Glutathione depletion reveals impairment of antigen processing and inhibition of cathepsin activity by nitric oxide in antigen-presenting cells.
Nitric oxide has been shown to induce immunosuppression by inhibiting class II MHC molecule expression and T-lymphocyte proliferation. However, much less is known about the ability of NO to interfere with antigen processing and presentation. So we questioned whether B lymphoma cells exposed to NO could be impaired in their ability to process lysozyme and to stimulate proliferation of a syngeneic T-cell hybridoma. As immunosuppressive pathological conditions are often associated with a pro-oxidative milieu, we also examined the influence of intracellular GSH levels on NO responsiveness. Exposure of GSH-depleted B cells to NO-releasing compounds lowered their capacity to present a reduced and alkylated lysozyme (TAP-HEL), although presentation of a lysozyme-derived peptide was unaffected. Cells with a normal GSH content were protected from this inhibition. Fluid phase endocytosis, protein synthesis and expression of class II molecules remained normal in GSH-depleted cells. However, proteolysis of a dye conjugate of ovalbumin was strongly inhibited, suggesting that protease inhibition might be involved. Cathepsin B activity, which was necessary to TAP-HEL processing, was inhibited by the NO-donors. The inhibition was higher in GSH-depleted cells and reproduced by treatment of A20 B cells by two cathepsin inhibitors. These results show that, in addition to cytostasis and reduction in class II expression, NO-induced immunosuppression could also implicate inhibition of antigen processing under oxidative stress conditions.
Lemaire
Geneviève
G
Unité Mixte de Recherche 8619, Centre National de la Recherche Scientifique, Institut de Biochimie et de Biophysique Moléculaire et Cellulaire, Université de Paris-Sud XI, Orsay, France.
Guittet
Olivier
O
Vesin
Marie-Françoise
MF
Lepoivre
Michel
M
Cottet
Marie-Hélène
MH
D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology*; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D002645:Chickens; D005978:Glutathione / Q000172:deficiency / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006825:Hybridomas / Q000276:immunology; D051379:Mice; D009113:Muramidase / Q000276:immunology / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009842:Oligopeptides / Q000276:immunology / Q000378:metabolism; D010047:Ovalbumin / Q000378:metabolism
D000949:Histocompatibility Antigens Class II; D020030:Nitric Oxide Donors; D009842:Oligopeptides; D009569:Nitric Oxide; D010047:Ovalbumin; D019001:Nitric Oxide Synthase; C421864:hen egg lysozyme; D009113:Muramidase; D002401:Cathepsin B; D005978:Glutathione