2003 Fiscal Year Final Research Report Summary

Re-evaluation of the role of reactive oxygen species in NP-kB signaling

Research Project

Project/Area Number	14572073
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Single-year Grants
Section	一般
Research Field	Biological pharmacy
Research Institution	Tokyo University of Pharmacy and Life Science
Principal Investigator	HAYAKAWA Makio Tokyo Univ.Pharm.& Life Sci., Dept.Pharm., Associate Professor, 薬学部, 助教授 (30198824)
Project Period (FY)	2002 – 2003
Keywords	NF-kB / IkB / reactive oxygen species / antioxidant / Rac / NADPH oxidase / NAC / PDTC
Research Abstract	It has been postulated that reactive oxygen species(ROS)may act as the second messengers leading to NP-kB activation.This hypothesis is mainly based on the findings that N-acetyl-L-cysteine(NAC) and pyrrolidine dithiocarbamate (PDTC), compounds recognized as potential antioxidants, can inhibit NF-kB activation in a wide variety of cell types.Here we reveal that both NAC and PDTC inhibit NF-KB activation independently of antioxidative function. NAG selectively blocks TNF-induced signaling by lowering the affinity of receptor to TNF.PDTC inhibits the IkB-ubiquitin ligase activity in the cell-free system where extracellular-stimuli-regulated ROS production does not occur.Furthermore, we present the evidence that endogenous ROS produced through Rac/NADPH oxidase do not mediate NF-kB signaling but instead they lower the magnitude of its activation.