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


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.


CONCLUSIONS
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.
Tsuchihashi
Sei-ichiro
S
The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-7054, USA.
Zhai
Yuan
Y
Bo
Qiao
Q
Busuttil
Ronald W
RW
Kupiec-Weglinski
Jerzy W
JW
D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002460:Cell Line; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000187:drug effects / Q000378:metabolism; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D007370:Interferon Type I / Q000037:antagonists & inhibitors* / Q000502:physiology; D007511:Ischemia / Q000473:pathology / Q000517:prevention & control*; D008099:Liver / Q000201:enzymology*; D008107:Liver Diseases / Q000473:pathology / Q000517:prevention & control*; D008264:Macrophages / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011524:Protoporphyrins / Q000494:pharmacology; D015427:Reperfusion Injury / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; C485433:Cxcl10 protein, mouse; D007370:Interferon Type I; D011524:Protoporphyrins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C007095:cobaltiprotoporphyrin; D051547:Heme Oxygenase-1; D007041:Hypoxanthine Phosphoribosyltransferase; D001219:Aspartate Aminotransferases