細菌感染における酸化ストレスシグナル制御と感染防御論  [in Japanese] Host defense and oxidative stress signaling in bacterial infection  [in Japanese]

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Author(s)

    • 赤池 孝章 AKAIKE Takaaki
    • 東北大学大学院医学系研究科環境保健医学分野 Department of Environmental Health Sciences and Molecular Toxicology, Tohoku University Graduate School of Medicine

Abstract

一酸化窒素(nitric oxide, NO)や活性酸素種(reactive oxygen species, ROS)は, 非特異的感染防御機構において重要な役割を演じている。細菌, ウイルス, 真菌といった病原体の種類の如何に関わらず, 感染病態においては, 誘導型NO合成酵素(inducible NO synthase, iNOS)が誘導される。iNOSは, 病原体の持つ様々な菌体由来成分が, 対応する病原体分子パターン認識受容体群(pattern recognition receptors)であるToll-like receptorによって認識されることによって誘導され, さらに感染に伴って産生される炎症性サイトカインやインターフェロンなどによって相乗的に誘導が増強される。iNOS誘導に伴って過剰に産生されたNOは, 感染局所のROSと反応し, パーオキシナイトライトなどの化学反応性に富んだ活性酸化窒素種となり, 特に細菌感染において, 強力な抗菌活性を発揮し, マクロファージ等の貪食細胞による自然免疫と感染防御機能に重要な役割を演じている。その反面, NOやROSは, 宿主の細胞・組織を損傷し酸化ストレスをもたらす。一方近年, NOとROSが生体の酸化ストレス応答の生理的なレドックスメディエーターとして機能していることが明らかになってきた。NOとROSによるレドックスシグナル制御は多岐にわたっており, 感染防御機構と感染・炎症が関わる病態を理解する上で重要な課題であるだけでなく, 感染症の新たな予防・治療戦略の構築に大きく貢献するであろう。

Nitric oxide (NO) and reactive oxygen species (ROS) produced during infection are involved critically in host defense mechanisms. It is quite important to physiologically regulate ROS, such as superoxide, and NO. These reactive species produced in excess may cause oxidative damage of biological molecules. An important cytoprotective and antimicrobial function of NO and ROS is mediated by induction of heme oxygenase (HO)-1. The signaling mechanism of this HO-1 induction has remained unclear, however. We discovered in 2007 a unique second messenger, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), that mediates electrophilic signal transduction during oxidative stress and other cellular redox signaling in general. 8-Nitro-cGMP is formed via guanine nitration with NO and ROS, and in fact, NO-dependent 8-nitro-cGMP formation and HO-1 induction were identified in <i>Salmonella</i>-infected mice. HO-1 induction was regulated solely by 8-nitro-cGMP formed in cells, and more important, its potent anti-apoptotic function was evident in such a <i>Salmonella</i> infection. 8-Nitro-cGMP has a potent cytoprotective function, of which signaling appears to be mediated via protein sulfhydryls to generate a post-translational modification called protein S-guanylation. 8-Nitro-cGMP specifically <i>S</i>-guanylates Keap1, a negative regulator of transcription factor Nrf2, which in turn up-regulates transcription of HO-1. Our recent study revealed that the autophagy might be involved in the 8-nitro-cGMP-dependent antimicrobial effect. The 8-nitro-cGMP signaling was also found to be regulated by reactive sulfur species that have superior antioxidant activity and unique signaling function. This review will discuss a new paradigm of the host defense that operates via formation of a unique cell signaling molecule, 8-nitro-cGMP, during microbial infections.

Journal

  • Nippon Saikingaku Zasshi

    Nippon Saikingaku Zasshi 70(3), 339-349, 2015

    JAPANESE SOCIETY FOR BACTERIOLOGY

Codes

  • NII Article ID (NAID)
    130005094695
  • Text Lang
    JPN
  • ISSN
    0021-4930
  • Data Source
    J-STAGE 
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