Heme oxygenase-1 mediated cytoprotection against liver ischemia and reperfusion injury: inhibition of type-1 interferon signaling

Transplantation. 2007 Jun 27;83(12):1628-34. doi: 10.1097/01.tp.0000266917.39958.47.

Abstract

Background: Toll-like receptor (TLR)-4 signaling plays a key role in initiating exogenous antigen-independent innate immunity-dominated liver ischemia/reperfusion injury (IRI). Heme oxygenase (HO)-1, a heat-shock protein 32, exerts potent adaptive anti-oxidant and anti-inflammatory functions. Signal transducers and activator of transcription (STAT)-1 activation triggers interferon (IFN)-inducible protein 10 (CXCL-10), one of major products of type-1 IFN pathway downstream of TLR4. This study focuses on the role of type-1 IFN pathway in the mechanism of HO-1 cytoprotection during liver IRI.

Methods and results: Cobalt protoporphyrin (CoPP)-induced HO-1 overexpression ameliorated liver damage in a well-defined mouse model of liver warm IRI, as evidenced by improved hepatic function (serum alanine aminotransferase levels) and liver histology (Suzuki's scores). HO-1 downregulated phospho-STAT-1 and its key product, CXCL-10. In contrast, TLR4 expression remained elevated regardless of the IRI status. To dissect the mechanism of HO-1 upon CXCL-10, we cultured RW 264.7 (macrophage) cells with exogenous rIFN-beta to stimulate CXCL-10 production via TLR4 pathway in vitro. Indeed, CoPP-induced HO-1 suppressed otherwise highly upregulated rIFN-beta-triggered CXCL-10. Moreover, consistent with our in vitro data, CoPP pretreatment diminished rIFN-beta-induced CXCL-10 production in normal mouse livers.

Conclusion: Hepatic IRI activates TLR4 signaling in vivo to elaborate CXCL-10. HO-1 overexpression downregulates activation of STAT1 via type-1 IFN pathway downstream of TLR4, which in turn decreases CXCL-10 production. This study provides evidence for a novel mechanism by which HO-1 exerts adaptive cytoprotective and anti-inflammatory functions in the context of innate TLR4 activation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aspartate Aminotransferases / blood
  • Cell Line
  • Chemokine CXCL10
  • Chemokines, CXC / genetics
  • Enzyme Induction / drug effects
  • Heme Oxygenase-1 / biosynthesis*
  • Heme Oxygenase-1 / drug effects
  • Heme Oxygenase-1 / metabolism
  • Hypoxanthine Phosphoribosyltransferase / genetics
  • Interferon Type I / antagonists & inhibitors*
  • Interferon Type I / physiology
  • Ischemia / pathology
  • Ischemia / prevention & control*
  • Liver / enzymology*
  • Liver Diseases / pathology
  • Liver Diseases / prevention & control*
  • Macrophages / enzymology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Protoporphyrins / pharmacology
  • Reperfusion Injury / prevention & control*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology
  • Toll-Like Receptor 4 / metabolism

Substances

  • Chemokine CXCL10
  • Chemokines, CXC
  • Cxcl10 protein, mouse
  • Interferon Type I
  • Protoporphyrins
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • cobaltiprotoporphyrin
  • Heme Oxygenase-1
  • Hypoxanthine Phosphoribosyltransferase
  • Aspartate Aminotransferases