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)-gamma appeared to be a cofactor for IFN-gamma induction by MLA. With low doses of MLA (<5 mu g), IFN-gamma induction was dependent upon exogenous TNF-a administered either in advance of or with MLA. A 25 mu g 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-gamma production with dexamethasone inhibited IFN-gamma induction, and this inhibition was overcome by administration of exogenous TNF-gamma 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.