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Cyclic amp synergy with calcium ion for production of ifn gamma by a cytolytic t cell clone is post transcriptional


, : Cyclic amp synergy with calcium ion for production of ifn gamma by a cytolytic t cell clone is post transcriptional. Journal of Immunology 146(7): 2382-2387

PGE2 or products increasing the intracellular concentration of cAMP ((cAMP)i) had opposite effects on the induction of IFN-.gamma. in a CTL clone, depending on the inducing agent. Activation via the TCR was inhibited, whereas induction by the Ca2+ ionophore ionomycin was enhanced in the presence of agents increasing (cAMP)i. Synergy between Ca2+-dependent and cAMP-dependent pathways was independent of the activation of protein kinase C (PKC). Low levels of IFN-.gamma. mRNA could be detected transiently after induction with ionomycin alone, whereas simultaneous induction with agents increasing (cAMP)i led to enhanced levels of IFN-.gamma. mRNA detectable up to 12 h. No IFN-.gamma. mRNA was detected when the CTL were activated with (cAMP)i-increasing agents alone or with PKC-activating agents such as PMA, suggesting that the transcriptional activation of the IFN-.gamma. gene was strictly dependent on the Ca2+-mediated and cyclosporin A-dependent event. Analyses of IFN-.gamma. mRNA transcription by "run-on" experiments on nuclei isolated after activation of the CTL indicated that the Ca2+ signal alone induces maximal transcription of the IFN-.gamma. gene, which is not increased by either PKC activation or an increase in cAMP, but that further processing or stabilization of the IFN-.gamma. precursor or mature mRNA require an additional signal, provided either via a PKC or via a PKA activation pathway. The data also suggest that a combination of inflammatory products leading to an increase in (Ca2+]i and to an increase in (cAMP)i may bypass the usually stringent control of T cell activation by the TCR/CD3 complex.

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