Effects of tumor necrosis factor and dexamethasone on the regulation of interferon-gamma induction by monophosphoryl lipid A.
Monophosphoryl lipid A (MLA), derived from lipopolysaccharide (LPS) of Salmonella minnesota strain R595, induced rapid accumulation of interferon (IFN)-gamma in mice. Tumor necrosis factor (TNF)-alpha appeared to be a cofactor for IFN-gamma induction by MLA. With low doses of MLA (< 5 micrograms), IFN-gamma induction was dependent upon exogenous TNF-alpha administered either in advance of or with MLA. A 25 micrograms dose of MLA induced significant IFN-gamma accumulation in the absence of exogenous TNF-alpha. In this case, endogenous TNF-alpha appeared to be a cofactor in the response, since suppression of TNF-alpha production with dexamethasone inhibited IFN-gamma induction, and this inhibition was overcome by administration of exogenous TNF-alpha with MLA. Treatment of animals with MLA tolerized them against LPS. Tolerant animals did not produce IFN-gamma when challenged with LPS, and this tolerance was not abrogated by supplementing mice with exogenous TNF-alpha during the challenge. Although dexamethasone inhibited IFN-gamma induction by MLA, it did not inhibit tolerance induction by MLA.
Gustafson
G L
GL
Ribi ImmunoChem Research, Inc., Hamilton, MT 59840.
Rhodes
M J
MJ
D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology*; D004357:Drug Synergism; D004361:Drug Tolerance; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis*; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D008050:Lipid A; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D007371:Interferon-gamma; C048436:monophosphoryl lipid A