title: Early release of macrophage migration inhibitory factor after liver ischemia and reperfusion injury in rats.
abstract: Macrophage migration inhibitory factor (MIF) is an important mediator of ischemia/reperfusion (I/R) injury in heart, brain and intestine. We previously demonstrated that MIF was released during warm/cold ischemia in vitro. However, the role of MIF in liver I/R injury remains unclear. We aimed to test the hypothesis that MIF acts as an early proinflammatory cytokine and could mediate the inflammatory injury in liver I/R. Rats (n=6 per group) were subjected to 90 min warm ischemia followed by 0.5h, 6h and 24h reperfusion, respectively to liver transplantation (LTx) after 6h of cold ischemia followed by 24h of reperfusion. The expression of MIF, its receptor (cluster of differentiation 74 (CD74)) and the downstream inflammatory cytokines (tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β)) were analyzed. Peritoneal macrophages were cultured for 6h alone or in the presence of effluent from cold-preserved livers or effluent depleted of MIF. Warm I/R increased hepatic MIF-mRNA and protein expression. MIF-protein was released into peripheral circulation in vivo with a maximum at 0.5h after reperfusion. Induction of MIF-expression was associated with the expression of proinflammatory cytokines and its receptor in both models. MIF released by isolated cold preserved livers, induced TNF-α and IL-1β production by cultured peritoneal macrophages. Intrahepatic upregulation of MIF, release into systemic circulation and the associated upregulation of the proinflammatory mediators suggest a role of MIF in mediating the inflammatory response to I/R injury. Blocking experiments will help to elucidate its role as potential molecular target for preventing hepatic I/R injury.
authors.affiliation: Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, Friedrich-Schiller-University Jena, Jena 07747, Germany.
authors.forename: Anding
authors.initials: A
authors.lastname: Liu
authors.forename: Haoshu
authors.initials: H
authors.lastname: Fang
authors.forename: Olaf
authors.initials: O
authors.lastname: Dirsch
authors.forename: Hao
authors.initials: H
authors.lastname: Jin
authors.forename: Uta
authors.initials: U
authors.lastname: Dahmen
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D007511:Ischemia / Q000097:blood / Q000150:complications / Q000473:pathology*; D008099:Liver / Q000098:blood supply* / Q000473:pathology*; D016031:Liver Transplantation; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000097:blood / Q000150:complications / Q000473:pathology*; D052096:Warm Ischemia
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D018836:Inflammation Mediators; D008263:Macrophage Migration-Inhibitory Factors; D012333:RNA, Messenger; C045084:invariant chain