Treatment of human T cells with bisperoxovanadium phosphotyrosyl phosphatase inhibitors leads to activation of cyclooxygenase-2 gene.
Protein-tyrosine phosphatase (PTP) inhibitors are potent activators of T lymphocytes, most likely by affecting the early steps of T cell receptor (TCR) signaling. We have analyzed the effect of the PTP inhibitor bisperoxovanadium (bpV) on expression of the human cyclooxygenase 2 (COX-2) gene, which is induced following TCR triggering. Here we show that COX-2 promoter activity is markedly up-regulated following exposure of Jurkat T cells to bpV(pic). Interestingly enough, treatment of Jurkat cells with cyclic AMP-elevating agents such as forskolin, in combination with bpV, resulted in a more important COX-2 transcriptional activation. Such activation is inhibited by the immunosuppressive drugs FK506 and cyclosporin A. The two nuclear factor of activated T cells (NFAT) binding sites located within the COX-2 promoter region are involved in bpV-mediated positive effect on COX-2 promoter. Electromobility shift assays showed that NFAT1 and activator protein-1 are both translocated to the nucleus following bpV treatment. The active participation of p56(lck), ZAP-70, p36(LAT), and calcium in the bpV-dependent signaling cascade leading to COX-2 transcriptional activation was demonstrated using deficient cell lines and specific inhibitors. Although several PTPs are most likely targeted by bpV, our data suggest that the bpV-mediated signaling cascade is initiated by inhibition of SHP-1, which leads to phosphorylation of p56(lck) and ZAP-70 and, ultimately, to NFAT and activator protein-1 nuclear translocation. These results suggest that PTP inhibitors can activate COX-2 gene expression in a manner very similar to the stimulation induced by TCR triggering.
Barat
Corinne
C
Centre de Recherche en Infectiologie, Hôpital CHUL, Centre Hospitalier, Universitaire de Québec and Département de Biologie Médicale, Faculté de Médecine, Université Laval, Ste-Foy, Québec G1V 4G2, Canada.
Tremblay
Michel J
MJ
D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D051546:Cyclooxygenase 2; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D008565:Membrane Proteins; D009154:Mutation; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects*; D016559:Tacrolimus / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014638:Vanadates / Q000494:pharmacology*; D017968:Vanadium Compounds / Q000494:pharmacology*; D051746:ZAP-70 Protein-Tyrosine Kinase
D048868:Adaptor Proteins, Signal Transducing; D022762:CCAAT-Enhancer-Binding Proteins; D002121:Calcium Channel Blockers; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007527:Isoenzymes; C110810:LAT protein, human; D008565:Membrane Proteins; D010750:Phosphoproteins; D013267:Stilbenes; D017968:Vanadium Compounds; C472777:bisperoxovanadium; D005576:Colforsin; D014638:Vanadates; C006014:8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate; D005707:Gallic Acid; C041525:3,3',4,5'-tetrahydroxystilbene; D016572:Cyclosporine; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D019703:Calcineurin; D017027:Protein Tyrosine Phosphatases; D002118:Calcium; D016559:Tacrolimus