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Departments of
* Medicine,
Microbiology and Immunology, and
Pathology, State University of New York, College of Medicine, Syracuse, NY 13210
Abnormal death signaling in lymphocytes of systemic lupus
erythematosus (SLE) patients has been associated with elevation of the
mitochondrial transmembrane potential (
m) and
increased production of reactive oxygen intermediates (ROI). The
resultant ATP depletion sensitizes T cells for necrosis that may
significantly contribute to inflammation in patients with SLE. In the
present study, the role of mitochondrial signal processing in T cell
activation was investigated. CD3/CD28 costimulation of PBL elicited
transient mitochondrial hyperpolarization and intracellular pH
(pHi) elevation, followed by increased ROI production.
Baseline m, ROI production, and pHi were
elevated, while T cell activation-induced changes were blunted in 15
patients with SLE in comparison with 10 healthy donors and 10
rheumatoid arthritis patients. Similar to CD3/CD28 costimulation,
treatment of control PBL with IL-3, IL-10, TGF-
1,
and IFN-
led to transient m elevation. IL-10 had
diametrically opposing effects on mitochondrial signaling in lupus and
control donors. Unlike healthy or rheumatoid arthritis PBL, cells of
lupus patients were resistant to IL-10-induced mitochondrial
hyperpolarization. By contrast, IL-10 enhanced ROI production and cell
death in lupus PBL without affecting ROI levels and survival of control
PBL. Ab-mediated IL-10 blockade or stimulation with antagonistic
lymphokine IL-12 normalized baseline and CD3/CD28-induced changes in
ROI production and pHi with no impact on
m of lupus PBL. The results suggest that
mitochondrial hyperpolarization, increased ROI production, and
cytoplasmic alkalinization play crucial roles in altered IL-10
responsiveness in SLE.
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