title: TPL2 Kinase Is a Crucial Signaling Factor and Mediator of NKT Effector Cytokine Expression in Immune-Mediated Liver Injury.
abstract: Invariant NKT (iNKT) cells represent a subset of innate-like T lymphocytes that function as orchestrators of hepatic inflammation underpinning liver damage. In this study, we demonstrate that TPL2, an MAP3 kinase that has mostly been appreciated for its physiological role in macrophage responses, is a signaling factor in CD3(+)NK1.1(+) iNKT cells and mediator of hepatic inflammation. Genetic ablation of TPL2 in the mouse ameliorates liver injury induced by Con A and impinges on hallmarks of NKT cell activation in the liver without affecting NKT cell development in the thymus. The pivotal role of TPL2 in iNKT cell functions is further endorsed by studies using the iNKT-specific ligand α-galactosylceramide, which causes mild hepatitis in the mouse in a TPL2-dependent manner, including production of the effector cytokines IL-4 and IFN-γ, accumulation of neutrophils and licensing and activation of other immune cell types in the liver. A TPL2 kinase inhibitor mirrors the effects of genetic ablation of TPL2 in vivo and uncovers ERK and Akt as the TPL2-regulated signaling pathways responsible for IL-4 and IFN-γ expression through the activation of the transcription factors JunB and NFAT. Collectively, these findings expand our understanding of the mechanisms of iNKT cell activation and suggest that modulation of TPL2 has the potential to minimize the severity of immune-driven liver diseases.
authors.affiliation: Laboratory of Molecular and Cellular Biology, University of Crete Medical School, 71003 Heraklion, Crete, Greece; Institute of Molecular Biology and Biotechnology, Foundation for Research & Technology-Hellas, 70013 Heraklion, Crete, Greece;
authors.forename: Dimitra
authors.initials: D
authors.lastname: Vyrla
authors.affiliation: Laboratory of Molecular and Cellular Biology, University of Crete Medical School, 71003 Heraklion, Crete, Greece; Laboratory of Translational Medicine and Experimental Therapeutics, University of Crete Medical School, 71003 Heraklion, Crete, Greece;
authors.forename: Georgios
authors.initials: G
authors.lastname: Nikolaidis
authors.affiliation: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom;
authors.forename: Fiona
authors.initials: F
authors.lastname: Oakley
authors.affiliation: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom; Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country, 20014 San Sebastian, Spain; and.
authors.forename: Maria J
authors.identifier: 0000-0002-7636-0972
authors.initials: MJ
authors.lastname: Perugorria
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Tsichlis
authors.affiliation: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom;
authors.forename: Derek A
authors.initials: DA
authors.lastname: Mann
authors.affiliation: Laboratory of Molecular and Cellular Biology, University of Crete Medical School, 71003 Heraklion, Crete, Greece; Institute of Molecular Biology and Biotechnology, Foundation for Research & Technology-Hellas, 70013 Heraklion, Crete, Greece; Laboratory of Translational Medicine and Experimental Therapeutics, University of Crete Medical School, 71003 Heraklion, Crete, Greece; eliopag@med.uoc.gr.
authors.forename: Aristides G
authors.identifier: 0000-0002-6403-6761
authors.initials: AG
authors.lastname: Eliopoulos
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology / Q000473:pathology; D003208:Concanavalin A; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005699:Galactosylceramides; D006505:Hepatitis / Q000276:immunology* / Q000473:pathology; D007155:Immunologic Factors / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008099:Liver / Q000276:immunology*; D008213:Lymphocyte Activation; D020930:MAP Kinase Kinase Kinases / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008934:Mitogens; D055611:Natural Killer T-Cells / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000276:immunology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D017252:CD3 Complex; D005699:Galactosylceramides; D007155:Immunologic Factors; D008934:Mitogens; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C493154:alpha-galactosylceramide; D003208:Concanavalin A; D015847:Interleukin-4; D007371:Interferon-gamma; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse