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Contrasting effects of the protein kinase C inhibitor staurosporine on the interleukin‐1 and phorbol ester activation pathways in the EL4–6.1 thymoma cell line
Author(s) -
Dornand Jacques,
Bouaboula Monsif,
D'Angeac Arnaud Dupuy,
Favero Jean,
Shire David,
Casellas Pierre
Publication year - 1992
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.1041510112
Subject(s) - staurosporine , protein kinase c , phorbol ester , protein kinase a , microbiology and biotechnology , thymoma , cell culture , chemistry , protein kinase inhibitor , phorbol , interleukin 2 , kinase , biology , biochemistry , immunology , in vitro , genetics
EL 4–6. 1 cells, variants of the murine EL4 thymoma cell line, can be activated by interleukin 1 (IL‐1) or phorbol 12‐myristate‐13‐acetate (PMA), or PMA + IL‐1 to secrete interleukin 2 (IL‐2) and interleukin 4 (IL‐4) and to express the IL‐2 receptor (IL‐2R). To compare the different activation pathways, we examined the effects of staurosporine (STAR) and 1‐(5‐isoquinolinylsulfonyl)‐2‐methylpiperazine (H7), two protein kinase C (PKC) inhibitors, on the induction of interleukin secretion and IL‐2R expression in these cells. We report here that nanomolar concentrations of STAR strongly potentiated (20‐ to 30‐fold) the production of IL‐2 or IL4, when EL 4–6.1 cells were induced by IL‐1 α (or IL‐1 β) alone. By contrast, at identical concentrations, STAR dose‐dependently inhibited the production of IL‐2 and IL‐4 resulting from PMA or PMA + IL‐1 cell treatment. STAR also negatively affected the expression of IL‐2R, which was dependent on PMA‐sensitive PKC with either IL‐1, PMA, or PMA + IL‐1 stimulation. The changes in interleukin production and IL‐2R expression in EL 4–6.1 activated cells were correlated with changes at the mRNA level measured by quantitative polymerase chain reaction (PCR). This finding suggests a pretranslational effect of the drug. At micromolar concentrations, H7 showed the same effects as STAR, but only increased IL‐1‐triggered interleukin secretions twofold. We observed that the action of PKC inhibitors did not result from modification of IL‐1 receptor (IL‐1R) expression in EL 4–6.1 cells. Thus, our data show that PKC inhibitors clearly distinguish between IL‐1 and PMA stimulatory pathways. In addition, they suggest that the IL‐1 stimulatory pathway involves PKC(s) [or other undefined kinase(s)] which regulate this pathway and differ from PKC(s) activated by PMA. © 1992 Wiley‐Liss, Inc.