N-acetylcysteine and glutathione as inhibitors of tumor necrosis factor production.
TNF is a major mediator in the pathogenesis of endotoxic shock, and its inhibition has a protective effect in various animal models of sepsis or endotoxin (lipopolysaccharide, LPS) toxicity. LPS treatment also induces an oxidative damage mediated by increased production of reactive oxygen intermediates. N-Acetylcysteine (NAC) is an antioxidant and a precursor of the synthesis of glutathione (GSH) and was reported to protect against LPS toxicity and LPS-induced pulmonary edema. In this study we investigated the effect of NAC on TNF production and LPS lethality in mice. The results indicated that oral administration of NAC protects against LPS toxicity and inhibits the increase in serum TNF levels in LPS-treated mice. The inhibition was not confined to the released form of TNF, since NAC also inhibited LPS-induced spleen-associated TNF. On the other hand, the inhibitor of GSH synthesis, DL-buthionine-(SR)-sulfoximine (BSO), had the opposite effect of potentiating LPS-induced TNF production, and this was associated with a decrease in liver GSH levels. Repletion of liver GSH with NAC reversed this effect. NAC was also active in inhibiting TNF production and hepatotoxicity in mice treated with LPS in association with a sensitizing dose of Actinomycin D. These data indicate that GSH can be an endogenous modulator of TNF production in vivo. On the other hand, NAC pretreatment did not inhibit other effects of LPS, particularly induction of serum IL-6, spleen IL-1 alpha, and corticosterone, in the same experimental model, suggesting that the observed effect could be specific for TNF.
Peristeris
P
P
Mario Negri Institute for Pharmacological Research, Milan, Italy.
Clark
B D
BD
Gatti
S
S
Faggioni
R
R
Mantovani
A
A
Mengozzi
M
M
Orencole
S F
SF
Sironi
M
M
Ghezzi
P
P
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D003345:Corticosterone / Q000097:blood; D003609:Dactinomycin / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D000685:Serum Amyloid A Protein / Q000032:analysis / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D000685:Serum Amyloid A Protein; D014409:Tumor Necrosis Factor-alpha; C065566:buthionine sulfoximine ethyl ester; D008717:Methionine Sulfoximine; D003609:Dactinomycin; D005978:Glutathione; D003345:Corticosterone; D000111:Acetylcysteine