Cytosolic NADP(+)-dependent isocitrate dehydrogenase protects macrophages from LPS-induced nitric oxide and reactive oxygen species.
Macrophages activated by microbial lipopolysaccharides (LPS) produce bursts of nitric oxide and reactive oxygen species (ROS). Redox protection systems are essential for the survival of the macrophages since the nitric oxide and ROS can be toxic to them as well as to pathogens. Using suppression subtractive hybridization (SSH) we found that cytosolic NADP(+)-dependent isocitrate dehydrogenase (IDPc) is strongly upregulated by nitric oxide in macrophages. The levels of IDPc mRNA and of the corresponding enzymatic activity were markedly increased by treatment of RAW264.7 cells or peritoneal macrophages with LPS or SNAP (a nitric oxide donor). Over-expression of IDPc reduced intracellular peroxide levels and enhanced the survival of H2O2- and SNAP-treated RAW264.7 macrophages. IDPc is known to generate NADPH, a cellular reducing agent, via oxidative decarboxylation of isocitrate. The expression of enzymes implicated in redox protection, superoxide dismutase (SOD) and catalase, was relatively unaffected by LPS and SNAP. We propose that the induction of IDPc is one of the main self-protection mechanisms of macrophages against LPS-induced oxidative stress.
Maeng
Oky
O
Department of Biology, Chungnam National University, Daejeon, Republic of Korea.
Kim
Yong Chan
YC
Shin
Han-Jae
HJ
Lee
Jie-Oh
JO
Huh
Tae-Lin
TL
Kang
Kwang-il
KI
Kim
Young Sang
YS
Paik
Sang-Gi
SG
Lee
Hayyoung
H
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D007521:Isocitrate Dehydrogenase / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology*
D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D007521:Isocitrate Dehydrogenase; C039355:isocitrate dehydrogenase (NADP+)