Effects of tumor necrosis factor and dexamethasone on the regulation of interferon-gamma induction by monophosphoryl lipid A.

Abstract

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.