Inhibition by interleukin 4 of leukemia inhibitory factor-, interleukin 6-, and dexamethasone-induced differentiation of mouse myeloid leukemia cells: role of c-myc and junB proto-oncogenes.
Interleukin 4 (IL-4) inhibited the differentiation of mouse myeloid leukemia M1 cells induced by leukemia inhibitory factor (LIF), interleukin 6, or dexamethasone and conversely enhanced the induction of M1 cell differentiation by 1 alpha,25-dihydroxyvitamin D3. IL-4 blocked LIF-induced differentiation of M1 cells when it was added to the culture medium within 10 h after LIF, but IL-4 did not block differentiation when it was added 12 h after LIF. These results indicate that IL-4 inhibited a critical intermediate step in myeloid leukemia cell differentiation. LIF markedly stimulated the expression of junB mRNA within 2 h but suppressed the expression of c-myb and c-myc after 2- and 12-h treatment, respectively. IL-4 did not significantly affect LIF-induced junB expression or suppression of c-myb expression. However, it interfered significantly with the LIF-induced suppression of c-myc gene expression. Similar results were obtained when interleukin 6 was used to induce differentiation of M1 cells. Dexamethasone and 1 alpha,25-dihydroxyvitamin D3 did not induce junB gene expression but suppressed the expression of c-myb and c-myc. IL-4 also interfered with dexamethasone-induced suppression of c-myc gene expression. On the other hand, IL-4 enhanced 1 alpha,25-dihydroxyvitamin D3-induced down-regulation of c-myc gene expression, consistent with its enhancement of differentiation. These results indicate that the change in c-myc expression induced by IL-4 in M1 cells is closely associated with the effect of IL-4 on the induction of differentiation of M1 cells.
Kasukabe
T
T
Department of Chemotherapy, Saitama Cancer Center Research Institute, Japan.
Okabe-Kado
J
J
Hozumi
M
M
Honma
Y
Y
D000818:Animals; D002117:Calcitriol / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D003907:Dexamethasone / Q000037:antagonists & inhibitors*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors*; D015847:Interleukin-4 / Q000008:administration & dosage / Q000494:pharmacology*; D053605:Leukemia Inhibitory Factor; D007951:Leukemia, Myeloid / Q000473:pathology*; D008222:Lymphokines / Q000037:antagonists & inhibitors*; D051379:Mice; D010587:Phagocytosis / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D000093242:Interleukin-6 Inhibitors
D002117:Calcitriol; D003907:Dexamethasone; D006131:Growth Inhibitors; D015847:Interleukin-4; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D000093242:Interleukin-6 Inhibitors; C507838:Lif protein, mouse