Effects of Tumor Necrosis Factor and Dexamethasone on the Regulation of Interferon-?? Induction by Monophosphoryl Lipid A

Abstract

Summary: Monophosphoryl lipid A (MLA), derived from lipopolysaccharide (LPS) of Salmonella minnesota strain R595, induced rapid accumulation of interferon (IFN)-γ in mice. Tumor necrosis factor (TNF)-α appeared to be a cofactor for IFN-γ induction by MLA. With low doses of MLA (<5 µg), IFN-γ induction was dependent upon exogenous TNF-α administered either in advance of or with MLA. A 25 µg dose of MLA induced significant IFN-γ accumulation in the absence of exogenous TNF-α. In this case, endogenous TNF-α appeared to be a cofactor in the response, since suppression of TNF-α production with dexamethasone inhibited IFN-γ induction, and this inhibition was overcome by administration of exogenous TNF-α with MLA. Treatment of animals with MLA tolerized them against LPS. Tolerant animals did not produce IFN-γ when challenged with LPS, and this tolerance was not abrogated by supplementing mice with exogenous TNF-α during the challenge. Although dexamethasone inhibited IFN-γ induction by MLA, it did not inhibit tolerance induction by MLA.