title: Priming of mouse macrophages with the macrophage colony-stimulating factor (CSF-1) induces a variety of pathways that regulate expression of the interleukin 6 (Il6) and granulocyte-macrophage colony-stimulating factor (Csfgm) genes.
abstract: Recent data have indicated that resident mouse peritoneal macrophages (PMo) transcribed the interleukin 6 (Il6) and granulocyte-macrophage colony-stimulating factor (Csfgm) genes in response to stimulation with the monocyte-macrophage colony-stimulating factor (CSF-1) but only Il6 mRNA was translated into secreted protein. In this paper, we extend these observations. It is shown that resident PMo incubated with protein kinase (PK)C inhibitors, staurosporine (SP) and its derivative GF109203-X, showed a several fold increase in the levels of Il6 mRNA in control and CSF-1-primed PMo and a parallel release of large amounts of protein. In contrast, SP was shown to have no effect on the release of GM-CSF from control or CSF-1-primed PMo, although it increased by approximately twofold the amount of Csfgm mRNA in CSF-1-primed Mo. When SP was added 4 h after CSF-1 priming to block CSF-1-induced protein kinase pathways, an increased amount of IL-6 release was again seen but without any increase in Il6 mRNA levels. Under these conditions, Csfgm gene expression was relatively unaffected. Activation of PKC by phorbol myristate acetate (PMA) also resulted in increased Il6 gene expression by control and CSF-1-primed PMo. PMA had no apparent effect on Csfgm transcription but appeared to influence translation at a low level, as measured by the release of small amounts of GM-CSF protein. The addition of lipopolysaccharide (LPS) to CSF-1-primed PMo resulted in a synergistic increase in the expression of both genes at the levels of transcription and protein release. The addition of SP to CSF-1-primed Mo before LPS, however, further enhanced IL-6 release but not GM-CSF release from the cells. The data indicate that CSF-1-priming drives a number of pathways involved in the regulation of expression of both genes and renders PMo highly susceptible to appropriate secondary stimulatory agents that transform the PMo into secretory inflammatory cells.
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, 04609, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Kamdar
authors.forename: J A
authors.initials: JA
authors.lastname: Fuller
authors.forename: S I
authors.initials: SI
authors.lastname: Nishikawa
authors.forename: R
authors.initials: R
authors.lastname: Evans
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D007211:Indoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis*; D007700:Kinetics; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D019311:Staurosporine / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D015850:Interleukin-6; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011494:Protein Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor; D019311:Staurosporine; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate