title: Macrophage-stimulating protein, the ligand for the stem cell-derived tyrosine kinase/RON receptor tyrosine kinase, inhibits IL-12 production by primary peritoneal macrophages stimulated with IFN-gamma and lipopolysaccharide.
abstract: IL-12, produced by APCs during the initial stages of an immune response, plays a pivotal role in the induction of IFN-gamma by NK and gammadeltaT cells and in driving the differentiation of Th1 cells, thus providing a critical link between innate and acquired immunity. Due to the unique position occupied by IL-12 in the regulation of immunity, many mechanisms have evolved to modulate IL-12 production. We have shown previously that macrophage-stimulating protein (MSP), the ligand for the stem cell-derived tyrosine kinase/recepteur d'origine nantais (RON) receptor, inhibits NO production by macrophages in response to IFN-gamma and enhances the expression of arginase. Mice lacking RON exhibit increased inflammation in a delayed-type hypersensitivity reaction and increased susceptibility to endotoxic shock. In this study we demonstrate that pretreatment of macrophages with MSP before IFN-gamma and LPS results in the complete inhibition of IL-12 production due to suppression of p40 expression. This response is mediated by the RON receptor, and splenocytes from RON(-/-) animals produce increased levels of IFN-gamma. MSP pretreatment of macrophages resulted in decreased tyrosine phosphorylation of Stat-1 and decreased expression of IFN consensus sequence binding protein in response to inflammatory cytokines. In addition to IL-12, the expression of IL-15 and IL-18, cytokines that are also dependent on IFN consensus sequence binding protein activation, is inhibited by pretreatment with MSP before IFN-gamma and LPS. We also show that the ability of MSP to inhibit IL-12 production is independent of IL-10. Taken together, these results suggest that MSP may actively suppress cell-mediated immune responses through its ability to down-regulate IL-12 production and thus inhibit classical activation of macrophages.
authors.affiliation: Department of Veterinary Science, Graduate Program in Biochemistry, Microbiology, and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Morrison
authors.forename: Caleph B
authors.initials: CB
authors.lastname: Wilson
authors.forename: Manujendra
authors.initials: M
authors.lastname: Ray
authors.forename: Pamela H
authors.initials: PH
authors.lastname: Correll
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma / Q000494:pharmacology*; D016753:Interleukin-10 / Q000502:physiology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008262:Macrophage Activation / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000276:immunology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism; D014443:Tyrosine / Q000037:antagonists & inhibitors; D000099185:Interferon Regulatory Factor-8
chemical_list: D004268:DNA-Binding Proteins; D017228:Hepatocyte Growth Factor; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D016753:Interleukin-10; D018664:Interleukin-12; D008024:Ligands; D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D014443:Tyrosine; D000099185:Interferon Regulatory Factor-8; C494080:Stat1 protein, mouse; C082332:macrophage stimulating protein; C080835:RON protein