{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T08:26:41Z","timestamp":1790670401174,"version":"4.1.0"},"reference-count":47,"publisher":"National Academy of Sciences","issue":"42","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,10,18]]},"abstract":"<jats:p>\n                    Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine that has been implicated in various inflammatory diseases. Chronic inflammation is a mainstay of liver fibrosis, a leading cause of morbidity worldwide, but the role of MIF in liver scarring has not yet been elucidated. Here we have uncovered an unexpected antifibrotic role for MIF. Mice genetically deleted in\n                    <jats:italic>Mif<\/jats:italic>\n                    (\n                    <jats:italic>Mif<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) showed strongly increased fibrosis in two models of chronic liver injury. Pronounced liver fibrosis in\n                    <jats:italic>Mif<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice was associated with alterations in fibrosis-relevant genes, but not by a changed intrahepatic immune cell infiltration. Next, a direct impact of MIF on hepatic stellate cells (HSC) was assessed in vitro. Although MIF alone had only marginal effects on HSCs, it markedly inhibited PDGF-induced migration and proliferation of these cells. The inhibitory effects of MIF were mediated by CD74, which we detected as the most abundant known MIF receptor on HSCs. MIF promoted the phosphorylation of AMP-activated protein kinase (AMPK) in a CD74-dependent manner and, in turn, inhibition of AMPK reversed the inhibition of PDGF-induced HSC activation by MIF. The pivotal role of CD74 in MIF-mediated antifibrotic properties was further supported by augmented liver scarring of\n                    <jats:italic>Cd74<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice. Moreover, mice treated with recombinant MIF displayed a reduced fibrogenic response in vivo. In conclusion, we describe a previously unexplored antifibrotic function of MIF that is mediated by the CD74\/AMPK signaling pathway in HSCs. The results imply MIF and CD74 as targets for treatment of liver diseases.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1107023108","type":"journal-article","created":{"date-parts":[[2011,10,4]],"date-time":"2011-10-04T00:09:41Z","timestamp":1317686981000},"page":"17444-17449","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":144,"title":["Macrophage migration inhibitory factor (MIF) exerts antifibrotic effects in experimental liver fibrosis via CD74"],"prefix":"10.1073","volume":"108","author":[{"given":"Daniel","family":"Heinrichs","sequence":"first","affiliation":[{"name":"Medical Department III and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meike","family":"Knauel","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Cell Biology, Rheinisch-Westf\u00e4lische Technische Hochschule Aachen University, 52074 Aachen, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Offermanns","sequence":"additional","affiliation":[{"name":"Medical Department III and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Luise","family":"Berres","sequence":"additional","affiliation":[{"name":"Medical Department III and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Nellen","sequence":"additional","affiliation":[{"name":"Medical Department III and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Leng","sequence":"additional","affiliation":[{"name":"Rheumatology Section, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Medical Department III and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Bucala","sequence":"additional","affiliation":[{"name":"Rheumatology Section, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Trautwein","sequence":"additional","affiliation":[{"name":"Medical Department III and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Weber","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Prevention, The Ludwig Maximilians University, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Bernhagen","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Cell Biology, Rheinisch-Westf\u00e4lische Technische Hochschule Aachen University, 52074 Aachen, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hermann E.","family":"Wasmuth","sequence":"additional","affiliation":[{"name":"Medical Department III and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,10,3]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)60383-9"},{"key":"e_1_3_3_2_2","first-page":"745","article-title":"Rising incidence of hepatocellular carcinoma in the United States N Engl","volume":"340","author":"El-Serag HB","year":"1999","unstructured":"HB El-Serag, AC Mason, Rising incidence of hepatocellular carcinoma in the United States N Engl. 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