Transduction of a signal for arachidonic acid metabolism by untriggered CSF-1 receptor induces an opposite effect to that induced by CSF-1 receptor and its ligand: separate regulation of phospholipase A2 and cyclooxygenase by CSF-1 receptor/CSF-1.
The mouse hematopoietic cell line, 32D, was transfected with c-fms, which encodes for the CSF-1 receptor, a tyrosine kinase (TK). In the absence of CSF-1, transfected cells show moderate levels of arachidonic acid (AA) release and produce a substantial amount of prostaglandin E2 (PGE2) in comparison with the original cell line. Exposure of transfected cells to CSF-1, while inducing a substantial increase in arachidonate release, nevertheless resulted in inhibition of PGE2 production. Addition of ST638, a tyrosine kinase inhibitor, to cells transfected with c-fms in the absence of CSF-1 inhibited PGE2 production within 10-60 min. Its addition to the same cells in the presence of CSF-1 induced an opposite effect, but required longer treatment (24 h). In either cell type, AA release was not affected by this agent. These data indicate that CSF-1 may regulate cyclooxygenase activity. The different effect of CSF-1 receptor on PGE2 production in the presence or absence of CSF-1 and the opposite effect of a tyrosine kinase inhibitor on PGE2 suggest that both the receptor alone or the receptor-ligand complex may transduce an active, but different, signal through tyrosine phosphorylation. CSF-1 receptor and CSF-1 may exert separate, but related, effects on phospholipase A2 and cyclooxygenase activity which, in concert, or along with other tyrosine kinases, regulate prostaglandin production.
Puri
J
J
Division of Hematology, US Food and Drug Administration, Bethesda, Maryland 20892.
Pierce
J H
JH
Hoffman
T
T
D000818:Animals; D017302:Annexins; D016718:Arachidonic Acid / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002934:Cinnamates / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins; D015398:Signal Transduction; D013440:Sulfides / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015054:Zymosan / Q000494:pharmacology
D017302:Annexins; D002135:Calcium-Binding Proteins; D002934:Cinnamates; D008563:Membrane Lipids; D011994:Recombinant Proteins; D013440:Sulfides; C060747:ST 638; D016718:Arachidonic Acid; D015759:Ionomycin; D016173:Macrophage Colony-Stimulating Factor; D015054:Zymosan; D011451:Prostaglandin-Endoperoxide Synthases; D011505:Protein-Tyrosine Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor; D011493:Protein Kinase C; D010741:Phospholipases A; D054467:Phospholipases A2; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate