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(Journal of Leukocyte Biology. 2002;71:339-347.)
© 2002 by Society for Leukocyte Biology

Glutathione redox regulates lipopolysaccharide-induced IL-12 production through p38 mitogen-activated protein kinase activation in human monocytes: role of glutathione redox in IFN- priming of IL-12 production

Mitsuyoshi Utsugi^*, Kunio Dobashi^*, Yasuhiko Koga^*, Yasuo Shimizu^*, Tamotsu Ishizuka^*, Kunihiko Iizuka^*, Junji Hamuro, Tsugio Nakazawa and Masatomo Mori^*

^* First Department of Internal Medicine, Faculty of Medicine, School of Medicine, and
Faculty of Health Sciences, Gunma University, Maebashi, Japan; and
Basic Research Laboratories, Ajinomoto Co., Kawasaki, Japan

Correspondence: Kunio Dobashi, M.D., Ph.D., First Department of Internal Medicine, Gunma University Faculty of Medicine, School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan. E-mail: dobashik{at}med.gunma-u.ac.jp

We examined whether changes in intracellular reduced (GSH) or oxidized (GSSG) glutathione of human monocytes regulate lipopolysaccharide (LPS)-induced IL-12 production and defined the molecular mechanism that underlies glutathione redox regulation. Monocytes exposed to glutathione reduced form ethyl ester (GSH-OEt) or maleic acid diethyl ester (DEM) increased or decreased the intracellular GSH/GSSG ratio, respectively. LPS-induced IL-12 production and p38 mitogen-activated protein (MAP) kinase activation were enhanced by GSH-OEt but suppressed by DEM. Selective p38 inhibitors showed that p38 promoted GSH-OEt-enhanced IL-12 production. Furthermore, IFN- priming increased the GSH/GSSG ratio and enhanced IL-12 production through p38, and DEM negated the priming effect of IFN- on p38 activation and IL-12 production as well as on the GSH/GSSG ratio. These findings reveal that glutathione redox regulates LPS-induced IL-12 production from monocytes through p38 MAP kinase activation and that the priming effect of IFN- on IL-12 production is partly a result of the glutathione redox balance.

Key Words: immune response • antigen-presenting cell • signal transduction

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