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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Heme Oxygenase-1 Alleviates Mouse Hepatic Failure through Suppression of Adaptive Immune Responses

Qiaoli Gu, Qiong Wu, Min Jin, Yichuan Xiao, Jingwei Xu, Chaoming Mao, Fang Zhao, Yi Zhang and Yanyun Zhang
Journal of Pharmacology and Experimental Therapeutics January 2012, 340 (1) 2-10; DOI: https://doi.org/10.1124/jpet.111.186551
Qiaoli Gu
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Qiong Wu
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Min Jin
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Yichuan Xiao
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Jingwei Xu
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Chaoming Mao
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Fang Zhao
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Yi Zhang
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Yanyun Zhang
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Abstract

Heme oxygenase-1 (HO-1) has protective effects on liver damage induced by noxious stimuli. The mechanism of action of HO-1 is not well understood. In the present study, we investigate the effect of HO-1 in a model of fulminant hepatic failure induced by Propionibacterium acnes and lipopolysaccharide (LPS). The expression of HO-1 mRNA and protein in the liver was increased after repeated administration of the HO-1 inducer cobalt protoporphyrin IX. We found that HO-1 protected mice from acute liver damage induced by P. acnes/LPS and prolonged survival. On the contrary, administration of the HO-1 inhibitor zinc protoporphyrin IX increased liver damage induced by P. acnes/LPS. Subsequently, to investigate the underlying mechanisms of HO-1 in the acute liver injury model, we primed mice with P. acnes only. We found that the expression of HO-1 mRNA and protein in dendritic cells (DCs) was increased after the administration of cobalt protoporphyrin IX. HO-1 decreased the mature markers major histocompatibility complex II and CD80 on liver DCs. The expression of CCR7, CCL2, and CCL22 mRNA, which are expressed by mature DCs, was also reduced. These liver DCs could not efficiently stimulate CD4+ T cell activation and proliferation. Consequently, HO-1 inhibited the activation, proliferation, and T helper 1 polarization of liver-infiltrating CD4+ T cells and reduced the production of serum alanine aminotransferase and proinflammatory cytokines such as interferon-γ and tumor necrosis factor-α. Taken together, our data suggest that HO-1 alleviates P. acnes/LPS-induced fulminant hepatic failure, probably by inhibiting DC-induced adaptive responses.

Footnotes

  • This work was supported by the Ministry of Science and Technology of China [Grants 2011CB966200, 2010CB945600]; the National Natural Science Foundation of China [Grants 30670911, 30901317]; the Knowledge Innovation Project of The Chinese Academy of Sciences [Grants KSCX2-YW-R-245, KSCX2-YW-R-175]; and the Leading Academic Discipline Project of Shanghai Municipal Education Commission [Grant J50207].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.186551.

  • ABBREVIATIONS:

    FHF
    fulminant hepatic failure
    ALT
    alanine aminotransferase
    BM
    bone marrow
    BrdU
    5-bromo-2′-deoxyuridine
    CO
    carbon monoxide
    CoPPIX
    cobalt protoporphyrin IX
    CIITA
    major histocompatibility complex class II transcription activator
    CT
    cycle threshold
    DC
    dendritic cell
    FACS
    fluorescence-activated cell sorting
    FBS
    fetal bovine serum
    FITC
    fluorescein isothiocyanate
    HO
    heme oxygenase
    IFN-1
    interferon-γ
    IL
    interleukin
    LPS
    lipopolysaccharide
    MACS
    magnetic cell sorting
    MHC
    major histocompatibility complex
    MLR
    mixed lymphocyte reaction
    MNC
    mononuclear cell
    NO
    nitric oxide
    NOS
    NO synthase
    PBS
    phosphate-buffered saline
    PCR
    polymerase chain reaction
    PE
    phosphatidylethanolamine
    STAT-1
    signal transducer and activator of transcription 1
    Th1
    T helper 1
    TNF-α
    tumor necrosis factor-α
    Treg
    regulatory T cell
    ZnPPIX
    zinc protoporphyrin IX.

  • Received August 2, 2011.
  • Accepted September 22, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 1
1 Jan 2012
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Immunomodulatory Capacity of HO-1 in Liver Damage

Qiaoli Gu, Qiong Wu, Min Jin, Yichuan Xiao, Jingwei Xu, Chaoming Mao, Fang Zhao, Yi Zhang and Yanyun Zhang
Journal of Pharmacology and Experimental Therapeutics January 1, 2012, 340 (1) 2-10; DOI: https://doi.org/10.1124/jpet.111.186551

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Immunomodulatory Capacity of HO-1 in Liver Damage

Qiaoli Gu, Qiong Wu, Min Jin, Yichuan Xiao, Jingwei Xu, Chaoming Mao, Fang Zhao, Yi Zhang and Yanyun Zhang
Journal of Pharmacology and Experimental Therapeutics January 1, 2012, 340 (1) 2-10; DOI: https://doi.org/10.1124/jpet.111.186551
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