Intrinsic Defects in Macrophage IL-12 Production Associated with Immune Dysfunction in the MRL/++ and New Zealand Black/White F1 Lupus-Prone Mice and theLeishmania major-Susceptible BALB/c Strain

Abstract

AbstractWe have demonstrated that macrophages (Mφ) from young, prediseased, lupus-prone MRL/++ and New Zealand Black/White F1 mice display defective production of TNF-α, IL-1, and IL-6, but normal production of IL-10. In an attempt to determine the potential functional implications of this phenotype for autoimmunity, we demonstrate here that endotoxin-activated Mφ from these lupus-prone mice showed dramatically reduced expression of IL-12, a cytokine essential for Th1 responses that may be defective during lupus. IL-12 production was also reduced by Mφ from the control BALB/c strain, compatible with the concept that a genetically programmed deficit in IL-12 levels may underlie the IL-4-dominated BALB/c response to infection by the parasite Leishmania major. Although both IL-12 and TNF-α expression defects by Mφ from lupus-prone strains are expressed rapidly after activation, treatment with each cytokine demonstrated that only TNF-α contributes to the subsequent dysregulation of Mφ IL-1 and IL-6 expression in these strains, and that the reduced autocrine activity of defective IL-12 or TNF-α levels was not causal to each other. Although the intrinsic defect in IL-12 expression by lupus-prone and BALB/c Mφ may lead to defective Th1 responses, these Mφ responded to the Th1-derived cytokine, IFN-γ, in a normal fashion suggesting a defective role in the induction, rather than the propagation, of Th1 responses in these mice. Our finding of a conserved intrinsic defect in IL-12 production by Mφ from the two principal mouse models of multigenic lupus provides insight into how excessive humoral responses may develop, and perhaps be prevented, in systemic autoimmune disease.