Negative feedback regulation of lipopolysaccharide-induced inducible nitric oxide synthase gene expression by heme oxygenase-1 induction in macrophages

Takashi Ashino, Rieko Yamanaka, Masayuki Yamamoto, Hiroaki Shimokawa, Kenji Sekikawa, Yoichiro Iwakura, Seiji Shioda, Satoshi Numazawa, Takemi Yoshida

Research output: Contribution to journalArticlepeer-review

85 Citations (Scopus)

Abstract

Heme oxygenase-1 (HO-1) is induced under infectious diseases in macrophages. We performed experiments using various gene deficient mouse-derived macrophages to determine a detailed induction mechanism of HO-1 by lipopolysaccharide (LPS) and the functional role of HO-1 induction in macrophages. LPS (1 μg/mL) maximally induced inducible nitric oxide synthase (iNOS) and HO-1 mRNAs in wild-type (WT) macrophages at 6 h and 12 h after treatment, respectively, and liberated tumor necrosis factor α (TNFα) from WT macrophages. LPS also induced iNOS and HO-1 in TNFα(-/-) macrophages, but not in iNOS(-/-) macrophages. Interestingly, although LPS strongly induced iNOS, it failed to induce HO-1 almost completely in nuclear-factor erythroid 2-related factor 2 (Nrf2)(-/-) macrophages. The LPS-induced iNOS gene expression was suppressed by pretreatment with HO-1 inducers, hemin and Co-protoporphyrin (CoPP), but not with HO-1 inhibitor, Sn-protoporphyrin in WT macrophages. In the Nrf2(-/-) macrophages, the ability of CoPP to induce HO-1 and its inhibitory effect on the LPS-induced iNOS gene expression were lower than seen in WT macrophages. The present findings suggest that HO-1 is induced via NO-induced nuclear translocation of Nrf2, and the enzymatic function of HO-1 inhibits the overproduction of NO in macrophages.

Original languageEnglish
Pages (from-to)2106-2115
Number of pages10
JournalMolecular Immunology
Volume45
Issue number7
DOIs
Publication statusPublished - 2008 Apr

Keywords

  • Heme oxygenase-1
  • Inducible nitric oxide synthase
  • Lipopolysaccharide
  • Macrophage
  • Nuclear-factor erythroid 2-related factor 2
  • Tumor necrosis factor α

ASJC Scopus subject areas

  • Immunology
  • Molecular Biology

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