Activation of the stem cell-derived tyrosine kinase/RON receptor tyrosine kinase by macrophage-stimulating protein results in the induction of arginase activity in murine peritoneal macrophages.
Regulation of macrophage activities in response to inflammatory stimuli must be finely tuned to promote an effective immune response while, at the same time, preventing damage to the host. Our lab and others have previously shown that macrophage-stimulating protein (MSP), through activation of its receptor RON, negatively regulates NO production in response to IFN-gamma and LPS by inhibiting the expression of inducible NO synthase (iNOS). Furthermore, activated macrophages from mice harboring targeted mutations in RON produce increased levels of NO both in vitro and in vivo, rendering them more susceptible to LPS-induced endotoxic shock. In this study, we demonstrate that stimulation of murine peritoneal macrophages with MSP results in the RON-dependent up-regulation of arginase, an enzyme associated with alternative activation that competes with iNOS for the substrate L-arginine, the products of which are involved in cell proliferation and matrix synthesis. Expression of other genes associated with alternative activation, including scavenger receptor A and IL-1R antagonist, is also up-regulated in MSP-stimulated murine macrophages. Stimulation of cells with IFN-gamma and LPS blocks the ability of MSP to induce arginase activity. However, pretreatment of cells with MSP results in the up-regulation of arginase and inhibits their ability to produce NO in response to IFN-gamma and LPS, even in the presence of excess substrate, suggesting that the inhibition of NO by MSP occurs primarily through its ability to regulate iNOS expression.
Morrison
Amy C
AC
Department of Veterinary Science and Graduate Program in Biochemistry, Microbiology, and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
Correll
Pamela H
PH
D000818:Animals; D001119:Arginase / Q000096:biosynthesis*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000276:immunology; D004790:Enzyme Induction / Q000276:immunology; D006133:Growth Substances / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000201:enzymology*; D017228:Hepatocyte Growth Factor; D007371:Interferon-gamma / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein; D016753:Interleukin-10 / Q000096:biosynthesis; 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; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism* / Q000502:physiology; D011956:Receptors, Cell Surface / Q000378:metabolism* / Q000502:physiology; D011971:Receptors, Immunologic / Q000096:biosynthesis; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D051116:Receptors, Scavenger; D012795:Sialoglycoproteins / Q000096:biosynthesis
D006133:Growth Substances; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D051116:Receptors, Scavenger; D012795:Sialoglycoproteins; C082332:macrophage stimulating protein; D016753:Interleukin-10; D009569:Nitric Oxide; D017228:Hepatocyte Growth Factor; D007371:Interferon-gamma; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D001119:Arginase