Macrophage Stimulating Protein (MSP) evokes superoxide anion production byhuman macrophages of different origin

1 Macrophage Stimulating Protein (MSP), a serum factor related to Hepatocyt e Growth Factor, was originally discovered to stimulate chemotaxis of murin e resident peritoneal macrophages. MSP is the ligand for Ron, a member of t he Met subfamily of tyrosine kinase receptors. The effects of MSP on human macrophages and the role played in human pathophysiology have long been elu sive. 2 We show here that human recombinant MSP (hrMSP) evokes a dose-dependent s uperoxide anion production in human alveolar and peritoneal macrophages as well as in monocyte-derived macrophages, but not in circulating human monoc ytes. Consistently, the mature Ron protein is expressed by the MSP responsi ve cells but not by the unresponsive monocytes. The respiratory burst evoke d by hrMSP is quantitatively higher than the one induced by N-formylmethion yl-leucyl-phenylalanine and similar to phorbol myristate acetate-evoked one . 3 To investigate the mechanisms involved in NADPH oxidase activation, leadi ng to superoxide anion production, different signal transduction inhibitors were used. By using the non selective tyrosine kinase inhibitor genistein, the selective c-Src inhibitor PPI, the tyrosine phosphatase inhibitor sodi um orthovanadate, the phosphatidylinositol 3-kinase inhibitor wortmannin, t he p38 inhibitor SB203580, the MEK inhibitor PD098059, we demonstrate that hrMSP-evoked superoxide production is mediated by tyrosine kinase activity, requires the activation of Src but not of PI 3-kinase. We also show that M AP kinase and p38 signalling pathways are involved. 4 These results clearly indicate that hrMSP induces the respiratory burst i n human macrophages but not in monocytes, suggesting for the MSP/Ron comple x a role of activator as well as of possible marker for human mature macrop hages.