Linomide, a novel immunomodulator that prevents death in four models of septic shock.
Intravenous injections of 50 micrograms Staphylococcus aureus enterotoxin B (SEB) or bacterial lipopolysaccharide (LPS) are lethal, provided that mice are simultaneously sensitized with either N-galactosamine (GalN) or the anti-glucocorticoid RU-38486. Similar to the synthetic glucocorticoid (GC) receptor agonist dexamethasone, pharmacological doses of the immunomodulator linomide (quinoline-3-carboxamide) prevent death in all four models of lethal septic shock (LPS + GalN, LPS + RU-38486, SEB + GalN, and SEB + RU-38486) and inhibit the secretion of tumor necrosis factor, one of the major intermediate effector molecules of SEB and LPS toxicity. In this system, cyclosporine A (CsA), although effective in suppressing SEB toxicity, fails to counteract the lethal effect of LPS. This observation, together with the fact that linomide acts in the presence of excess amounts of GC receptor antagonist, indicates that linomide functions in a different way to that of known immunosuppressive agents like CsA and GC.
Gonzalo
J A
JA
Centro de Biología Molecular (CSIC), Universidad Autónoma de Madrid, Spain.
González-García
A
A
Kalland
T
T
Hedlund
G
G
Martínez
C
C
Kroemer
G
G
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004768:Enterotoxins / Q000633:toxicity; D006912:Hydroxyquinolines / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012772:Shock, Septic / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000276:Adjuvants, Immunologic; D004768:Enterotoxins; D006912:Hydroxyquinolines; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C045282:roquinimex; C031818:enterotoxin B, staphylococcal