TY - JOUR
T1 - Activation of T-cells by bryostatins
T2 - Induction of the IL-2 receptor gene transcription and down-modulation of surface receptors
AU - Esa, Ahmed H.
AU - Boto, William O.
AU - Adler, William H.
AU - Stratford May, W.
AU - Hess, Allan D.
N1 - Funding Information:
Acknowledgements -- The authors wish to thank Ms Julie Mergerian for her technical studies and Mr Jim Flook for his expert help with the flow cytometric analysis. This work was supported by NCI Institutional Grant No. IN-11-28, NIH grant Nos. AI24682, CA15396, CA27903, CA47993 and ACS IM398.
PY - 1990
Y1 - 1990
N2 - Bryostatins are macrocyclic lactones isolated from the marine bryozoan Bugula neritina. They are currently evaluated for putative antineoplastic activity. Bryostatins bind and activate protein kinase C (PK-C), the cellular receptor for the phorbol esters, and elicit PK-C-dependent cellular functions. Such functions include the expression of the interleukin-2 receptor (IL-2R). Northern blot hybridization with a human IL-2R and an IL-2 cDNA showed that bryostatin 1 (bryo 1), like the phorbol ester, PMA, activates the IL-2R gene. Activation with bryo 1 or PMA in the presence of a calcium ionophore, A23187, increased IL-2 message. These findings indicate that calcium mobilization is necessary for bryo 1 or PMA induced IL-2 gene expression. Unlike PMA, bryo 1 did not cause a vigorous proliferative response of T-lymphocytes unless A23187 was added to the cultures. A bryostatin congener, bryo 13, was inactive in the above assays. Short-term treatment of T-cells with bryo 1 and PMA resulted in an equivalent down-regulation of surface CD3 and CD4 receptors withour affecting the CD8 receptor. Bryo 1 or PMA mediated expression of surface IL-2R and T-cell proliferation induced by bryo 1 or PMA were sensitive to inhibition by the PK-C antagonists staurosporine (Sts) and H-7. In contrast, CD4 and CD3 down regulation were resistant to H-7, but could be blocked by Sts, although the Sts concentration required to block bryo 1 or PMA-induced down-modulation was 2.5-fold higher than required to inhibit IL-2R expression and T-cell proliferation. These results indicate that bryostatins activate T-cells through PK-C.
AB - Bryostatins are macrocyclic lactones isolated from the marine bryozoan Bugula neritina. They are currently evaluated for putative antineoplastic activity. Bryostatins bind and activate protein kinase C (PK-C), the cellular receptor for the phorbol esters, and elicit PK-C-dependent cellular functions. Such functions include the expression of the interleukin-2 receptor (IL-2R). Northern blot hybridization with a human IL-2R and an IL-2 cDNA showed that bryostatin 1 (bryo 1), like the phorbol ester, PMA, activates the IL-2R gene. Activation with bryo 1 or PMA in the presence of a calcium ionophore, A23187, increased IL-2 message. These findings indicate that calcium mobilization is necessary for bryo 1 or PMA induced IL-2 gene expression. Unlike PMA, bryo 1 did not cause a vigorous proliferative response of T-lymphocytes unless A23187 was added to the cultures. A bryostatin congener, bryo 13, was inactive in the above assays. Short-term treatment of T-cells with bryo 1 and PMA resulted in an equivalent down-regulation of surface CD3 and CD4 receptors withour affecting the CD8 receptor. Bryo 1 or PMA mediated expression of surface IL-2R and T-cell proliferation induced by bryo 1 or PMA were sensitive to inhibition by the PK-C antagonists staurosporine (Sts) and H-7. In contrast, CD4 and CD3 down regulation were resistant to H-7, but could be blocked by Sts, although the Sts concentration required to block bryo 1 or PMA-induced down-modulation was 2.5-fold higher than required to inhibit IL-2R expression and T-cell proliferation. These results indicate that bryostatins activate T-cells through PK-C.
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U2 - 10.1016/0192-0561(90)90110-9
DO - 10.1016/0192-0561(90)90110-9
M3 - Article
C2 - 2210911
AN - SCOPUS:0025130478
VL - 12
SP - 481
EP - 490
JO - International Immunopharmacology
JF - International Immunopharmacology
SN - 1567-5769
IS - 5
ER -