Redox paradox: Effect of N-acetylcysteine and serum on oxidation reduction-sensitive mitogen-activated protein kinase signaling pathways

The thiol reducing agent N-acetylcysteine (NAC) is commonly used as an "ant ioxidant" in studies examining gene expression, signaling pathways, and out come in acute and chronic models of lung injury. It is less widely apprecia ted that NAC can also undergo auto-oxidation and behave as an oxidant. We s howed previously that NAC can have opposite effects on the activation of nu clear factor-kappaB depending on whether or not serum is present, and that the effects of NAC in the absence of serum are mimicked by various oxidants . Here we show that in a serum-depleted environment (0.1% fetal bovine seru m), NAC substantially inhibited lipopolysaccharide (LPS) activation of the mitogen-activated protein kinases (MAPKs), namely extracellular signal-regu lated kinase (ERK), p38(mapk), and c-jun NH2-terminal kinase (JNK). By cont rast, in the presence of 10% serum, NAC had no effect on LPS activation of p42 and p44 ERK and in fact enhanced LPS induction of p38(mapk) and JNK pho sphorylation. Because serum can significantly alter the redox state, these findings highlight the importance of the local redox milieu in signal trans duction.