cAMP inhibits both Ras and Rap1 activation in primary human T lymphocytes, but only Ras inhibition correlates with blockade of cell cycle progression
| Autor: | Andre A. F. L. van Puijenbroek, Thomas Grader-Beck, Lee M. Nadler, Vassiliki A. Boussiotis |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
medicine.medical_specialty
T-Lymphocytes CD3 Immunology Receptors Antigen T-Cell Protein Serine-Threonine Kinases Biology Lymphocyte Activation Biochemistry chemistry.chemical_compound CD28 Antigens 1-Methyl-3-isobutylxanthine Proto-Oncogene Proteins Internal medicine Cyclic AMP medicine Humans Cyclic adenosine monophosphate Forskolin Kinase Cell Cycle Colforsin T-cell receptor rap1 GTP-Binding Proteins CD28 Cell Biology Hematology Cell cycle Cell biology Endocrinology chemistry ras Proteins biology.protein Cytokines Mitogen-Activated Protein Kinases Signal transduction Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Blood. 101:998-1006 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2002-06-1665 |
| Popis: | Cyclic adenosine monophosphate (cAMP) is a negative regulator of T-cell activation. However, the effects of cAMP on signaling pathways that regulate cytokine production and cell cycle progression remain unclear. Here, using primary human T lymphocytes in which endogenous cAMP was increased by the use of forskolin and 3-isobutyl-1-methylxanthine (IBMX), we show that increase of cAMP resulted in inhibition of T-cell receptor (TCR)/CD3 plus CD28–mediated T-cell activation and cytokine production and blockade of cell cycle progression at the G1 phase. Increase of cAMP inhibited Ras activation and phosphorylation of mitogen-induced extracellular kinase (MEK) downstream targets extracellular signal–related kinase 1/2 (ERK1/2) and phosphatidylinositol-3-kinase (PI3K) downstream target protein kinase B (PKB; c-Akt). These functional and biochemical events were secondary to the impaired activation of ZAP-70 and phosphorylation of LAT and did not occur when cells were stimulated with phorbol ester, which bypasses the TCR proximal signaling events and activates Ras. Increase of cAMP also inhibited activation of Rap1 mediated by TCR/CD3 plus CD28. Importantly, inhibition of Rap1 activation by cAMP was also observed when cells were stimulated with phorbol ester, although under these conditions Ras was activated and cells progressed into the cell cycle. Thus, TCR plus CD28–mediated activation of ERK1/2 and PKB, cytokine production, and cell cycle progression, all of which are inhibited by cAMP, require activation of Ras but not Rap1. These results indicate that signals that regulate cAMP levels after encounter of T cells by antigen will likely determine the functional fate toward clonal expansion or repression of primary T-cell responses. |
| Databáze: | OpenAIRE |
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