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B Activity in T Lymphocytes from Patients with Systemic Lupus Erythematosus Is Associated with Decreased p65-RelA Protein Expression1 ,2
Departments of
*
Cellular Injury and
Medicine, Walter Reed Army Institute of Research, Washington, DC 20307;
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157.
Numerous cellular and biochemical abnormalities in immune
regulation have been described in patients with systemic lupus
erythematosus (SLE), including surface Ag receptor-initiated signaling
events and lymphokine production. Because NF-
B contributes to the
transcription of numerous inflammatory genes and has been shown to be a
molecular target of antiinflammatory drugs, we sought to characterize
the functional role of the NF-B protein complex in lupus T cells.
Freshly isolated T cells from lupus patients, rheumatoid arthritis (RA)
patients, and normal individuals were activated physiologically via the
TCR with anti-CD3 and anti-CD28 Abs to assess proximal membrane
signaling, and with PMA and a calcium ionophore (A23187) to bypass
membrane-mediated signaling events. We measured the NF-B binding
activity in nuclear extracts by gel shift analysis. When compared with
normal cells, the activation of NF-B activity in SLE patients was
significantly decreased in SLE, but not in RA, patients. NF-B
binding activity was absent in several SLE patients who were not
receiving any medication, including corticosteroids. Also, NF-B
activity remained absent in follow-up studies. In supershift
experiments using specific Abs, we showed that, in the group of SLE
patients who displayed undetectable NF-B activity, p65 complexes
were not formed. Finally, immunoblot analysis of nuclear extracts
showed decreased or absent p65 protein levels. As p65 complexes are
transcriptionally active in comparison to the p50 homodimer, this novel
finding may provide insight on the origin of abnormal cytokine or other
gene transcription in SLE patients.
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