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Transforming growth factor beta 1 (TGF\u03b21) is elevated during liver injury and influences hepatocyte senescence during APAP-induced hepatotoxicity. This study investigated TGF\u03b21 signaling in the context of inflammation, necrotic cell death, and oxidative stress during APAP-induced liver injury. Male C57Bl\/6 mice were injected with 600 mg\/kg APAP to generate liver injury in the presence or absence of the TGF\u03b2 receptor 1 inhibitor, GW788388, 1 h prior to APAP administration. Acetaminophen-induced liver injury was characterized using histological and biochemical measures. Transforming growth factor beta 1 expression and signal transduction were assessed using immunohistochemistry, Western blotting and ELISA assays. Hepatic necrosis, liver injury, cell proliferation, hepatic inflammation, and oxidative stress were assessed in all mice. Acetaminophen administration significantly induced necrosis and elevated serum transaminases compared with control mice. Transforming growth factor beta 1 staining was observed in and around areas of necrosis with phosphorylation of SMAD3 observed in hepatocytes neighboring necrotic areas in APAP-treated mice. Pretreatment with GW788388 prior to APAP administration in mice reduced hepatocyte cell death and stimulated regeneration. Phosphorylation of SMAD3 was reduced in APAP mice pretreated with GW788388 and this correlated with reduced hepatic cytokine production and oxidative stress. These results support that TGF\u03b21 signaling plays a significant role in APAP-induced liver injury by influencing necrotic cell death, inflammation, oxidative stress, and hepatocyte regeneration. In conclusion, targeting TGF\u03b21 or downstream signaling may be a possible therapeutic target for the management of APAP-induced liver injury.<\/jats:p>","DOI":"10.1093\/toxsci\/kfz122","type":"journal-article","created":{"date-parts":[[2019,5,16]],"date-time":"2019-05-16T19:16:50Z","timestamp":1558034210000},"page":"549-561","source":"Crossref","is-referenced-by-count":16,"title":["The TGF\u03b21 Receptor Antagonist GW788388 Reduces JNK Activation and Protects Against Acetaminophen Hepatotoxicity in Mice"],"prefix":"10.1093","volume":"170","author":[{"given":"Matthew","family":"McMillin","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, Texas 78712"},{"name":"Central Texas Veterans Health Care System, Austin, Texas, 78712"},{"name":"Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas, 76504"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Grant","sequence":"additional","affiliation":[{"name":"Central Texas Veterans Health Care System, Austin, Texas, 78712"},{"name":"Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas, 76504"},{"name":"Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Austin, Texas, 78712"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriel","family":"Frampton","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, Texas 78712"},{"name":"Central Texas Veterans Health Care System, Austin, Texas, 78712"},{"name":"Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas, 76504"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anca D","family":"Petrescu","sequence":"additional","affiliation":[{"name":"Central Texas Veterans Health Care System, Austin, Texas, 78712"},{"name":"Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas, 76504"},{"name":"Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Austin, Texas, 78712"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elaina","family":"Williams","sequence":"additional","affiliation":[{"name":"Central Texas Veterans Health Care System, Austin, Texas, 78712"},{"name":"Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas, 76504"},{"name":"Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Austin, Texas, 78712"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brandi","family":"Jefferson","sequence":"additional","affiliation":[{"name":"Central Texas Veterans Health Care System, Austin, Texas, 78712"},{"name":"Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas, 76504"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharon","family":"DeMorrow","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, Texas 78712"},{"name":"Central Texas Veterans Health Care System, Austin, Texas, 78712"},{"name":"Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas, 76504"},{"name":"Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Austin, Texas, 78712"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,5,27]]},"reference":[{"key":"2019103013315385600_kfz122-B1","doi-asserted-by":"crossref","first-page":"27678","DOI":"10.1074\/jbc.272.44.27678","article-title":"TbetaRI phosphorylation of Smad2 on Ser465 and Ser467 is required for Smad2-Smad4 complex formation and signaling","volume":"272","author":"Abdollah","year":"1997","journal-title":"J. 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