LIPOPOLYSACCHARIDE AND MONOPHOSPHORYL LIPID A DIFFERENTIALLY REGULATEINTERLEUKIN-12, GAMMA-INTERFERON, AND INTERLEUKIN-10 MESSENGER-RNA PRODUCTION IN MURINE MACROPHAGES

Monophosphoryl lipid A (MPL) is a nontoxic derivative of the lipid A r egion of lipopolysaccharide (LPS) that is being developed as both an a djuvant and prophylactic drug for septic shock. We compared the abilit y of LPS and MPL to induce interleukin-10 (IL-10), IL-12 p35, IL-12 p4 0, gamma interferon (IFN-gamma), glucocorticoid receptor (GR), IL-1 re ceptor antagonist (IL-1ra), and inducible nitric oxide synthase mRNA e xpression in murine peritoneal macrophages. These genes were chosen fo r their ability to positively or negatively regulate the host immune r esponse and thus for their potential involvement in MPL-induced adjuva nticity or in its ability to protect against sepsis. LPS was a more po tent inducer of IL-12 p35, IL-12 p40, and IFN-gamma mRNA, as well as o f IL-12 protein, than MPL. In contrast, MPL induced higher levels of I L-10 mRNA than did LPS from 1 to 1,000 ng/ml. In general, MPL was not a more potent inducer of negative regulatory genes, since MPL and LPS induced similar levels of GR and IL-1ra mRNA. Addition of anti-IL-10 a ntibody to cultures increased the induction of MPL-induced IL-12 p35, IL-12 p40, and IFN-gamma mRNA, suggesting that the enhanced production of IL-10 by MPL-stimulated macrophages contributes to decreased produ ction of mRNA for IL-12 (p35 and p40) and IFN-gamma. Conversely, the a ddition of exogenous IL-10 to LPS-treated macrophages reduced the mRNA expression of these cytokine genes. These studies suggest that enhanc ed production of IL-10 by MPL-stimulated macrophages may contribute to the reduced toxicity of MPL through its negative action on induction of cytokines shown to enhance endotoxicity.