T-cell antigen receptor-mediated enhancement of the adenylate cyclase pathway depends on tyrosine protein kinases.
We have examined in the human T-cell line Jurkat the interaction between the activation through the T-cell receptor/CD3 complex and the adenylate cyclase pathway. OKT3, an anti-CD3 monoclonal antibody, did not activate by itself adenylate cyclase but produced a 3-7-fold increase of the cAMP accumulation induced by indirect (chloroadenosine, PGE2) or direct (forskolin) agonists of adenylate cyclase. A more detailed study with forskolin showed that OKT3 enhanced the effect of low concentrations of the agonist without affecting the maximal capacity of cAMP synthesis of the cells. The same concentrations of OKT3 produced both the enhancement of the adenylate cyclase pathway and the activation of phospholipase C. The enhancement by OKT3 of the adenylate cyclase pathway was inhibited by 0.5 microM staurosporine, a potent inhibitor of protein kinases, including tyrosine kinases and protein kinase C, whereas it was not inhibited by H7, a specific inhibitor of PKC. Staurosporine, at the same concentration, also inhibited the OKT3-induced activation of phospholipase C, a tyrosine kinase-dependent process. Taken together, these data indicate that activation of T-cell through the T-cell receptor enhances the adenylate cyclase pathway by a tyrosine protein kinase-dependent mechanism.
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Laboratoire de Biochimie Métabolique et Pharmacologique, INSERM U75, Faculté de Médecine Necker-Enfants Malades, Paris, France.
Moncion
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Hamet
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Perignon
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JL
D000262:Adenylyl Cyclases / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D016853:Muromonab-CD3 / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology; D014407:Tumor Cells, Cultured
D016853:Muromonab-CD3; D011948:Receptors, Antigen, T-Cell; D005576:Colforsin; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D000262:Adenylyl Cyclases