Hyperexpression of cyclooxygenase 2 in the lupus immune system and effect of cyclooxygenase 2 inhibitor diet therapy in a murine model of systemic lupus erythematosus

Abstract

Objective. To investigate the role of cyclooxygenase 2 (COX-2) in the functioning of different cell types involved in the lupus autoimmune response, and to examine the therapeutic effect of COX-2 inhibitors in mice prone to spontaneously develop systemic lupus erythematosus (SLE).Methods. Lupus-prone (SWR ؋ NZB)F 1 mice were fed with a diet containing different doses of the COX-2-specific inhibitor celecoxib or the nonspecific inhibitor aspirin, or a combination of both, and the effects of the therapy on autoantibody production, development of lupus nephritis, and mortality were determined. Expression of COX-2 by different cells of the lupus immune system and the effect of COX-2 inhibitors on the function of these cells in vitro and in vivo were assessed.Results. The immune cells of mice with SLE spontaneously hyperexpressed COX-2, and COX-2 inhibitors could cause cell apoptosis. Treatment with COX-2 inhibitors resulted in decreased autoantibody production and inhibition of the T cell response to the major lupus autoantigen, nucleosome, and its presentation by antigen-presenting cells. Surprisingly, a significant increase in survival occurred only in mice receiving intermittent therapy with the lowest dose of celecoxib (500 parts per million), approximating <100 mg of celecoxib/day in humans. A continuous diet, but not intermittent feeding, with the combination of celecoxib and aspirin delayed development of nephritis temporarily, but failed to prolong survival. Indeed, treatment with aspirin alone increased mortality.Conclusion. The contributions of the major players in the pathogenic autoimmune response, namely, T cells, B cells, dendritic cells, and macrophages that are abnormally hyperactive in lupus, depend on the increased expression and activity of COX-2, similar to inflammatory cells in target organs. Intermittent pulse therapy with low doses of select COX-2 inhibitors would be of value in the treatment of lupus.In systemic lupus erythematosus (SLE), hyperactivity of the immune system leads to activation of certain autoimmune T helper cells, which drive autoimmune B cells to produce somatically mutated IgG autoantibodies against apoptotic nuclear antigens (1-6). IgG immune complexes containing autoantigenic DNA and RNA bind Fc␥ receptors and Toll-like receptors (TLRs), which results in stimulation of type I interferon (IFN) production by hyperactive dendritic cells (DCs); moreover, autoimmune B cells bearing the T helper celldriven, high-affinity, somatically mutated B cell receptors are dually stimulated by TLRs (7-9). These events further amplify the ability of antigen-presenting cells (APCs) to present autoantigens to pathogenic T helper cells, which is an essential element of disease development (10-13).Normally, autoreactive T and B cells are eliminated by functional inactivation (anergy) and by activation-induced cell death (AICD; apoptosis), via Fas signaling (14). However, autoimmune T helper cells in human lupus resist AICD by up-regulating the expression of cyclooxygenase 2 (COX-2) and the anti...

A Cyclooxygenase-2/Prostaglandin E2 Pathway Augments Activation-Induced Cytosine Deaminase Expression within Replicating Human B Cells

“…Although it provides further support for the contention of Phipps and colleagues (8,9) that COX-2 inhibitors are contraindicated after vaccine administration, it also raises the possibility that inhibitors of the COX-2 pathway could profit patients with B cell autoimmunity. In support of the latter, intermittent treatment of mice prone to systemic lupus erythematosus with COX-2 inhibitor resulted in reduced IgG autoantibody titers and improved survival (98). Interference with the COX-2/mPGES-1/EP2 pathway might be particularly important for patients with Sjögren's syndrome, a salivary gland disorder characterized by salivationimpairing IgG autoantibodies (99) and a high predisposition to lymphoma (100,101).…”

Aspirin and immune system

“…In another study, ASA and celecoxib exhibited therapeutic efficacy against the autoimmune murine model of systemic lupus erythematosus. The intermittent pulse therapy with ASA and celecoxib caused a significant inhibition of autoantibodies production and T cell response through the COX-II inhibitory mechanism [137].…”

Effects of simvastatin on the function of dendritic cells in patients with rheumatic arthritis

“…This may be due to relatively shorter period of time of simvastatin treatment. In another study, Shurin et al found methotrexate are not able to inhibit maturation of DCs [25] , and celexoib is able to promote apoptosis of DCs [26] , suggesting the reduction of hyperfunction of DCs may be unlikely to be related to use of methotrexate or celexoib.…”