c-Jun N-Terminal Kinase Negatively Regulates Lipopolysaccharide-Induced IL-12 Production in Human Macrophages: Role of Mitogen-Activated Protein Kinase in Glutathione Redox Regulation of IL-12 Production

• Published in: The Journal of immunology (1950) 2003-07, Vol.171 (2), p.628-635
• Main Authors: Utsugi, Mitsuyoshi, Dobashi, Kunio, Ishizuka, Tamotsu, Endou, Katsuaki, Hamuro, Junji, Murata, Yukie, Nakazawa, Tsugio, Mori, Masatomo
• Format: Article
• Language: English
• Subjects: 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; Macrophages - drug effects; Macrophages - enzymology; Macrophages - immunology; Macrophages - metabolism; MAP Kinase Signaling System - genetics; MAP Kinase Signaling System - immunology; 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; p38 Mitogen-Activated Protein Kinases; 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
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.171.2.628

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.