title: Endogenous IFN-alpha beta suppresses colony-stimulating factor (CSF)-1-stimulated macrophage DNA synthesis and mediates inhibitory effects of lipopolysaccharide and TNF-alpha.
abstract: Murine bone marrow-derived macrophages (BMM) are widely used as a suitable model to study the proliferative response to macrophage-CSF or CSF-1. We report here that the amount of DNA synthesis observed in BMM cultures in response to CSF-1 can be masked quite significantly by low levels of IFN-alpha beta produced in the cultures. It was found that Ab to IFN-alpha beta could enhance the proliferative response in CSF-treated BMM that were able to respond to endogenous IFN-alpha beta; however, BMM from mice lacking a component of the type I IFN receptor did not show any enhancement of CSF-1-dependent DNA synthesis on addition of the Ab. While DNA synthesis in CSF-1-stimulated BMM from normal mice was also very sensitive to the inhibitory actions of very low concentrations of added IFN-alpha beta, DNA synthesis in BMM from the "knockout" mice was not, indicating that the type I IFN receptor component containing the null mutation was essential for signal transduction. Previously it was shown that bacterial LPS, TNF-alpha, IFN-gamma, and cAMP could all inhibit CSF-1-stimulated BMM DNA synthesis and proliferation. Using the combined approach of blocking IFN-alpha beta Ab and the IFN receptor "knockout" mice, it was found here that the growth-inhibitory effects of LPS and TNF-alpha are due, to a significant extent, to endogenous IFN-alpha beta, whereas those of IFN-gamma and cAMP occur by a different mechanism. it is proposed that the type I IFN receptor (IFNAR 1) "knockout" mice may be useful in delineating some of the in vivo actions of CSF-1, LPS, TNF-alpha, and possibly other agents.
authors.affiliation: Department of Medicine, University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Hamilton
authors.forename: G A
authors.initials: GA
authors.lastname: Whitty
authors.forename: I
authors.initials: I
authors.lastname: Kola
authors.forename: P J
authors.initials: PJ
authors.lastname: Hertzog
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D000242:Cyclic AMP / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis*; D005260:Female; D066298:In Vitro Techniques; D016898:Interferon-alpha / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016898:Interferon-alpha; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D004247:DNA; D000242:Cyclic AMP