title: HO-1 upregulation suppresses type 1 IFN pathway in hepatic ischemia/reperfusion injury.
abstract: Upregulation of heme oxygenase (HO)-1, a heat shock protein 32, protects against hepatic ischemia/reperfusion (I/R) injury. Activation of "innate" toll-like receptor (TLR) 4 system triggers the I/R injury cascade. This study explores cytoprotective functions of HO-1 overexpression following exogenous administration of cobalt protoporphyrin (CoPP), and its relationship with the TLR4 pathway in a model of mouse partial hepatic warm I/R injury. CoPP treatment markedly improved hepatic function and histology, and suppressed pro-inflammatory cytokine elaboration profile, as compared with untreated controls. Although administration of CoPP did not affect intrahepatic TLR4, it downregulated IFN-inducible protein 10 (IP-10) expression. As IP-10 is the major product of type-1 IFN pathway downstream of TLR4, we then infused recombinant IFN-beta (rIFN-beta) directly into mouse livers. Interestingly, infusion of rIFN-beta upregulated hepatic IP-10 expression. In contrast, adjunctive CoPP treatment decreased IP-10 levels in mouse livers infused with rIFN-beta. Thus, CoPP-induced HO-1 upregulation suppresses type-1 IFN pathway downstream of TLR4 system in hepatic warm I/R injury model.
authors.affiliation: The Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California 90095-7054, USA.
authors.forename: S
authors.initials: S
authors.lastname: Tsuchihashi
authors.forename: Y
authors.initials: Y
authors.lastname: Zhai
authors.forename: C
authors.initials: C
authors.lastname: Fondevila
authors.forename: R W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: J W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
mesh_terms: D000818:Animals; D015415:Biomarkers; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D007370:Interferon Type I / Q000008:administration & dosage / Q000627:therapeutic use*; D008102:Liver Circulation; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D011524:Protoporphyrins / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000032:analysis; D011994:Recombinant Proteins; D015427:Reperfusion Injury / Q000517:prevention & control*; D051197:Toll-Like Receptor 4
chemical_list: D015415:Biomarkers; D007370:Interferon Type I; D008565:Membrane Proteins; D011524:Protoporphyrins; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C007095:cobaltiprotoporphyrin; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse