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

Sei Ichiro Tsuchihashi, Yuan Zhai, Qiao Bo, Ronald W. Busuttil, Jerzy W. Kupiec-Weglinski

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

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-β to stimulate CXCL-10 production via TLR4 pathway in vitro. Indeed, CoPP-induced HO-1 suppressed otherwise highly upregulated rIFN-β-triggered CXCL-10. Moreover, consistent with our in vitro data, CoPP pretreatment diminished rIFN-β-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.

Original languageEnglish (US)
Pages (from-to)1628-1634
Number of pages7
JournalTransplantation
Volume83
Issue number12
DOIs
StatePublished - Jun 2007

Keywords

  • Heme oxygenase-1
  • IFN-inducible protein 10
  • Ischemia/reperfusion injury
  • Signal transducers and activators of transcription-1
  • Toll-like receptor

ASJC Scopus subject areas

  • Transplantation

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