Dissection of signals controlling T cell function and activation: H7, an inhibitor of protein kinase C, blocks induction of primary T cell proliferation by suppressing interleukin (IL)2 receptor expression without affecting IL2 production.
T cell activation induced via cross-linking of the T cell receptor (TcR) stimulates hydrolysis of phosphatidylinositol to the second messengers diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). DAG is necessary for the activation and function of protein kinase C (PKC) which is suggested to play a key role in the cascade of signal transduction when translocated from the cytosol to the cell membrane. In this report, we investigated responses of resting vs. activated Ly-2+ and L3T4+ T lymphocytes in the presence of the PKC inhibitor H7 [1-(5-isoquinolinylsulfonyl)-2-methylpiperazine]. H7 inhibited the induction of primary T cell proliferation, while interleukin 2 (IL 2) production was fully retained. The effect of the PKC inhibitor on primary T cells depended on the type of ligand interacting with the TcR: increasing doses of concanavalin A or of immobilized anti-CD3 monoclonal antibody (mAb), but not of anti-V beta 8 or of anti-TcR alpha/beta mAb, partly overcame the blockade, indicating a differential signaling compared to the former stimuli. The blockade of T cell proliferation by H7 was not due to an inhibition of PKC translocation, but occurred even 4-8 h after T cell induction and correlated with a significant reduction of IL 2 receptor (IL 2R) expression. In contrast, the mRNA levels of IL 2R and the cellular proto-oncogenes c-fos and c-myc were not affected. On activated T cells, H7 neither blocked proliferation nor IL2R expression. Consequently, H7 dissects the signal resulting in T cell proliferation from those governing the triggering of other T cell functions, i.e. IL 2 production, during primary responses of Ly-2+ or L3T4+ murine T lymphocytes.
Hengel
H
H
Institute of Microbiology, University of Ulm, FRG.
Allig
B
B
Wagner
H
H
Heeg
K
K
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D007376:Interleukin-2 / Q000096:biosynthesis*; D007546:Isoquinolines / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D015375:Receptors, Interleukin-2 / Q000032:analysis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology
D007376:Interleukin-2; D007546:Isoquinolines; D010879:Piperazines; D015375:Receptors, Interleukin-2; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C