Protein kinase C plays an inhibitory role in interleukin 3- and interleukin 4-mediated mast cell proliferation.
Interleukin 3 (IL-3) is required for the survival and proliferation of mouse bone marrow derived mast cells (BMMC). Although interleukin 4 (IL-4) has no direct effect on growth activity, it synergizes with IL-3 in promoting the growth of these cells. The intracellular mechanism by which these ligand-receptor interactions promote mast cell growth are not well documented in the literature. Here we present evidence that both IL-3 and IL-4 have been found to activate protein kinase C (PKC) and phosphatidylinositol turnover in BMMC, in a similar time- and dose-dependent manner, indicating that activation of PKC is not sufficient to induce proliferation in these cells. In this work we addressed the question as to whether the activation of PKC is necessary for mast cell proliferation. Activation of PKC by phorbol myristate acetate causes inhibition of IL-3-mediated growth for the first 72 h of incubation. The inhibition in IL-3-mediated proliferation gradually lessens with the stages of PKC depletion, which is complete after 72 h. The enhancement in phorbol myristate acetate-treated cells grows as PKC is depleted. The inactive phorbol ester, 4-alpha-phorbol, had no effect on proliferation of BMMC. Cells, PKC-depleted by chronical phorbol ester treatment, responded to IL-3 or IL-4 with a significant increase in [3H] thymidine uptake over PKC containing cells stimulated with the same lymphokine. Use of antibodies to these lymphokines showed that the enhanced response of the PKC-depleted BMMC was not due to the additional autocrine production of IL-3 or IL-4 by these cells. The PKC-depleted cells retain the capacity to return to almost normal levels of PKC activity and sensitivity to IL-3 and IL-4, after 72 and 120 h, respectively. These results indicate that PKC plays an important inhibitory role in IL-3- and IL-4-mediated proliferation of BMMC.
Chaikin
E
E
Institute of Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Ziltener
H J
HJ
Razin
E
E
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured; D003600:Cytosol / Q000201:enzymology; D004261:DNA Replication / Q000187:drug effects; D007294:Inositol / Q000378:metabolism; D007295:Inositol Phosphates / Q000302:isolation & purification / Q000378:metabolism; D007377:Interleukin-3 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008407:Mast Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D010704:Phorbols / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism
D007295:Inositol Phosphates; D007377:Interleukin-3; D010704:Phorbols; D015847:Interleukin-4; D007294:Inositol; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D013936:Thymidine