Human lupus T cells resist inactivation and escape death by upregulating COX-2.
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.
Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave. Chicago, Illinois 60611, USA.
Luting
L
Xu
Li
L
Zhang
Yajun
Y
Yi
Hee-Kap
HK
Kang
Syamal K
SK
Datta
D001483:Base Sequence; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D017931:DNA Primers; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology*; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D015854:Up-Regulation
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D017931:DNA Primers; D007527:Isoenzymes; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases