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

Abstract

1 Macrophage Stimulating Protein (MSP), a serum factor related to Hepatocyte Growth Factor, was originally discovered to stimulate chemotaxis of murine resident peritoneal macrophages. MSP is the ligand for Ron, a member of the Met subfamily of tyrosine kinase receptors. The e ects of MSP on human macrophages and the role played in human pathophysiology have long been elusive. 2 We show here that human recombinant MSP (hrMSP) evokes a dose-dependent superoxide anion production in human alveolar and peritoneal macrophages as well as in monocyte-derived macrophages, but not in circulating human monocytes. Consistently, the mature Ron protein is expressed by the MSP responsive cells but not by the unresponsive monocytes. The respiratory burst evoked by hrMSP is quantitatively higher than the one induced by N-formylmethionyl-leucylphenylalanine and similar to phorbol myristate acetate-evoked one. 3 To investigate the mechanisms involved in NADPH oxidase activation, leading to superoxide anion production, di erent signal transduction inhibitors were used. By using the non selective tyrosine kinase inhibitor genistein, the selective c-Src inhibitor PP1, the tyrosine phosphatase inhibitor sodium orthovanadate, the phosphatidylinositol 3-kinase inhibitor wortmannin, the 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 MAP kinase and p38 signalling pathways are involved. 4 These results clearly indicate that hrMSP induces the respiratory burst in human macrophages but not in monocytes, suggesting for the MSP/Ron complex a role of activator as well as of possible marker for human mature macrophages.

Angiotensin II Stimulation of NAD(P)H Oxidase Activity

“…However, in macrophage-stimulating protein-activated macrophages, ROS generation is not inhibited by wortmannin. 37 In some cell types, only the sustained phase of O 2 ·Ϫ production is mediated by PI3-K, 38 whereas in others, intracellular, but not extracellular, release of ROS is PI3-K dependent. 39 These data raise the possibility that PI3-K regulates those NAD(P)H oxidases that generate ROS inside the cell, such as the VSMC oxidases.…”

“…PIP 3 binds the PX domain of p47phox, the cytosolic regulator of both neutrophil and nonphagocytic oxidases, possibly controlling localization to distinct intracellular compartments. 22 An involvement of Src in activation of NAD(P)H oxidases has been suggested in eosinophils and macrophages, 37,38 but its role in regulating novel Nox isoforms, such as those expressed in VSMCs, is not known. In eosinophils stimulated with leukotriene-B 4 , PP1 inhibited both the rapid and sustained phases of O 2 ·Ϫ release, 38 whereas in macrophages, it blocked macrophage-stimulating protein-mediated ROS generation.…”

The Receptor Tyrosine Kinase RON Represses HIV-1 Transcription by Targeting RNA Polymerase II Processivity

“…RON is primarily expressed on human tissue resident macrophages which are not readily accessible or amendable to biochemical studies (22,23,30,31). Therefore, to gain further insight into mechanisms by which RON repress HIV-1 provirus transcription we used site-directed mutagenesis to generate several mutations in the RON cytoplasmic domain (25,26).…”

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-γ and Lipopolysaccharide

“…Signaling through this family of receptors has been shown to recruit a number of SH2-containing signaling molecules, including PLC-␥, phosphoinositol 3-kinase, Shc, and Grb2 (25,27), as well as the adaptor protein Gab 1 (28). RON is expressed on tissue-resident macrophages, including resident peritoneal macrophages (29), human alveolar macrophages (30), osteoclasts (31), and dermal macrophages (19), but is not present on circulating monocytes or bone marrow macrophages (29). RON expression, which is regulated during inflammation, is inhibited by proinflammatory cytokines and NO (32), but is upregulated on day 3 peritoneal exudate macrophages (29) and burn wound exudate macrophages (19).…”