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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) signaling1,2,3. However, mutations in the genes encoding Fas and its ligand (FasL) are rare in classical SLE4. 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 E2 (PGE2). These findings could be useful in the design of lupus therapies.

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Figure 1: Clustering analysis of lupus T-cell differential gene set.
Figure 2: COX-2 inhibition induces apoptosis of anti-CD3-stimulated human lupus CD4+ T cells.
Figure 3: Mechanisms of COX-2 inhibitor–induced apoptosis.
Figure 4: COX-2 inhibitors suppress lupus autoimmunity.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (R37-AR39157 and RO1-AI41985). We thank C.–S. Chen for giving us purified and recrystallized celecoxib and rofecoxib, and A. Traynor for providing the samples from five lupus patients included in this study.

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Correspondence to Syamal K Datta.

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Xu, L., Zhang, L., Yi, Y. et al. Human lupus T cells resist inactivation and escape death by upregulating COX-2. Nat Med 10, 411–415 (2004). https://doi.org/10.1038/nm1005

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