelial cells with IFNα initiated dramatic changes in IL-22 signaling normally dominated by signal transducer and activator of transcription (STAT)-3. Specifically, by using human DLD1 colon epithelial/carcinoma cells we demonstrate that, upon IFNα, IL-22 converts into a cytokine robustly activating STAT1 and its downstream pro-inflammatory targets CXCL9, CXCL10, and inducible nitric oxide synthase (iNOS). Accordingly, only after IFNα pre-incubation was IL-22-induced STAT1 binding to the CXCL10 promoter detectable. Using the viral mimic polyinosinic:polycytidylic acid and the IFNα/β antagonist B18R we furthermore demonstrate the capability of endogenous IFN to promote IL-22-induced STAT1 activation and expression of CXCL10. IL-22-induced STAT1 activation subsequent to IFNα priming became likewise apparent in human Caco2 colon epithelial/carcinoma cells, HepG2 hepatoma cells, and primary keratinocytes. Current observations may relate to characteristics of IFNα/β in clinical therapy and expose margins of tissue protection by IL-22 application.
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. M.Bachmann@med.uni-frankfurt.de
authors.forename: Malte
authors.initials: M
authors.lastname: Bachmann
authors.forename: Solongo
authors.initials: S
authors.lastname: Ulziibat
authors.forename: Lorena
authors.initials: L
authors.lastname: Härdle
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
authors.forename: Heiko
authors.initials: H
authors.lastname: Mühl
mesh_terms: D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D000097043:Interleukin-22
chemical_list: D016898:Interferon-alpha; D007378:Interleukins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D050794:STAT1 Transcription Factor; D000097043:Interleukin-22; C494079:STAT1 protein, human; C415369:interleukin-22 receptor