Regulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors in a GM-CSF-dependent human myeloid leukemia cell line (AML-193) by interleukin-6.
AML-193 is a cytokine-dependent human leukemia cell line established from the bone marrow of an M5-type acute monocytic leukemia (AML) patient. The effect of recombinant human interleukin-6 (rhIL-6) on the proliferation of AML-193 cells was investigated. Both granulocyte-macrophage colony-stimulating factor (rhGM-CSF) and rhIL-3 promoted the DNA synthesis and growth of AML-193 cells in vitro. rhIL-6 alone did not support the growth of AML-193 cells, yet pretreatment of AML-193 cells with rhIL-6 markedly enhanced their proliferative response to subsequent rhGM-CSF or rhIL-3 stimulation. The growth-promoting effect induced by rhIL-6 was attributable in part to the upregulation of GM-CSF receptors on AML-193 cells; treatment of AML-193 cells with rhIL-6 for 24 to 48 hours greatly increased their GM-CSF binding activity, which occurred in a dose-dependent manner. Both the growth-promoting and receptor-upregulating effects induced by rhIL-6 could be blocked by treating AML-193 cells with neutralizing anti-gp130 antibodies (GPX7). Treatment of AML-193 cells with anti-gp130 antibodies alone also led to a notable decline in GM-CSF binding activity, suggesting a possible role of gpl30 in regulating the expression of GM-CSF receptors. When AML-193 cells were starved in cytokine-free medium and then restimulated with rhGM-CSF, a rapid increase (5 minutes) in lyn kinase activity was observed. A similar upregulation of lyn kinase activity by rhIL-6 treatment also was noted in AML-193 cells, but only after a prolonged incubation of the cells with rhIL-6 (>24 hours). These findings show that the growth-promoting effects of rhIL-6 are mediated through the upregulation of GM-CSF receptors on AML-193 cells by mechanisms that appear to involve the activation of both gp130 and lyn kinase.
Li
Y
Y
Division of Hematology/Oncology, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Valeriote
F
F
Chen
B
B
D015703:Antigens, CD / Q000378:metabolism; D002455:Cell Division; D050822:Cytokine Receptor gp130; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D007948:Leukemia, Monocytic, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis* / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*; D019061:src-Family Kinases / Q000378:metabolism
D015703:Antigens, CD; C494199:IL6ST protein, human; D007377:Interleukin-3; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D011994:Recombinant Proteins; D050822:Cytokine Receptor gp130; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases