Intrinsic Defects in Macrophage IL-12 Production Associated with Immune Dysfunction in the MRL/++ and New Zealand Black/White F sub(1) Lupus-Prone Mice and the Leishmania major-Susceptible BALB/c Strain

• Published in: The Journal of immunology (1950) Vol. 161; no. 12; pp. 6878 - 6884
• Main Authors: Alleva, D G, Kaser, S B, Beller, DI
• Format: Journal Article
• Language: English
• Published: 15.12.1998
• ISSN: 0022-1767

We have demonstrated that macrophages (M) from young, prediseased, lupus-prone MRL/++ and New Zealand Black/White F sub(1) mice display defective production of TNF- alpha , 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 M 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 M 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- alpha expression defects by M from lupus-prone strains are expressed rapidly after activation, treatment with each cytokine demonstrated that only TNF- alpha contributes to the subsequent dysregulation of M IL-1 and IL-6 expression in these strains, and that the reduced autocrine activity of defective IL-12 or TNF- alpha levels was not causal to each other. Although the intrinsic defect in IL-12 expression by lupus-prone and BALB/c M may lead to defective Th1 responses, these M 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 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.