title: Interleukin 13 gene transfer in liver ischemia and reperfusion injury: role of Stat6 and TLR4 pathways in cytoprotection.
abstract: Ischemia and reperfusion injury (IRI) represents the major problem in clinical liver transplantation. We have shown that transcription of signal transducer and activator of transcription 4 (Stat4) plays a key role in the mechanism of hepatic IRI, whereas local induction of interleukin 13 (IL-13) is cytoprotective. The disruption of innate Toll-like receptor 4 (TLR4) signaling prevents mouse livers from undergoing fulminant IRI. This study analyzes in vivo interplay between innate (TLR4) and adaptive (Stat6) immunity in Ad-IL-13 (recombinant adenovirus encoding IL-13) cytoprotection in hepatic IRI. Using a partial 90-min lobar warm ischemia model, groups of wild-type and Stat6-deficient knockout mice were assessed for the severity of hepatocellular damage at 6 hr postreperfusion. Unlike in wild-type mice, treatment of Stat6 knockout recipients with Ad-IL-13 failed to improve hepatic function/histology. The expression of mRNAs encoding tumor necrosis factor alpha/IL-1 beta and IL-2/interferon gamma remained depressed in the wild-type plus Ad-IL-13 group, but not in the Stat6 knockout plus Ad-IL-13 group. Ad-IL-13 increased antioxidant heme oxygenase 1 (HO-1) expression and prevented TLR4 activation in livers of Stat6-competent (wild-type) mice. In contrast, low HO-1 expression and enhanced TLR4 expression were recorded in Stat6 knockout recipients despite Ad-IL-13 therapy. Thus (1) Stat6 is required for Ad-IL-13 to prevent IRI, and (2) depression of TLR4 activation is Stat6 dependent. In conclusion, the Stat6 pathway operates as a key negative regulator in the hepatic inflammatory ischemia-reperfusion response. This study outlines requirements for Ad-IL-13 use to maximize the organ donor pool through the use of liver transplants despite prolonged ischemia.
authors.affiliation: Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplant Center, Department of Surgery, and David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Bibo
authors.initials: B
authors.lastname: Ke
authors.forename: Xiu-Da
authors.initials: XD
authors.lastname: Shen
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
mesh_terms: D000818:Animals; D019610:Cytoprotection; D018014:Gene Transfer Techniques; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D018793:Interleukin-13 / Q000096:biosynthesis / Q000235:genetics*; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000098:blood supply* / Q000473:pathology; D016031:Liver Transplantation; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D050800:STAT6 Transcription Factor; D051197:Toll-Like Receptor 4; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D007375:Interleukin-1; D018793:Interleukin-13; D007376:Interleukin-2; D008565:Membrane Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse