Inhibition of cyclooxygenase-2 impairs the expression of essential  plasma cell transcription factors and human B-lymphocyte  differentiation.
Cyclooxygenase (Cox) inhibitors are among the most widely used and commonly prescribed medications. Relatively little is understood about their influence on human immune responses. Herein, we discovered a novel and important mechanism whereby non-steroidal anti-inflammatory drugs (NSAIDs) blunt human B-cell antibody production. We demonstrate that the Cox-2 selective small molecule inhibitors SC-58125 and NS-398 attenuate the production of human antibody isotypes including immunoglobulin M (IgM), IgG1, IgG2, IgG3 and IgG4. In addition, inhibition of Cox-2 significantly reduced the generation of CD38+ IgM+ and CD38+ IgG+ antibody-secreting cells. Interestingly, we discovered that inhibition of Cox-2 activity in normal human B cells severely reduced the messenger RNA and protein levels of the essential plasma cell transcription factor, Blimp-1. These observations were mirrored in Cox-2-deficient mice, which had reduced CD138+ plasma cells and a near loss of Blimp-1 expression. These new findings demonstrate a critical role for Cox-2 in the terminal differentiation of human B lymphocytes to antibody-secreting plasma cells. The use of NSAIDs may adversely influence the efficacy of vaccines, especially in the immunocompromised, elderly and when vaccines are weakly immunogenic.
Bernard
Matthew P
MP
Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. matthew_bernard@urmc.rochester.edu
Phipps
Richard P
RP
D051997:ADP-ribosyl Cyclase 1 / Q000096:biosynthesis; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D000075202:Contraindications; D016861:Cyclooxygenase Inhibitors; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis* / Q000235:genetics; D017053:Infection Control; D009578:Nitrobenzenes / Q000494:pharmacology*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011720:Pyrazoles / Q000494:pharmacology*; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*; D014612:Vaccines
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007132:Immunoglobulin Isotypes; D009578:Nitrobenzenes; D011720:Pyrazoles; D012097:Repressor Proteins; D013449:Sulfonamides; D014612:Vaccines; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C087042:PRDM1 protein, human; C090859:1-((4-methylsulfonyl)phenyl)-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051997:ADP-ribosyl Cyclase 1