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Rheumatology Section, Evans Memorial Department of Clinical Research and Department of Medicine, Boston University Medical Center, Boston, MA 02118
We have demonstrated that macrophages (M
) from young,
prediseased, lupus-prone MRL/++ and New Zealand Black/White
F1 mice display defective production of TNF-
, 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- expression defects by
M from lupus-prone strains are expressed rapidly after activation,
treatment with each cytokine demonstrated that only TNF- 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- 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-
, 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.
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