Physiologic activation of protein kinase C limits IL-2 secretion.
Interaction of Ag, antibodies against the T cell receptor complex, or mitogenic lectins with T lymphocytes induces hydrolysis of membrane phospholipids leading to the production of diacylglycerol (DAG). DAG then activates the Ca2+- and phospholipid-dependent phosphotransferase, protein kinase C (PKC). Increases in DAG concentrations are transient as is the increase in PKC activity. Phorbol esters, which induce potent, prolonged activation of PKC, augment many T lymphocyte responses, including cell proliferation and secretion of the T cell growth factor IL-2. Therefore, it has been suggested that activation of PKC is a positive regulatory signal in T lymphocytes. We have determined the consequences of transient stimulation of PKC, and of depletion of PKC, on early cell activation signals and on production of IL-2 by the murine lymphoma line LBRM 331A5. When this cell line is depleted of PKC overnight incubation in high concentrations of phorbol esters, lectin-induced IL-2 secretion is augmented. Similarly, mitogen-induced changes in [Ca2+]i and phosphoinositide metabolism were augmented in these cells. In contrast, a short preactivation of PKC abrogated these early transmembrane signaling events. This suggested that normal physiologic activation of PKC may limit cell activation and decrease IL-2 production. We compared the effects of phorbol esters and mezerein, which produce prolonged activation of PKC, with those of diacylglycerol analogs, which induce transient activation of PKC. At concentrations that give similar levels of PKC activation, phorbol esters and mezerein, but not DAG analogs, increased IL-2 secretion. This suggests that prolonged, nonphysiologic activation of PKC is required to augment IL-2 secretion. Therefore, physiologic activation of PKC may not augment T cell activation but instead may function to decrease cell activation and limit IL-2 secretion.
Mills
G B
GB
Oncology Research, Toronto General Hospital, Ontario, Canada.
May
C
C
Hill
M
M
Ebanks
R
R
Roifman
C
C
Mellors
A
A
Gelfand
E W
EW
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004224:Diterpenes; D004789:Enzyme Activation / Q000187:drug effects; D007295:Inositol Phosphates / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008223:Lymphoma / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D010703:Phorbol Esters / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D010835:Phytohemagglutinins; D011493:Protein Kinase C / Q000378:metabolism*; D013729:Terpenes / Q000494:pharmacology; D013997:Time Factors
D004224:Diterpenes; D007295:Inositol Phosphates; D007376:Interleukin-2; D010703:Phorbol Esters; D010716:Phosphatidylinositols; D010835:Phytohemagglutinins; D013729:Terpenes; C011309:mezerein; D011493:Protein Kinase C; D002118:Calcium