Human lupus T cells resist inactivation and escape death by upregulating COX-2

Abstract

Autoimmune T-helper cells drive pathogenic autoantibody production in systemic lupus erythematosus (SLE), but the mechanisms maintaining those T cells are unknown. Autoreactive T cells are normally eliminated by functional inactivation (anergy) and activation-induced cell death (AICD) or apoptosis through death receptor (Fas) signaling. However, mutations in the genes encoding Fas and its ligand (FasL) are rare in classical SLE. By gene microarray profiling, validated by functional and biochemical studies, we establish here that activated T cells of lupus patients resist anergy and apoptosis by markedly upregulating and sustaining cyclooxygenase-2 (COX-2) expression. Inhibition of COX-2 caused apoptosis of the anergy-resistant lupus T cells by augmenting Fas signaling and markedly decreasing the survival molecule c-FLIP (cellular homolog of viral FLICE inhibitory protein). Studies with COX-2 inhibitors and Cox-2-deficient mice confirmed that this COX-2/FLIP antiapoptosis program is used selectively by anergy-resistant lupus T cells, and not by cancer cells or other autoimmune T cells. Notably, the gene encoding COX-2 is located in a lupus-susceptibility region on chromosome 1. We also found that only some COX-2 inhibitors were able to suppress the production of pathogenic autoantibodies to DNA by causing autoimmune T-cell apoptosis, an effect that was independent of prostaglandin E(2) (PGE(2)). These findings could be useful in the design of lupus therapies.

NF‐κB protects Behçet's disease T cells against CD95‐induced apoptosis up‐regulating antiapoptotic proteins

“…Sustained up-regulation of cyclooxygenase 2 protects activated SLE T cells from induction of anergy and apoptosis (42). Differently from BD cells, SLE T lymphocytes do not constitutively express high levels of FLIP S and Bcl-xL, which is consistent with the reported decrease in NF-B activity in SLE T cells (52).…”

Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression

“…The COX-2-cFLIP positive axis was recently described for some cell systems [52] and it is likely to be true in melanomas as well, where both COX-2 and cFLIP are permanently active. We suppressed COX-2 expression in LU1205 and WM9 cell lines using several COX-2 RNAi expressing constructs: COX-2-379 RNAi was the most effective.…”

Anti‐DNA Ig peptides promote Treg cell activity in systemic lupus erythematosus patients

“…To study T cells, short-term cultures were chosen over freshly isolated peripheral blood cells because T cells in SLE patients may be desensitized from repeated autoantigenic stimulation in vivo and from steroid therapy (32), whereas the activity of lupus T cells can reemerge after resting (33,34). Ficoll gradient-separated peripheral blood mononuclear cells (PBMCs) from patients with SLE and from healthy subjects were cultured under identical conditions at a concentration of 1 ϫ 10 6 /ml in 48-well plates in AIM-V (Invitrogen, Carlsbad, CA) with 20 units/ml IL-2, 10 ng/ml IL-7, and 10 ng/ml IL-15 (to prevent the death of memory T cells) (32). After 16 hours, cells were washed and then transferred onto 96-well plates and cultured for 3 days (without IL-2) with 1 g/ml anti-CD28/CD49d antibody, 0.1-0.5 anti-CD3/28 beads/cell, 1-10 g/ml tetanus toxoid (TT; Statens Serum Institut, Copenhagen, Denmark), 20 g/ml synthetic peptides, or medium only, as control.…”