[ODP6F] f. 免疫機構・ワクチン開発

[ODP-179] NADPHオキシダーゼおよび一酸化窒素合成酵素による超硫黄種活性化と宿主防御機構

○髙田 剛¹，井田 智章¹，松永 哲郎¹，守田 匡伸¹，土屋 幸弘²，渡邊 泰男²，住本 英樹³，本橋 ほづみ⁴，赤池 孝章¹ (¹東北大院・医・環境医学，²昭和薬大・薬理学，³九州大院・医・生化学，⁴東北大・加齢医学・遺伝子発現制御)

Reactive oxygen species (ROS) and nitric oxide (NO) generated by NADPH oxidase (NOX) and NO synthase (NOS) have important role in the host defense for various pathogens. Our previous report showed a potent anti-bacterial effect of ROS and NO that was identified clearly during Salmonella infection. It is now unexpectedly found that NOS and NOX can transfer the electrons to sulfur rather than oxygen, and super sulfide species like reactive persulfides generated thereby appears to be involved in NOS- and NOX-dependent anti-Salmonella activity. We thus aimed further to elucidate the mechanisms of supersulfide production by NOS and NOX and its anti-bacterial consequences. HEK293T cells overexpressing either three NOS isoforms (nNOS, eNOS, iNOS) or two NOX isoforms (NOX2, NOX4) were treated with oxidized glutathione trisulfide (GS-S-SG), which resulted in a markedly increased reactive persulfides in a manner depending on each enzyme expression. Recombinant nNOS and eNOS in the presence of NADPH reduce GS-S-SG and oxidatively activate (or reactivate) the super sulfide to form persulfides with elongated polysulfide chains (e.g., GS-SH and GS-S-SH) having higher redox activity in vitro. We herein propose a novel function of NOS and NOX as an NADPH-dependent sulfur oxidoreductase (NSOR) to potentiate the host defense functions possibly through activation of various super sulfur species.