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* Section of Rheumatology, Department of Medicine,
Section of Immunobiology, and Departments of
Pathology and
Dermatology, Yale School of Medicine, New Haven, CT 06520; and
¶ Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
MRL/MpJ-Tnfrsf6lpr
(MRL/MpJ-Faslpr;
MRL-Faslpr) mice develop a spontaneous
lupus syndrome closely resembling human systemic lupus erythematosus.
To define the role of IL-10 in the regulation of murine lupus, IL-10
gene-deficient (IL-10-/-)
MRL-Faslpr
(MRL-Faslpr IL-10-/-)
mice were generated and their disease phenotype was compared with
littermates with one or two copies of an intact IL-10 locus
(MRL-Faslpr IL-10+/- and
MRL-Faslpr IL-10+/+ mice,
respectively). MRL-Faslpr
IL-10-/- mice developed severe lupus, with earlier
appearance of skin lesions, increased lymphadenopathy, more severe
glomerulonephritis, and higher mortality than their IL-10-intact
littermate controls. The increased severity of lupus in
MRL-Faslpr IL-10-/- mice
was closely associated with enhanced IFN-
production by both
CD4+ and CD8+ cells and increased serum
concentration of IgG2a anti-dsDNA autoantibodies. The protective
effect of IL-10 in this lupus model was further supported by the
observation that administration of rIL-10 reduced IgG2a anti-dsDNA
autoantibody production in wild-type
MRL-Faslpr animals. In summary, our
results provide evidence that IL-10 can down-modulate murine lupus
through inhibition of pathogenic Th1 cytokine responses. Modulation of
the level of IL-10 may be of potential therapeutic benefit for human
lupus.
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