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 antioxidant in studies examining gene expression, signaling pathways, and outcome in acute and chronic models of lung injury. It is less widely appreciated that NAC can also undergo auto-oxidation and behave as an oxidant. We showed previously that NAC can have opposite effects on the activation of nuclear 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 serum), NAC substantially inhibited lipopolysaccharide (LPS) activation of the mitogen-activated protein kinases (MAPKs), namely extracellular signal-regulated kinase (ERK), p38(mapk), and c-jun NH2-terminal kinase (JNK). By contrast, 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 phosphorylation. Because serum can significantly alter the redox state, these findings highlight the importance of the local redox milieu in signal transduction.