Activated Human B Lymphocytes Express Cyclooxygenase-2 and Cyclooxygenase Inhibitors Attenuate Antibody Production

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of inflammatory diseases and target cyclooxygenases 1 and 2 (Cox-1, Cox-2) that are responsible for PG production. Newer Cox-2-selective drugs have been heavily prescribed to quench inflammation. Little is known about whether or not these drugs influence human B lymphocytes and their ability to produce Ab. We report herein that activated human B cells not only highly express Cox-2 and produce PGs, but that the NSAID indomethacin and Cox-2-selective drugs profoundly inhibit the ability of human B cells to produce IgG and IgM in vitro. Human blood B cells highly express Cox-2 mRNA and protein and produce PGs after activation with CD40L, pansorbin, or CD40L plus BCR engagement. Cox-2 is also highly expressed by human tonsil B cells, as shown by immunohistochemistry. Cox-inhibiting drugs modestly affect purified B cell proliferation but profoundly reduce Ab production. The ability of whole blood to produce IgM and IgG following stimulation is also strongly inhibited. In support that Cox-2 plays a seminal role in B lymphocyte Ab production, Cox-2 knockout mice have 64% less IgM and 35% less IgG than normal littermate controls. These findings support that NSAIDs and the new Cox-2-selective drugs have an unsuspected target, the B cell, and attenuate Ab production in humans. Use of NSAIDs may therefore influence autoantibody production in autoimmune diseases and may dampen humoral immunity in response to antigenic challenge/vaccination.

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

“…We have found that spontaneously activated lupus B cells constitutively express high levels of COX-2, as do mitogenically stimulated, normal human B cells (40,41). Interestingly, CD86 high (activated) B cells from SNF 1 mice expressed more COX-2 than did the same subset from nonautoimmune strains, indicating a lupus-intrinsic defect (Figure 4).…”

Functional Synergy between CD40 Ligand and HIV-1 Tat Contributes to Inflammation: Implications in HIV Type 1 Dementia

“…For control studies, the same purification method was used in conjunction with uninfected SF9 cells; this preparation was then used as a negative control. Analogous to our previous reports (28,29) and that of others (27), the concentrations of CD40L used in experimental analyses are described in terms of the relative dilution of the CD40L-containing stock prepared.…”

Effect of antipyretic analgesics on immune responses to vaccination

“…To date, results have been mixed, with one study showing that indomethacin inhibited antibody production without loss of cell viability. However, other studies showed that NSAIDs decreased antibody secreting cells 61 or resulted in a modest reduction in B cell proliferation without inducing apoptosis. 49 Overall, antipyretic analgesics actions on cells and on signaling pathways appear to be diverse and studies to date have shown opposing effects.…”

“…60 COX-1 and COX-2 inhibitors have been shown to markedly reduce antibody production. [61][62][63] Human B cells strongly express COX mRNA and protein and produce prostaglandins upon activation 61 suggesting a potential target for antipyretic analgesics in antibody producing cells. However, this reduction was also observed in COX-deficient mouse models, 49,61 indicating that the mechanism is not solely dependent on that pathway.…”