title: Intrinsic defects in macrophage IL-12 production associated with immune dysfunction in the MRL/++ and New Zealand Black/White F1 lupus-prone mice and the Leishmania major-susceptible BALB/c strain.
abstract: We have demonstrated that macrophages (Mphi) from young, prediseased, lupus-prone MRL/++ and New Zealand Black/White F1 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 Mphi 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 Mphi 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 Mphi from lupus-prone strains are expressed rapidly after activation, treatment with each cytokine demonstrated that only TNF-alpha contributes to the subsequent dysregulation of Mphi 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 Mphi may lead to defective Th1 responses, these Mphi 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 Mphi 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.
authors.affiliation: Evans Memorial Department of Clinical Research, Boston University Medical Center, MA 02118-2393, USA.
authors.forename: D G
authors.initials: DG
authors.lastname: Alleva
authors.forename: S B
authors.initials: SB
authors.lastname: Kaser
authors.forename: D I
authors.initials: DI
authors.lastname: Beller
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015551:Autoimmunity; D002478:Cells, Cultured; D003433:Crosses, Genetic; D017077:Culture Media, Conditioned / Q000737:chemistry; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D018320:Leishmania major; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008814:Mice, Inbred NZB; D008815:Mice, Inbred Strains / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013045:Species Specificity; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics
chemical_list: D017077:Culture Media, Conditioned; D007375:Interleukin-1; D015850:Interleukin-6; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma