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.
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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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