| Generation of protective humoral immune responses against vaccines and pathogens depends on optimal B lymphocyte production of high-affinity antibodies. Non-steroidal anti-inflammatory drugs (NSAIDs) are used to curb undesirable symptoms of vaccination and infection, including pain, fever and swelling. However, relatively little is known about how these drugs may influence humoral immunity. NSAIDs function by inhibiting cyclooxygenase-1 (Cox-1), the constitutively expressed isoform and Cox-2, the inducible isoform. Our lab has previously shown that Cox-2 can be induced in response to T-dependent stimuli and that Cox-2 activity is important for B cell antibody production. However, no mechanism for the attenuated antibody production in the presence of Cox-2 selective inhibitors has been described. I hypothesized that: (i) T-independent stimuli, such as CpG DNA, induce Cox-2 in human B cells, (ii) CpG-induced antibody production is dependent on Cox-2 activity, (iii) Cox-2 activity is essential for B cell differentiation to antibody secreting plasma cells and (iv) Cox-2 activity is necessary for the optimal in vivo generation of neutralizing antibodies to live virus infection. Results presented herein, demonstrate that inducible human B cell Cox-2 activity is crucial for the optimal production of IgM and IgG. Expression of essential plasma cell transcriptional regulatory factors, including Blimp-1 and Xbp-1, were found to be dependent on Cox-2 activity. Significantly fewer CD38+antibody secreting plasma cell precursors were generated in the presence of Cox-2 selective inhibitors, further indicating that Cox-2 is essential for optimal B cell terminal differentiation.;Cox-2 selective inhibitors were administered in vivo to determine the role of Cox-2 in a humoral immune response to live infection with vaccinia virus. Mice chronically treated with Cox-2 selective inhibitors produced less viral neutralizing IgG following live virus infection. Furthermore, inhibition of Cox-2 resulted in a reduced frequency of IFN-gamma producing T cells, indicating that T cell priming of B cells was attenuated.;Overall, these data support the idea that impaired humoral immunity in the absence of Cox-2 activity can be dependent on both B cells and T cells. This work further suggests that the use of NSAIDs and Cox-2 selective inhibitors have the potential to dampen humoral immunity to live virus infection and vaccines. |
