title: Nuclear Localization of Suppressor of Cytokine Signaling-1 Regulates Local Immunity in the Lung.
abstract: Suppressor of cytokine signaling 1 (SOCS1) is a negative feedback inhibitor of cytoplasmic Janus kinase and signal transducer and activator of transcription (STAT) signaling. SOCS1 also contains a nuclear localization sequence (NLS), yet, thein vivoimportance of nuclear translocation is unknown. We generated transgenic mice containing mutated Socs1ΔNLS that fails to translocate in the cell nucleus (MGLtgmice). Whereas mice fully deficient for SOCS1 die within the first 3 weeks due to excessive interferon signaling and multiorgan inflammation, mice expressing only non-nuclearSocs1ΔNLS(Socs1-/-MGLtgmice) were rescued from early lethality. Canonical interferon gamma signaling was still functional inSocs1-/-MGLtgmice as shown by unaltered tyrosine phosphorylation of STAT1 and whole genome expression analysis. However, a subset of NFκB inducible genes was dysregulated.Socs1-/-MGLtgmice spontaneously developed low-grade inflammation in the lung and had elevated Th2-type cytokines. Upon ovalbumin sensitization and challenge, airway eosinophilia was increased inSocs1-/-MGLtgmice. Decreased transepithelial electrical resistance in trachea epithelial cells fromSocs1-/-MGLtgmice suggests disrupted epithelial cell barrier. The results indicate that nuclear SOCS1 is a regulator of local immunity in the lung and unravel a so far unrecognized function for SOCS1 in the cell nucleus.
authors.affiliation: Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg , Heidelberg , Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Zimmer
authors.affiliation: Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg , Heidelberg , Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Weitnauer
authors.affiliation: Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC), Heidelberg, Germany; German Center for Lung Research (DZL), Germany.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Boutin
authors.affiliation: German Cancer Research Center (DKFZ) , Heidelberg , Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Küblbeck
authors.affiliation: Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg , Heidelberg , Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Thiele
authors.affiliation: Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg , Heidelberg , Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Walker
authors.affiliation: Institute of Pathology, University Hospital Heidelberg , Heidelberg , Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Lasitschka
authors.affiliation: German Center for Lung Research (DZL), Germany; Division of Asthma Mouse Model, Research Center Borstel, Borstel, Germany; Airway Research Center North, Borstel, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Lunding
authors.affiliation: German Center for Lung Research (DZL), Germany; Airway Research Center North, Borstel, Germany; Division of Experimental Pneumology, Prority Area Asthma & Allergy, Research Center Borstel, Borstel, Germany.
authors.forename: Zane
authors.initials: Z
authors.lastname: Orinska
authors.affiliation: German Center for Lung Research (DZL), Germany; Airway Research Center North, Borstel, Germany; Division of Experimental Pneumology, Prority Area Asthma & Allergy, Research Center Borstel, Borstel, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Vock
authors.affiliation: German Cancer Research Center (DKFZ) , Heidelberg , Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Arnold
authors.affiliation: German Center for Lung Research (DZL), Germany; Division of Asthma Mouse Model, Research Center Borstel, Borstel, Germany; Airway Research Center North, Borstel, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wegmann
authors.affiliation: Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC), Heidelberg, Germany; German Center for Lung Research (DZL), Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dalpke
keywords: SOCS1; inflammation; lung; rodent; signal transduction; transgenic mice