Inhibition of the signaling pathways for macrophage proliferation by cyclic AMP. Lack of effect on early responses to colony stimulating factor-1.
Colony stimulating factor-1 (CSF-1) stimulates DNA synthesis in quiescent murine bone marrow-derived macrophages (BMM). CSF-1 action has been shown to involve activation of the CSF-1 receptor kinase. The protein kinase C activator, 12-O-tetradecanoylphorbol 13-acetate (PMA), is itself weakly mitogenic and synergises with CSF-1 for stimulation of BMM DNA synthesis suggesting a possible role for protein kinase C in the stimulation of BMM DNA synthesis. In this report we show that several agents which raise intracellular cAMP (8-bromoadenosine 3':5'-cyclic monophosphate, 3-isobutyl-1-methylxanthine, cholera toxin, and prostaglandin E2) reversibly inhibit DNA synthesis in BMM induced by CSF-1, granulocyte macrophage-colony stimulating factor, interleukin-3, and PMA. The suppressive action of cAMP elevation on the proliferative response to CSF-1 can be manifested even late in the G1 phase of the cell cycle. Several CSF-1-stimulated earlier responses, viz. protein synthesis, Na+/H+ exchange, Na+,K(+)-ATPase and c-myc-mRNA expression, were not inhibited thus showing a striking difference from some other cellular systems involving growth factor-mediated responses. c-fos-mRNA levels were raised and stabilized by the cAMP-elevating agents, and this modulation was not altered by CSF-1. Thus, the signaling pathways in the macrophages involving tyrosine kinase and protein kinase C activation are associated with increased proliferation while those involving elevation of cAMP (and presumably activation of cAMP-dependent protein kinases) appear to have an inhibitory effect.
Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, Australia.
G
G
Vairo
S
S
Argyriou
A M
AM
Bordun
G
G
Whitty
J A
JA
Hamilton
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology*; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology*; D000818:Animals; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000494:pharmacology; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D000242:Cyclic AMP / Q000502:physiology*; D004261:DNA Replication / Q000187:drug effects; D015232:Dinoprostone / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000166:cytology; D007700:Kinetics; D016173:Macrophage Colony-Stimulating Factor; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D009857:Oncogenes / Q000187:drug effects; D014176:Protein Biosynthesis; D015398:Signal Transduction / Q000187:drug effects*; D017923:Sodium-Hydrogen Exchangers; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013806:Theophylline / Q000031:analogs & derivatives*
D002352:Carrier Proteins; D003115:Colony-Stimulating Factors; D017923:Sodium-Hydrogen Exchangers; D015124:8-Bromo Cyclic Adenosine Monophosphate; D016173:Macrophage Colony-Stimulating Factor; D002772:Cholera Toxin; D013806:Theophylline; D000242:Cyclic AMP; D000254:Sodium-Potassium-Exchanging ATPase; D015232:Dinoprostone; D015056:1-Methyl-3-isobutylxanthine