TY - JOUR
T1 - Negative feedback regulation of lipopolysaccharide-induced inducible nitric oxide synthase gene expression by heme oxygenase-1 induction in macrophages
AU - Ashino, Takashi
AU - Yamanaka, Rieko
AU - Yamamoto, Masayuki
AU - Shimokawa, Hiroaki
AU - Sekikawa, Kenji
AU - Iwakura, Yoichiro
AU - Shioda, Seiji
AU - Numazawa, Satoshi
AU - Yoshida, Takemi
N1 - Funding Information:
We thank R. Kani, M. Kunii and S. Sawada for their technical assistance. This work was supported by a “High-Tech Research Center” Project for Private Universities: matching fund subsidy from MEXT (Ministry of Education, Culture, Sports, Science and Technology) 2007–2009, a Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science and a Showa University Research Grant for Young Researchers from Showa University Research Found.
PY - 2008/4
Y1 - 2008/4
N2 - 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.
AB - 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.
KW - Heme oxygenase-1
KW - Inducible nitric oxide synthase
KW - Lipopolysaccharide
KW - Macrophage
KW - Nuclear-factor erythroid 2-related factor 2
KW - Tumor necrosis factor α
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U2 - 10.1016/j.molimm.2007.10.011
DO - 10.1016/j.molimm.2007.10.011
M3 - Article
C2 - 18022235
AN - SCOPUS:38949110010
VL - 45
SP - 2106
EP - 2115
JO - Immunochemistry
JF - Immunochemistry
SN - 0161-5890
IS - 7
ER -
