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Upregulation of cAMP-specific PDE-4 activity following ligation of the TCR complex on thymocytes is blocked by selective inhibitors of protein kinase C and tyrosyl kinases

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Abstract

We have previously shown that the major cAMP phosphodiesterase (PDE) isoforms present in murine thymocytes are the cGMP-stimulated PDE activity (PDE-2) and the cAMP-specific PDE activity (PDE-4), and that these isoforms are differentially regulated following ligation of the TCR (Michie, A. M., Lobban, M. D., Mueller, T., Harnett, M. M., and Houslay, M. D. [1996]Cell. Signalling 8, 97–110). We show here that the anti-CD3-stimulated elevation in PDE-4 activity in murine thymocytes is dependent on protein tyrosine kinase and protein kinase C (PKC)-mediated signals as the TCR-coupled increase in PDE-4 activity can be abrogated by both the tyrosine kinase inhibitor, genistein, and the PKC selective inhibitors chelerythrine and staurosporine. Moreover, the PKC-activating phorobol ester, phorbol-12-myristate, 13-acetate (PMA) caused an increase in PDE-4 activity, similar to that observed in cells challenged with anti-CD3 monoclonal antibodies and which was not additive with cochallenge using anti-CD3 antibodies. Both the PMA-and the anti-CD3 antibody-mediated increases in PDE-4 activity were blocked by treatment with either cycloheximide or actinomycin D. Despite the upregulation of PDE-4 activity consequent to TCR ligation, intracellular cAMP levels increased on challenge of thymocytes with anti-CD3 antibody, indicating that adenylate cyclase activity was also increased by TCR ligation. It is suggested that the anti-CD3-mediated increase in PDE-4 activity was owing to a rapid PKC-dependent induction of PDE-4 activity following crosslinking of the TCR complex. This identifies “crosstalk” occurring between the PKA and PKC signaling pathways initiated by ligation of the antigen receptor in murine thymocytes. That both adenylate cyclase and PDE-4 activities were increased may indicate the presence of compartmentalized cAMP responses present in these cells.

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Abbreviations

cAMP:

cyclic 3′,5′ adenosine monophosphate

cGMP:

cyclic 3′,5′ guanosine monophosphate

PDE:

phosphodiesterase

TCR:

T-cell antigen receptor/CD3 complex

PHA:

phytohemagglutinin

IBMX:

isobutylmethylxanthine

rolipram:

4-(3-[cyclopentoxyl]-4-methoxyphenyl)-2-pyrrolidone

EHNA:

erythro-9-(2-hyroxy-3-nonyl)-adenine (previously known as MEP-1)

genistein:

4,5,7-trihydroxyisoflavone

H89:

N-(2-[{p-bromocinnamyl}amino]ethyl)-5-isoquinolinesulfonamide

PMA:

phorbol-12-myristate, 13-acetate

tyrphostin A1:

α-cyano-(4-methoxy)cinamonitrile

tyrphostin A25:

α-cyano-(3,4,5 trihydroxy)-cinnamonitrole

PTK:

protein tyrosine kinase

PIP2 :

phosphatidylinositol-4,5-bis-phosphate

IP3 :

inositol-1,4,5-trisphosphate

DAG:

diacylglycerol

PKA:

cAMP-dependent protein kinase

PKC:

protein kinase C

PI-3-K:

phosphatidylinositol-3-kinase

PTP:

protein tyrosine kinase

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  1. Alison M. Michie

    Present address: Department of Immunology, Medical Sciences Building, 1 Kings College Circle, University of Toronto, M5S 1A8, Toronto, Ontario, Canada

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  1. Molecular Pharmacology Group, Division of Biochemistry & Molecular Biology, IBLS, University of Glasgow, Wolfson and Davidson Buildings, G12 8QQ, Glasgow, Scotland, UK

    Alison M. Michie, Graham Rena, Margaret M. Harnett & Miles D. Houslay

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Michie, A.M., Rena, G., Harnett, M.M. et al. Upregulation of cAMP-specific PDE-4 activity following ligation of the TCR complex on thymocytes is blocked by selective inhibitors of protein kinase C and tyrosyl kinases. Cell Biochem Biophys 28, 161–185 (1998). https://doi.org/10.1007/BF02737810

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