* Department of Medicine, University of Colorado School of Medicine, Denver Health Medical Center, Denver; and
Division of Neurosurgery, The First Affiliated Teaching Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
Correspondence: M-H. Wang, Department of Medicine, UCHSC, Denver Health Medical Center, Mail 4000, 777 Bannock Street, Denver, CO 80204. E-mail: ming-hai.wang{at}uchsc.edu
RON is a receptor tyrosine kinase activated by macrophage-stimulating protein. We demonstrate here that RON activation inhibits LPS-induced apoptosis of mouse peritoneal macrophages and Raw264.7 cells expressing RON or a constitutively active RON mutant. The antiapoptotic effect of RON was accompanied with the inhibition of LPS-induced production of nitric oxide (NO), a molecule responsible for LPS-induced cell apoptosis. This conclusion is supported by experiments using a chemical NO donor GSNO, in which RON activation directly blocked GSNO-induced apoptotic death of Raw264.7 cells and inhibited LPS-induced p53 accumulation. Furthermore, we showed that treatment of cells with wortmannin, which inhibits phosphatidylinositol (PI)-3 kinase, prevents the inhibitory effect of RON on LPS-induced macrophage apoptosis. These results were confirmed further by expression of a dominant inhibitory PI-3 kinase p85 subunit. These data suggest that by activating PI-3 kinase and inhibiting p53 accumulation, RON protects macrophage from apoptosis induced by LPS and NO. The antiapoptotic effect of RON might represent a novel mechanism for the survival of activated macrophages during inflammation.
Key Words: MSP • apoptosis • PI-3 kinase • iNOS
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