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Department of Internal Medicine, Division of Pulmonary/Critical Care Medicine, Wayne State University School of Medicine, Detroit, MI 48201
RON (recepteur d’origine nantais) is a receptor tyrosine kinase
expressed in murine peritoneal resident macrophages and activated by
macrophage-stimulating protein (MSP). The objectives of this
investigation were to study the RON expression in exudate macrophages
and the mechanisms by which RON inhibits inducible nitric oxide
synthase (iNOS) expression induced by LPS and IFN-
. We found that
mouse peritoneal resident and Con A-elicited macrophages collected on
day 3 or day 5 express RON. Acute exudate macrophages collected on day
1 did not express RON. Activation of RON inhibited LPS- and
IFN--induced macrophage nitric oxide production and iNOS mRNA
accumulation. Similar inhibition was observed also in Raw264.7
macrophage cell lines transfected with human RON cDNA. In these cells,
MSP induced RON phosphorylation concomitant with reduced iNOS mRNA
expression and protein synthesis. Further, we show that activated RON
inhibited the iNOS gene transcription activity as assessed by
chloramphenicol acetyltransferase activity in Raw264.7 cells expressing
RON. Wortmannin, a specific inhibitor of phosphatidylinositol-3 (PI-3)
kinase, prevented the inhibitory effect of RON on the iNOS gene
promoter activity and on the nitric oxide production induced by LPS and
IFN-. These effects were confirmed further by introducing a
dominant-inhibitory PI-3 kinase p85 subunit in RON-expressing Rwa264.7
cells. Taken together, our results suggest that RON is expressed in
peritoneal macrophages at later stages of inflammation. Activation of
RON by MSP in mature exudate macrophages inhibits LPS- and
IFN--induced iNOS synthesis. PI-3 kinase is an important effector
molecule required for RON-mediated inhibition of iNOS expression in
macrophages.
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