Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice: HO-1 dependence of Stat4 disruption-mediated cytoprotection

Shen, Xiu-Da

doi:10.1053/jhep.2003.50066

Cited by 103 publications

(94 citation statements)

References 45 publications

(65 reference statements)

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“…The disruption of TLR4 might interact with a number of pathways that mediate IRI cytotoxicity: 1) by stabilizing cytoprotective antioxidant proteins and preventing cell death by reactive oxygen species; 2) by inhibiting postmitochondrial apoptosis and influencing apoptosome formation 39 ; and 3) by amplifying antiinflammatory/ antiapoptotic pathways, possibly via p38 mitogen-activated protein kinase 40 or signal transducer and activator of transcription (STAT) 6-dependent signaling. 34 In conclusion, the functional sentinel TLR4 complex in the donor organ plays a key role in the mechanism of cold hepatic IRI after OLT. The disruption of TLR4 signaling diminished the early proinflammatory responses and ameliorated hepatic IRI.…”

Section: Tlr4 Deletion In Donor Liver Reduces Iri 1441mentioning

confidence: 93%

“…32,33 Furthermore, we have shown that CD4 ϩ T cells play a major role in the pathogenesis of liver IRI, as signal transducer and activator of transcription4 KO (deficient in Th1 development), but not signal transducer and activator of transcription6 KO, mice were protected from the injury, whereas reconstitution of nude mice with T cells from signal transducer and activator of transcription6 KO, but not signal transducer and activator of transcription4 KO, mice restored liver IRI. 34 Moreover, adoptive transfer of T cells, particularly the CD4 ϩ T subset, readily restored IRI in otherwise T cell-deficient hosts. Recently, we demonstrated that intrahepatic CD4 T cells are enriched in CXCR3ϩ subset represent preactivated Th1 cells.…”

Section: Tlr4 Deletion In Donor Liver Reduces Iri 1441mentioning

confidence: 99%

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Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model

Shen

Zhai

et al. 2007

Liver Transpl

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This study analyzes how toll-like receptor 4 (TLR4) signaling in the donor organ affects the ischemia and reperfusion injury (IRI) sequel following liver transplantation. Isogenic orthotopic liver transplantations (OLTs) with rearterialization were performed in groups of wild-type (WT) and TLR4 knockout (KO) mice after donor liver preservation in University of Wisconsin solution at 4°C for 24 hours. Unlike WT OLTs, TLR4-deficient OLTs transplanted to either WT or TLR4 KO recipients suffered significantly less hepatocellular damage, as evidenced by serum alanine aminotransferase levels, and histological Suzuki's grading of liver IRI. Disruption of TLR4 signaling in OLTs decreased local neutrophil sequestration, CD4 ϩ T cell infiltration, interferon (IFN)-␥-inducible protein 10 (CXCL10) and an intercellular adhesion molecule (ICAM-1), as well as tumor necrosis factor (TNF)-␣, interleukin (IL)-1␤, IL-2, and IFN-␥, yet increased IL-4 and IL-10 expression. The well-functioning OLTs from TLR4 KO donors revealed attenuated activity of capase-3, and enhanced heme oygenase-1 (HO-1) expression, along with decreased levels of apoptotic endothelial cells/hepatocytes, as compared with WT OLTs with intact TLR4 signaling. Thus, the functional sentinel TLR4 complex in the donor organ plays a key role in the mechanism of hepatic IRI after OLT. Disruption of TLR4 pathway downregulated the early proinflammatory responses and ameliorated hepatic IRI. These results provide the rationale to locally modify innate TLR4 signaling in the donor organ to more efficiently control the adaptive posttransplantation IRI-dependent responses. Liver Transpl 13:1435-1443, 2007. © 2007 AASLD. Received February 7, 2007 accepted May 19, 2007.The ischemia and reperfusion injury (IRI), an antigenindependent event, is an unavoidable consequence of liver transplantation. The IRI causes up to 10% of early organ failure, and can lead to a higher incidence of both acute and chronic rejection. Indeed, IRI is more frequently observed with the use of marginal donors or following prolonged cold ischemia times. 1-3 Moreover, IRI contributes to the shortage of livers available for transplantation because of the higher susceptibility of marginal organs to the ischemic insult. Thus, minimizing the impact of IRI could significantly increase the number of patients successfully undergoing liver transplantation. The mechanisms of IRI include activation of Kupffer cells with production of reactive oxygen species, upregulation of the inducible nitric oxide synthase, release of proinflammatory cytokines, increased expres-

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Section: Tlr4 Deletion In Donor Liver Reduces Iri 1441mentioning

confidence: 93%

Section: Tlr4 Deletion In Donor Liver Reduces Iri 1441mentioning

confidence: 99%

Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model

Shen

Zhai

et al. 2007

Liver Transpl

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“…STAT6 deficient mice developed more severe renal injury after ischemia, while STAT4 deficient mice had mildly improved function, suggesting the Th2 cells protect against renal IRI [55]. STAT6 may also protect against liver IRI [56]. Recent data showed that IL-4 but not IL-12 deficient mice developed more severe renal injury after ischemia, also suggesting a protective effect of Th2 cells in IRI [57].…”

Section: Different Roles Of T Cell Subsets In Irimentioning

confidence: 99%

Ischemia–reperfusion and immediate T cell responses

Huang¹,

Rabb²,

Womer³

2007

Cellular Immunology

132

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“…One possibility is that it produces CO. Alternatively, dHO may function in the removal of harmful uncommitted heme and exert an indirect influence. The former idea is supported by studies of mouse HO-1, showing that knockout of HO-1 impaired DNA repair through activation of ATM, including an increase in γ-H2A.X (Shen et al 2003;Otterbein et al 2011). Then, the phosphorylation of ATM in response to anti-cancer drugs was markedly decreased in HO-1-deficient cells, resulting in a marked increase in DNA damage.…”

Section: Discussionmentioning

confidence: 93%

Genetic Link between Heme Oxygenase and the Signaling Pathway of DNA Damage in<i> Drosophila</i> <i>Melanogaster</i>

Ida

Suyari

Shimamura

et al. 2013

Tohoku J. Exp. Med.

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Heme oxygenase (HO) is a rate-limiting step of heme degradation, which catalyzes the conversion of heme into biliverdin, iron, and CO. HO has been characterized in microorganisms, insects, plants, and mammals. The mammalian enzyme participates in adaptive and protective responses to oxidative stress and various inflammatory stimuli. The present study reports that eye imaginal disc-specific knockdown of the Drosophila HO homologue (dHO) conferred serious abnormal eye morphology in adults, resulting in the generation of reactive oxygen species and apoptosis in third-instar larvae. Oxidative stress frequently induces DNA lesions that are recognized by damage sensors, including ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and rad3-related (ATR) proteins. The knockdown of dHO took place in G0/ G1-arrested cells posterior to the morphogenetic furrow and thus prevented these cells from entering S-phase, with an increase in the level of histone H2A.V, a DNA damage marker. Moreover, the knockdown of dHO resulted in the enhancement of the rough eye phenotype in ATM-deficient flies or was lethal in ATR-deficient flies. These results indicate that dHO functions in control of the signal pathway of DNA damage. On the other hand, genetic crosses with a collection of Drosophila deficiency stocks allowed us to identify eight genomic regions, each deletion of which caused suppression of the rough eye phenotype induced by dHO knockdown. This information should facilitate the identification of HO regulators in Drosophila and clarification of the roles of HO in eye development.

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Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice: HO-1 dependence of Stat4 disruption-mediated cytoprotection

Cited by 103 publications

References 45 publications

Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model

Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model

Ischemia–reperfusion and immediate T cell responses

Genetic Link between Heme Oxygenase and the Signaling Pathway of DNA Damage in<i> Drosophila</i> <i>Melanogaster</i>

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