Cytotoxic and cytoprotective actions of O2- and NO (ONOO-) are determined both by cellular GSH level and HO activity in macrophages.
Survival of macrophages, which serve as the first-line defense against invading pathogens by invoking the overproduction of highly toxic peroxynitrite (ONOO-), depends on their ability to maintain the intracellular GSH level and to induce the expression of heme oxygenase-1 (HO-1). The ONOO- is produced by macrophages stimulated by pathogens and is a powerful oxidant reacting directly with cellular GSH and proteins, killing both invading pathogens and macrophages themselves. However, macrophages can survive the toxicity of ONOO- by replenishing the depleted GSH level and by inducing HO-1 expression. In macrophages exposed to conditions overproducing O2-, NO, or ONOO-, the cellular level of GSH decreased rapidly, and when excessive, cells died. However, in cells surviving the toxicity caused by lower doses of O2-, NO, or ONOO-, the depleted intracellular GSH level was replenished, and HO-1 expression was increased, but not when they were coexposed to an inhibitor of HO-1 activity. Cells exposed to an inhibitor of GSH synthesis had greater induction of HO-1 expression and survived. However, cells exposed to an inhibitor of HO-1 activity died extensively and could not be revived by addition of N-acetylcysteine (NAC), a precursor of GSH synthesis. Thus, the dichotomous cytotoxic or cytoprotective effects of O2-, NO, or ONOO- in macrophages are determined both by cellular GSH level and by HO-1 activity.
Srisook
Klaokwan
K
Department of Pharmacology and Toxicology, Medicinal Toxicology Center, College of Medicine, Inha University, Inchon, South Korea.
Kim
Chaekyun
C
Cha
Young-Nam
YN
D000818:Animals; D002460:Cell Line; D005978:Glutathione / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*
D013481:Superoxides; D009569:Nitric Oxide; D006419:Heme Oxygenase (Decyclizing); D005978:Glutathione