Induction of cyclooxygenase-2 on activated T lymphocytes: regulation of T cell activation by cyclooxygenase-2 inhibitors.
Cyclooxygenase (COX), known to exist in two isoforms, COX-1 and COX-2, is a key enzyme in prostaglandin synthesis and the target for most nonsteroidal anti-inflammatory drugs. In this study, we show that human T lymphocytes express the COX-2 isoenzyme. COX-2 mRNA and protein were induced in both Jurkat and purified T cells stimulated by TCR/CD3 or PMA activation. COX-2 mRNA was induced very early after activation and superinduced by protein synthesis inhibitors, whereas it was inhibited by the immunosuppressive drug cyclosporin A, identifying it as an early T cell activation gene. Interestingly, treatment with COX-2-specific inhibitors such as NS398 or Celecoxib severely diminished early and late events of T cell activation, including CD25 and CD71 cell surface expression, IL-2, TNF-alpha, and IFN-gamma production and cell proliferation, but not the expression of CD69, an immediate early gene. COX-2 inhibitors also abolished induced transcription of reporter genes driven by IL-2 and TNF-alpha promoters. Moreover, induced transcription from NF-kappaB- and NF-AT-dependent enhancers was also inhibited. These results may have important implications in anti-inflammatory therapy and open a new field on COX-2-selective nonsteroidal anti-inflammatory drugs as modulators of the immune activation.
Iñiguez
M A
MA
Centro de Biología Molecular Severo Ochoa, Facultad de Ciencias, Universidad Autónoma de Madrid, Cantoblanco, Spain.
Punzón
C
C
Fresno
M
M
D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000235:genetics; D008565:Membrane Proteins; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000276:immunology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases