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Nitric oxide negatively regulates c-Jun N-terminal kinase/stress-activated protein kinase by means of S-nitrosylation.

Park, HS; Huh, SH; Kim, MS; Lee, SH; Choi, EJ
Proceedings of the National Academy of Sciences of the United States of America, 97(26):14382-14387, 2000
Journal Title
Proceedings of the National Academy of Sciences of the United States of America
NO, produced from l-arginine in a reaction catalyzed by NO synthase, is an endogenous free radical with multiple functions in mammalian cells. Here, we demonstrate that endogenously produced NO can suppress c-Jun N-terminal kinase (JNK) activation in intact cells. Treatment of BV-2 murine microglial cells with IFN-gamma induced endogenous NO production, concomitantly suppressing JNK1 activation. Similarly, IFN-gamma induced suppression of JNK1 activation in RAW264.7 murine macrophage cells and rat alveolar macrophages. The IFN-gamma-induced suppression of JNK1 activation in BV-2, RAW264.7, or rat alveolar macrophage cells was completely prevented by N(G)-nitro-l-arginine, a NO synthase inhibitor. Interestingly, the IFN-gamma-induced suppression of JNK1 activation was not affected by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of guanylyl cyclase. 8-Bromo-cGMP, a membrane-permeant analogue of cGMP, did not change JNK1 activation in intact cells either. In contrast, S-nitro-N-acetyl-dl-penicillamine (SNAP), a NO donor, inhibited JNK1 activity in vitro. Furthermore, a thiol reducing agent, DTT, reversed not only the in vitro inhibition of JNK1 activity by SNAP but also the in vivo suppression of JNK1 activity by IFN-gamma. Substitution of serine for cysteine-116 in JNK1 abolished the inhibitory effect of IFN-gamma or SNAP on JNK1 activity in vivo or in vitro, respectively. Moreover, IFN-gamma enhanced endogenous S-nitrosylation of JNK1 in RAW264.7 cells. Collectively, our data suggest that endogenous NO mediates the IFN-gamma-induced suppression of JNK1 activation in macrophage cells by means of a thiol-redox mechanism.
MeSH terms
AnimalsCell LineCells, CulturedCyclic GMP/metabolismCysteine/metabolismEnzyme ActivationHumansInterferon-gamma/metabolism/pharmacologyJNK Mitogen-Activated Protein Kinases*MAP Kinase Kinase 4*MAP Kinase Kinase Kinase 1Macrophages/cytology/drug effectsMaleMiceMitogen-Activated Protein Kinase 8Mitogen-Activated Protein Kinase KinasesMitogen-Activated Protein Kinases/*metabolismNitric Oxide/*metabolismNitric Oxide Donors/*metabolism/pharmacologyOxidation-ReductionPenicillamine/*analogs & derivatives/*metabolism/pharmacologyProtein-Serine-Threonine Kinases/metabolismRatsRats, Sprague-DawleySulfhydryl Compounds/metabolism
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