Abstract
Although c-Jun N-terminal kinase (JNK) plays an important role in cytokine expression, its function in IL-12 production is obscure. The present study uses human macrophages to examine whether the JNK pathway is required for LPS-induced IL-12 production and defines how JNK is involved in the regulation of IL-12 production by glutathione redox, which is the balance between intracellular reduced (GSH) and oxidized glutathione (GSSG). We found that LPS induced IL-12 p40 protein and mRNA in a time- and concentration-dependent manner in PMA-treated THP-1 macrophages, and that LPS activated JNK and p38 mitogen-activated protein (MAP) kinase, but not extracellular signal-regulated kinase, in PMA-treated THP-1 cells. Inhibition of p38 MAP kinase activation using SB203580 dose dependently repressed LPS-induced IL-12 p40 production, as described. Conversely, inhibition of JNK activation using SP600125 dose dependently enhanced both LPS-induced IL-12 p40 production from THP-1 cells and p70 production from human monocytes. Furthermore, JNK antisense oligonucleotides attenuated cellular levels of JNK protein and LPS-induced JNK activation, but augmented IL-12 p40 protein production and mRNA expression. Finally, the increase in the ratio of GSH/GSSG induced by glutathione reduced form ethyl ester (GSH-OEt) dose dependently enhanced LPS-induced IL-12 p40 production in PMA-treated THP-1 cells. GSH-OEt augmented p38 MAP kinase activation, but suppressed the JNK activation induced by LPS. Our findings indicate that JNK negatively affects LPS-induced IL-12 production from human macrophages, and that glutathione redox regulates LPS-induced IL-12 production through the opposite control of JNK and p38 MAP kinase activation.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Anthracenes / pharmacology
-
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
-
Cells, Cultured
-
Down-Regulation / immunology*
-
Enzyme Activation / immunology
-
Enzyme Inhibitors / pharmacology
-
Glutathione / analogs & derivatives*
-
Glutathione / metabolism*
-
Glutathione / pharmacology
-
Humans
-
Imidazoles / pharmacology
-
Interleukin-12 / antagonists & inhibitors*
-
Interleukin-12 / biosynthesis*
-
Interleukin-12 / genetics
-
Interleukin-12 / metabolism
-
Interleukin-12 Subunit p40
-
JNK Mitogen-Activated Protein Kinases
-
Lipopolysaccharides / antagonists & inhibitors
-
Lipopolysaccharides / pharmacology*
-
MAP Kinase Signaling System / genetics
-
MAP Kinase Signaling System / immunology
-
Macrophages / drug effects
-
Macrophages / enzymology*
-
Macrophages / immunology*
-
Macrophages / metabolism
-
Mitogen-Activated Protein Kinase 8
-
Mitogen-Activated Protein Kinase 9
-
Mitogen-Activated Protein Kinases / antagonists & inhibitors
-
Mitogen-Activated Protein Kinases / genetics
-
Mitogen-Activated Protein Kinases / metabolism
-
Mitogen-Activated Protein Kinases / physiology*
-
Oligonucleotides, Antisense / pharmacology
-
Oxidation-Reduction
-
Protein Subunits / antagonists & inhibitors
-
Protein Subunits / biosynthesis
-
Protein Subunits / genetics
-
Pyridines / pharmacology
-
RNA, Messenger / antagonists & inhibitors
-
RNA, Messenger / biosynthesis
-
Tumor Cells, Cultured
-
Up-Regulation / genetics
-
Up-Regulation / immunology
-
p38 Mitogen-Activated Protein Kinases
Substances
-
Anthracenes
-
Anti-Inflammatory Agents, Non-Steroidal
-
Enzyme Inhibitors
-
Imidazoles
-
Interleukin-12 Subunit p40
-
Lipopolysaccharides
-
Oligonucleotides, Antisense
-
Protein Subunits
-
Pyridines
-
RNA, Messenger
-
Interleukin-12
-
pyrazolanthrone
-
S-ethyl glutathione
-
Mitogen-Activated Protein Kinase 9
-
JNK Mitogen-Activated Protein Kinases
-
Mitogen-Activated Protein Kinase 8
-
Mitogen-Activated Protein Kinases
-
p38 Mitogen-Activated Protein Kinases
-
Glutathione
-
SB 203580