Functional expression of the macrophage colony-stimulating factor receptor in human THP-1 monocytic leukemia cells.
Macrophage colony-stimulating factor (M-CSF) is required for the proliferation, differentiation, and activation of monocytes. High-affinity receptors for M-CSF are encoded by the c-fms proto-oncogene. In the present study, we show that c-fms transcripts are detectable in human THP-1 myeloid leukemia cells. Furthermore, radiolabeled 125I-M-CSF is rapidly internalized into THP-1 cells and then degraded intracellularly. The results also show that treatment of THP-1 cells with M-CSF is associated with the activation of protein kinase C (PKC) and the induction of tumor necrosis factor (TNF) gene expression. TNF transcript levels were low to undetectable in uninduced THP-1 cells, reached maximal levels by 1 hour of exposure to M-CSF, and returned to those of control cells by 24 hours. Transcriptional run-on analysis showed that a low level of TNF transcription is detectable in untreated THP-1 cells, and M-CSF treatment increased the rate of TNF transcription. Pretreatment of THP-1 cells with pertussis toxin inhibited the increase in PKC activity but not the induction of TNF transcripts by M-CSF. Moreover, exposure of THP-1 cells to inhibitors of protein kinase activity blocked the increase in TNF messenger RNA. These findings suggest that at least two M-CSF-mediated signaling pathways exist in THP-1 cells and that the induction of TNF may be regulated by a protein kinase-dependent mechanism distinct from PKC.
Datta
R
R
Laboratory of Clinical Pharmacology, Dana-Farber Cancer Institute, Boston, MA 02115.
Imamura
K
K
Goldman
S J
SJ
Dianoux
A C
AC
Kufe
D W
DW
Sherman
M L
ML
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D001710:Biotin; D004789:Enzyme Activation; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D015479:Leukemia, Myelomonocytic, Acute / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D037342:Pertussis Toxin; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D007546:Isoquinolines; C000715470:MAS1 protein, human; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D010566:Virulence Factors, Bordetella; D001710:Biotin; D016173:Macrophage Colony-Stimulating Factor; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D037342:Pertussis Toxin; D016186:Receptor, Macrophage Colony-Stimulating Factor; D011493:Protein Kinase C