Interaction between nitric oxide and subsets of human T lymphocytes with differences in glutathione metabolism.
Nitric oxide (NO) modulates human T-lymphocyte responses through several mechanisms. In the current study we show that interactions between NO and glutathione (GSH) metabolism are related to the selective persistent inhibition of interferon-gamma (IFN-gamma) production by NO, which we previously identified. T cells were exposed to NO using the NO-donor compound Spermine-nonoate (Sper) and activated using anti-CD3 plus anti-CD28 monoclonal antibodies. Persistent inhibition of IFN-gamma by Sper was prevented by addition of the GSH precursor l-cysteine, which inhibits Sper induced GSH depletion. Subsets of cells were either susceptible (GSH(low)) or resistant (GSH(high)) to NO-induced GSH depletion. The GSH(low) subset was characterized by enhanced numbers of CD4+ cells, reduced numbers of activated cells as characterized by CD25 and CD69, and reduced numbers of memory (CD45RO+) cells relative to the GSH(high) population. Rather than directly affecting susceptibility to NO, these surface markers reflected different expression patterns. Particularly, the GSHlow subset was further characterized by decreased activity of the GSH synthesis related enzymes multi-drug resistance related protein (MRP)-1 and gamma-glutamyltranspeptidase (gamma-GT). Blocking gamma-GT, using acivicin was shown to exacerbate NO-induced GSH depletion and NO-induced apoptosis. Since NO induced apoptosis selectively affects IFN-gamma production these findings implicate GSH metabolism in the modulation and maintenance of the T helper (Th)1/Th2 balance.
Roozendaal
Ramon
R
Division of Allergology, Department of Internal Medicine, Faculty of Medicine, Groningen University, Groningen University Hospital, Hanzeplein 1, 9713 GZ Groningen, the Netherlands.
Kauffman
Henk F
HF
Dijkhuis
Anne-Jan
AJ
Ommen
Elisabeth T V
ET
Postma
Dirkje S
DS
de Monchy
Jan G R
JG
Vellenga
Edo
E
D017209:Apoptosis / Q000187:drug effects; D018929:Cell Culture Techniques; D005978:Glutathione / Q000097:blood*; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D009569:Nitric Oxide / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000378:metabolism
D009569:Nitric Oxide; D007371:Interferon-gamma; D005978:Glutathione