Intrinsic defects in macrophage IL-12 production associated with immune dysfunction in the MRL/++ and New Zealand Black/White F-1 lupus-prone mice and the Leishmania major-susceptible BALB/c strain

We have demonstrated that macrophages (M phi) from young, prediseased, lupu s-prone MRL/++ and New Zealand Black/White F-1 mice display defective produ ction of TNF-alpha; IL-1, and IL-6, but normal production of IL-IO, In an a ttempt to determine the potential functional implications of this phenotype for autoimmunity, me demonstrate here that endotoxin-activated M phi from these lupus-prone mice showed dramatically reduced expression of IL-12, a c ytokine essential for Th1 responses that may be defective during lupus, IL- 12 production was also reduced by M phi from the control BALB/c strain, com patible with the concept that a genetically programmed deficit in IL-12 lev els may underlie the IL-4-dominated BALB/c response to infection by the par asite Leishmania major, Although both IL-12 and TNF-alpha expression defect s by Mg from lupus-prone strains are expressed rapidly after activation, tr eatment with each cytokine demonstrated that only TNF-alpha contributes to the subsequent dysregulation of M phi IL-l, and IL-6 expression in these st rains, and that the reduced autocrine activity of defective IL-12 or TNF-al pha levels was not causal to each other, Although the intrinsic defect in I L-12 expression by lupus-prone and BALB/c M phi may lead to defective Th1 r esponses, these M phi responded to the Th1-derived cytokine, IFN-gamma, 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 M phi from the two principal mouse models of multigenic lupus provides insight into how excessive humoral res ponses may develop, and perhaps be prevented, in systemic autoimmune diseas e.