{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:37:45Z","timestamp":1790253465684,"version":"4.1.0"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2016,5,1]],"date-time":"2016-05-01T00:00:00Z","timestamp":1462060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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 \u03b1-galactosylceramide, which causes mild hepatitis in the mouse in a TPL2-dependent manner, including production of the effector cytokines IL-4 and IFN-\u03b3, 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-\u03b3 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.<\/jats:p>","DOI":"10.4049\/jimmunol.1501609","type":"journal-article","created":{"date-parts":[[2016,4,7]],"date-time":"2016-04-07T05:16:48Z","timestamp":1460006208000},"page":"4298-4310","source":"Crossref","is-referenced-by-count":13,"title":["TPL2 Kinase Is a Crucial Signaling Factor and Mediator of NKT Effector Cytokine Expression in Immune-Mediated Liver Injury"],"prefix":"10.1093","volume":"196","author":[{"given":"Dimitra","family":"Vyrla","sequence":"first","affiliation":[{"name":"Laboratory of Molecular and Cellular Biology, University of Crete Medical School , 71003 Heraklion, Crete ,","place":["Greece"]},{"name":"Institute of Molecular Biology and Biotechnology, Foundation for Research & Technology-Hellas , 70013 Heraklion, Crete ,","place":["Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios","family":"Nikolaidis","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Biology, University of Crete Medical School , 71003 Heraklion, Crete ,","place":["Greece"]},{"name":"Laboratory of Translational Medicine and Experimental Therapeutics, University of Crete Medical School , 71003 Heraklion, Crete ,","place":["Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"Oakley","sequence":"additional","affiliation":[{"name":"Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University , Newcastle upon Tyne NE2 4HH ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7636-0972","authenticated-orcid":false,"given":"Maria J","family":"Perugorria","sequence":"additional","affiliation":[{"name":"Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University , Newcastle upon Tyne NE2 4HH ,","place":["United Kingdom"]},{"name":"Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country , 20014 San Sebastian ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip N","family":"Tsichlis","sequence":"additional","affiliation":[{"name":"Molecular Oncology Research Institute, Tufts Medical Center , Boston, MA 02111"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek A","family":"Mann","sequence":"additional","affiliation":[{"name":"Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University , Newcastle upon Tyne NE2 4HH ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6403-6761","authenticated-orcid":false,"given":"Aristides G","family":"Eliopoulos","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Biology, University of Crete Medical School , 71003 Heraklion, Crete ,","place":["Greece"]},{"name":"Institute of Molecular Biology and Biotechnology, Foundation for Research & Technology-Hellas , 70013 Heraklion, Crete ,","place":["Greece"]},{"name":"Laboratory of Translational Medicine and Experimental Therapeutics, University of Crete Medical School , 71003 Heraklion, Crete ,","place":["Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,5,15]]},"reference":[{"key":"2025030702171287400_r1","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.it.2013.04.005","article-title":"The innate immune response during liver inflammation and metabolic disease","volume":"34","author":"Bieghs","year":"2013","journal-title":"Trends Immunol."},{"key":"2025030702171287400_r2","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.coi.2013.09.008","article-title":"Natural killer T (NKT) cells in autoimmune hepatitis","volume":"25","author":"Mattner","year":"2013","journal-title":"Curr. 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