Regulation of LPS induced IL-12 production by IFN-gamma and IL-4 through intracellular glutathione status in human alveolar macrophages.
Interleukin-12 (IL-12) is secreted from monocytes and macrophages; it exerts pleiotropic effects on T cells and natural killer (NK) cells, and stimulates interferon-gamma (IFN-gamma) secretion. Glutathione tripeptide regulates the intracellular redox status and other aspects of cell physiology. We examined whether IFN-gamma and IL-4 affect the balance between intracellular reduced glutathione (GSH) and oxidized (GSSG) glutathione, as this may affect IL-12 production in human alveolar macrophages (AM). We used both AM from healthy non-smokers obtained by bronchoalveolar lavage and the monocytic THP-1 cell line in this study. Incubation of AM for 2 h with the GSH precursor N-acetylcysteine (NAC) increased the intracellular GSH/GSSG ratio, and enhanced lipopolysaccharide (LPS)-induced IL-12 secretion by AM. In THP-1 cells, NAC increased the GSH/GSSG ratio and the expression of LPS-induced IL-12 mRNA, whereas L-buthionine-[S,R]-sulphoximine (BSO) decreased these. NAC and BSO offset their own effects on the intracellular GSH/GSSG ratio and the expression of LPS-induced IL-12 mRNA. Furthermore, exposure of AM to the helper T cell type 1 (Th1) cytokine IFN-gamma or the helper T cell type 2 (Th2) cytokine IL-4 for 72 h increased and decreased the GSH/GSSG ratio, respectively. Lipopolysaccharide (LPS)-induced secretion of IL-12 in AM was enhanced by IFN-gamma but inhibited by IL-4. These results suggest that IFN-gamma and IL-4 oppositely affect the GSH/GSSG balance, which may regulate IL-12 secretion from AM in response to LPS.
Dobashi
K
K
First Department of Internal Medicine, Gunma University Faculty of Medicine, School of Medicine, Maebashi, Gunma, Japan. dobashik@med.gunma-u.ac.jp
Aihara
M
M
Araki
T
T
Shimizu
Y
Y
Utsugi
M
M
Iizuka
K
K
Murata
Y
Y
Hamuro
J
J
Nakazawa
T
T
Mori
M
M
D000111:Acetylcysteine / Q000494:pharmacology; D002460:Cell Line; D005978:Glutathione / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D018664:Interleukin-12 / Q000378:metabolism*; D015847:Interleukin-4 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology; D010616:Phenanthrenes
C410511:1-keto-1,2,3,4-tetrahydrophenanthrene; D008070:Lipopolysaccharides; D010616:Phenanthrenes; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D005978:Glutathione; D019803:Glutathione Disulfide; D000111:Acetylcysteine