title: MAPKAP kinase 2 regulates IL-10 expression and prevents formation of intrahepatic myeloid cell aggregates during cytomegalovirus infections.
abstract: OBJECTIVE
  The kinase p38(MAPK) and its downstream target MAPKAP kinase (MK) 2 are critical regulators of inflammatory responses towards pathogens. To date, the relevance of MK2 for regulating IL-10 expression and other cytokine responses towards cytomegalovirus (CMV) infection and the impact of this pathway on viral replication in vitro and in vivo is unknown and the subject of this study.
  
  
  METHODS
  The effect of MK2, interferon-α receptor (IFNAR)1, tristetraprolin (TTP) and IL-10 on mouse (M)CMV virus titres, cytokine expression, signal transduction, transcript stability, liver enzymes release, immune cell recruitment and aggregation in response to MCMV infection were studied ex vivo in hepatocytes and macrophages, as well as in vivo.
  
  
  RESULTS
  MK2 is critical for MCMV-induced production of IL-10, IFN-α2 and 4, IFN-β, IL-6, and TNF-α but not for IFN-γ. The MCMV-induced IL-10 production requires activation of IFNAR1 and is further regulated by MK2 and TTP-dependent stabilization of IL-10 transcripts. MK2(-/-) mice are able to control acute MCMV replication, despite deregulated cytokine production. This may be related to the observation that MCMV-infected MK2(-/-) mice show enhanced formation of focal intrahepatic lymphocyte infiltrates resembling intrahepatic myeloid cell aggregates of T cell expansion (iMATEs), which were also observed in MCMV-infected IL-10(-/-) mice but are almost absent in MCMV-infected wild-type controls.
  
  
  CONCLUSIONS
  The data suggest that MK2 is critical for regulating cytokine responses towards acute MCMV infection, including that of IL-10 via IFNARI-mediated circuits. MCMV stimulates expression of MK2-dependent cytokines, in particular IL-10 and thereby prevents enhanced formation of intrahepatic iMATE-like cellular aggregates.
authors: Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Medical Faculty, Heinrich-Heine-University of Düsseldorf, Germany.
authors: Christian
authors: C
authors: Ehlting
authors: Institute for Virology, University Hospital, University Duisburg-Essen, Germany; Institute for Virology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Germany.
authors: Mirko
authors: M
authors: Trilling
authors: Institute of Physiological Chemistry, Hannover Medical School, Hannover, Germany.
authors: Christopher
authors: C
authors: Tiedje
authors: Institute for Virology, University Hospital, University Duisburg-Essen, Germany; Institute for Virology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Germany.
authors: Vu Thuy Khanh
authors: VTK
authors: Le-Trilling
authors: Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Medical Faculty, Heinrich-Heine-University of Düsseldorf, Germany.
authors: Ute
authors: U
authors: Albrecht
authors: Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Medical Faculty, Heinrich-Heine-University of Düsseldorf, Germany.
authors: Stefanie
authors: S
authors: Kluge
authors: Institute for Virology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Germany.
authors: Albert
authors: A
authors: Zimmermann
authors: Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Medical Faculty, Heinrich-Heine-University of Düsseldorf, Germany.
authors: Dirk
authors: D
authors: Graf
authors: Institute of Physiological Chemistry, Hannover Medical School, Hannover, Germany.
authors: Matthias
authors: M
authors: Gaestel
authors: Institute of Virology, University Medical Center, Albert-Ludwigs-University of Freiburg, Germany.
authors: Hartmut
authors: H
authors: Hengel
authors: Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Medical Faculty, Heinrich-Heine-University of Düsseldorf, Germany.
authors: Dieter
authors: D
authors: Häussinger
authors: Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Medical Faculty, Heinrich-Heine-University of Düsseldorf, Germany. Electronic address: Johannes.Bode@med.uni-duesseldorf.de.
authors: Johannes Georg
authors: JG
authors: Bode
mesh_terms: D000818:Animals; D002449:Cell Aggregation / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000473:pathology; D016898:Interferon-alpha / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D022423:Myeloid Cells / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D051816:Tristetraprolin / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D016898:Interferon-alpha; D016753:Interleukin-10; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D053633:Receptor, Interferon alpha-beta; D051816:Tristetraprolin; D000099190:MAP-Kinase-Activated Kinase 2; C508032:Ifnar1 protein, mouse
keywords: Antiviral immunity; Cytokine circuits; Cytokines; Cytomegalovirus; Interferon-beta; Interleukin-10; Intrahepatic myeloid cell aggregates of T cell expansion, MK2