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Prostaglandin E2 and other cyclic AMP elevating agents inhibit interleukin 2 gene transcription by counteracting
F Paliogianni1, R L Kincaid, D T Boumpas
1Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland 20892.
Abstract:
We have previously shown that prostaglandin E2 and other cAMP elevating agents inhibit the nuclear transcription of the human IL-2 gene by interfering with a Ca(2+)-sensitive T cell signal transduction pathway. Calcineurin, a Ca2+/calmodulin-dependent 2B protein phosphatase, is an essential component of the T cell receptor signal transduction pathway leading to IL-2 gene expression. We have therefore tested the hypothesis that this phosphatase may be a target for the inhibitory effects of cAMP on IL-2 gene transcription. We report here that PGE2 markedly reduces the IL-2 promoter activity that is induced by a constitutively active form of calcineurin. In contrast to the complete inhibition of promoter activity produced by the immunosuppressants cyclosporin A and FK-506, this partial block suggests that PGE2 modulates downstream events needed for lymphokine gene activation. Overexpression of calcineurin in Jurkat cells decreases their apparent sensitivity to the inhibitory effects of PGE2 consistent with the fact that this enzyme plays a physiological role in dephosphorylating substrates of cAMP-dependent kinases in several tissues. These results provide evidence that cAMP-dependent pathways may antagonize calcineurin-regulated cascades for T cell activation in vivo, and suggest crosstalk between the Ca2+ and the cAMP signaling pathways during T cell activation.
Insights
Prostaglandin E2 (PGE2) partially inhibits interleukin-2 (IL-2) gene transcription by affecting calcineurin, a key T cell signaling enzyme. This suggests cAMP pathways antagonize calcineurin in T cell activation.
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- Interleukin-2 (IL-2) gene transcription is crucial for T cell activation and relies on Ca(2+)-sensitive signaling pathways.
- Prostaglandin E2 (PGE2) and cAMP-elevating agents are known inhibitors of IL-2 nuclear transcription.
- Calcineurin, a Ca(2+)/calmodulin-dependent phosphatase, is a critical component of the T cell receptor signaling pathway for IL-2 expression.
Purpose of the Study:
- To investigate whether calcineurin is a molecular target for the inhibitory effects of cAMP on IL-2 gene transcription.
- To elucidate the mechanism by which PGE2 interferes with T cell activation signaling.
Main Methods:
- Assessed IL-2 promoter activity induced by a constitutively active calcineurin mutant in the presence of PGE2.
- Compared the inhibitory effects of PGE2 with known immunosuppressants cyclosporin A and FK-506.
- Examined the impact of calcineurin overexpression on PGE2 sensitivity in Jurkat T cells.
Main Results:
- PGE2 significantly reduced IL-2 promoter activity induced by active calcineurin, indicating a partial block.
- The inhibition by PGE2 was less complete than that observed with cyclosporin A and FK-506.
- Overexpression of calcineurin diminished the inhibitory effect of PGE2 on Jurkat cells.
Conclusions:
- cAMP-dependent pathways antagonize calcineurin-regulated signaling cascades essential for T cell activation in vivo.
- Evidence suggests crosstalk between calcium (Ca2+) and cyclic AMP (cAMP) signaling pathways during T cell activation.
- Calcineurin may be a target for PGE2's modulation of lymphokine gene activation downstream of T cell receptor stimulation.