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

被引：91

作者：

Ashino, Takashi ^{[1
]}

Yamanaka, Rieko ^{[1
]}

Yamamoto, Masayuki ^{[2
,3
]}

Shimokawa, Hiroaki ^{[4
]}

Sekikawa, Kenji ^{[5
]}

Iwakura, Yoichiro ^{[6
]}

Shioda, Seiji ^{[7
]}

Numazawa, Satoshi ^{[1
]}

Yoshida, Takemi ^{[1
]}

机构：

[1] Showa Univ, Sch Pharmaceut Sci, Dept Biochem Toxicol, Shinagawa Ku, Tokyo 1428555, Japan

[2] Tohoku Univ, Sch Med, Dept Med Biochem, Aoba Ku, Sendai, Miyagi 980, Japan

[3] ERATO JST, Aoba Ku, Sendai, Miyagi, Japan

[4] Tohoku Univ, Grad Sch Med, Dept Cardiovasc Med, Sendai, Miyagi 980, Japan

[5] Natl Inst Agrobiol Sci, Dept Mol Biol & Immunol, Tsukuba, Ibaraki, Japan

[6] Univ Tokyo, Inst Med Sci, Ctr Med Expt, Div Cell Biol,Minato Ku, Tokyo, Japan

[7] Showa Univ, Sch Med, Dept Anat, Shinagawa Ku, Tokyo 142, Japan

来源：

MOLECULAR IMMUNOLOGY | 2008年 / 45卷 / 07期

基金：

日本学术振兴会;

关键词：

heme oxygenase-1; inducible nitric oxide synthase; nuclear-factor erythroid 2-related factor 2; lipopolysaccharide; macrophage; tumor necrosis factor alpha;

D O I：

10.1016/j.molimm.2007.10.011

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 mu g/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 alpha (TNF alpha) from WT macrophages. LPS also induced iNOS and HO-1 in TNF alpha(-/-) 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. (C) 2007 Elsevier Ltd. All rights reserved.

引用

页码：2106 / 2115

页数：10

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