{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T15:19:29Z","timestamp":1778253569420,"version":"3.51.4"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2015,1,30]],"date-time":"2015-01-30T00:00:00Z","timestamp":1422576000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2015,1,30]],"date-time":"2015-01-30T00:00:00Z","timestamp":1422576000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2015,3]]},"abstract":"<jats:p>Molecular factors driving immune\u2010mediated inflammation in the liver are incompletely understood. The transcription factor, cyclic adenosine monophosphate\u2010responsive element modulator alpha (CREM\u03b1) can endorse differentiation of T lymphocytes toward T\u2010helper (Th)17 cells, thereby promoting autoimmunity in systemic lupus erythematosus or lung inflammation. To investigate the role of CREM\u03b1 in liver disease, we subjected transgenic (Tg) mice overexpressing CREM\u03b1 under control of the CD2 promoter (crem<jats:sup>tg<\/jats:sup>mice), which restrains expression mainly to lymphocytes (T, natural killer [NK], and NKT cells), to acute and chronic liver injury models. Already in steady state, Tg CREM\u03b1 overexpression broadly reduced hepatic immune cell numbers by decreasing their viability, but did not affect immune cell migration or the fibrogenic response to chronic liver injury. Strikingly, crem<jats:sup>tg<\/jats:sup>mice developed more severe immune\u2010mediated hepatitis with a higher mortality rate, compared to wild\u2010type (wt) mice, upon concanavalin A (ConA) administration. Unlike in T cells from spleen, CREM\u03b1 overexpression did not induce a predominant Th17 response in intrahepatic T cells, given that hepatic crem<jats:sup>tg<\/jats:sup>CD4<jats:sup>+<\/jats:sup>T cells expressed less interleukin (IL)\u201017 than wt T cells. Reconstitution of<jats:italic toggle=\"yes\">Rag1\u2212\/\u2212<\/jats:italic>mice with<jats:italic toggle=\"yes\">Crem\u2212\/\u2212<\/jats:italic>T cells did not ameliorate ConA hepatitis. Overexpression of CREM\u03b1 did not influence NK and NKT\u2010cell effector functions either. Interestingly, a subset of monocytic myeloid\u2010derived suppressor cells (MDSCs) also expressed CD2 and CREM\u03b1. Crem<jats:sup>tg<\/jats:sup>MDSCs isolated from liver expressed reduced inducible nitric oxide synthase and arginase 1 and displayed a reduced T\u2010cell suppressive activity. The adoptive transfer of wt MDSCs was capable of reducing the fulminant immune\u2010mediated liver damage in crem<jats:sup>tg<\/jats:sup>mice to wt level.<jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: These results suggest compartmental differences of T cell activation pathways between liver and other organs in autoimmunity and define a functional role of CREM\u03b1 in hepatic monocytic MDSCs for the pathogenesis of immune\u2010mediated liver disease. (H<jats:sc>epatology<\/jats:sc>2015;61:990\u20131002)<\/jats:p>","DOI":"10.1002\/hep.27571","type":"journal-article","created":{"date-parts":[[2014,10,20]],"date-time":"2014-10-20T09:55:28Z","timestamp":1413798928000},"page":"990-1002","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":30,"title":["Cyclic adenosine monophosphate\u2013responsive element modulator alpha overexpression impairs function of hepatic myeloid\u2010derived suppressor cells and aggravates immune\u2010mediated hepatitis in mice"],"prefix":"10.1097","volume":"61","author":[{"given":"Linda","family":"Hammerich","sequence":"first","affiliation":[{"name":"Department of Medicine III,RWTH University\u2010Hospital Aachen,Aachen,Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaudia Theresa","family":"Warzecha","sequence":"additional","affiliation":[{"name":"Department of Medicine III,RWTH University\u2010Hospital Aachen,Aachen,Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Stefkova","sequence":"additional","affiliation":[{"name":"Department of Medicine III,RWTH University\u2010Hospital Aachen,Aachen,Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Bartneck","sequence":"additional","affiliation":[{"name":"Department of Medicine III,RWTH University\u2010Hospital Aachen,Aachen,Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kim","family":"Ohl","sequence":"additional","affiliation":[{"name":"Department of Pediatrics,RWTH University\u2010Hospital Aachen,Aachen,Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikolaus","family":"Gassler","sequence":"additional","affiliation":[{"name":"Institute of Pathology,RWTH University\u2010Hospital Aachen,Aachen,Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom","family":"Luedde","sequence":"additional","affiliation":[{"name":"Department of Medicine III,RWTH University\u2010Hospital Aachen,Aachen,Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Trautwein","sequence":"additional","affiliation":[{"name":"Department of Medicine III,RWTH University\u2010Hospital Aachen,Aachen,Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaus","family":"Tenbrock","sequence":"additional","affiliation":[{"name":"Department of Pediatrics,RWTH University\u2010Hospital Aachen,Aachen,Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"Tacke","sequence":"additional","affiliation":[{"name":"Department of Medicine III,RWTH University\u2010Hospital 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