Interleukin 13 gene transfer in liver ischemia and reperfusion injury: role of Stat6 and TLR4 pathways in cytoprotection

Hum Gene Ther. 2004 Jul;15(7):691-8. doi: 10.1089/1043034041361244.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cytoprotection
  • Gene Transfer Techniques
  • Heme Oxygenase (Decyclizing) / genetics
  • Heme Oxygenase (Decyclizing) / metabolism
  • Heme Oxygenase-1
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Interleukin-1 / genetics
  • Interleukin-1 / metabolism
  • Interleukin-13 / biosynthesis
  • Interleukin-13 / genetics*
  • Interleukin-2 / genetics
  • Interleukin-2 / metabolism
  • Liver / blood supply*
  • Liver / pathology
  • Liver Transplantation*
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Reperfusion Injury / genetics
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / prevention & control*
  • STAT6 Transcription Factor
  • Toll-Like Receptor 4
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Up-Regulation


  • Interleukin-1
  • Interleukin-13
  • Interleukin-2
  • Membrane Proteins
  • RNA, Messenger
  • Receptors, Cell Surface
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Trans-Activators
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • Hmox1 protein, mouse