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

Abstract

IL-12, produced by APCs during the initial stages of an immune response, plays a pivotal role in the induction of IFN-γ by NK and γδT cells and in driving the differentiation of Th1 cells, thus providing a critical link between innate and acquired immunity. Due to the unique position occupied by IL-12 in the regulation of immunity, many mechanisms have evolved to modulate IL-12 production. We have shown previously that macrophage-stimulating protein (MSP), the ligand for the stem cell-derived tyrosine kinase/recepteur d’origine nantais (RON) receptor, inhibits NO production by macrophages in response to IFN-γ and enhances the expression of arginase. Mice lacking RON exhibit increased inflammation in a delayed-type hypersensitivity reaction and increased susceptibility to endotoxic shock. In this study we demonstrate that pretreatment of macrophages with MSP before IFN-γ and LPS results in the complete inhibition of IL-12 production due to suppression of p40 expression. This response is mediated by the RON receptor, and splenocytes from RON−/− animals produce increased levels of IFN-γ. MSP pretreatment of macrophages resulted in decreased tyrosine phosphorylation of Stat-1 and decreased expression of IFN consensus sequence binding protein in response to inflammatory cytokines. In addition to IL-12, the expression of IL-15 and IL-18, cytokines that are also dependent on IFN consensus sequence binding protein activation, is inhibited by pretreatment with MSP before IFN-γ and LPS. We also show that the ability of MSP to inhibit IL-12 production is independent of IL-10. Taken together, these results suggest that MSP may actively suppress cell-mediated immune responses through its ability to down-regulate IL-12 production and thus inhibit classical activation of macrophages.

Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis

“…First, proteolytic activation of MSP have been proposed to occur in areas of active inflammation through cell-surface proteases located on macrophages (38), (39). Second, while MSP was originally identified as a protein that could elicit macrophage chemotaxis and activation, signaling though the MSP/MST1R has recently been shown to inhibit LPS or cytokine mediated production of inflammatory mediators (such as NO, COX2, PGE2 and IL-12p40) by macrophages, through the inhibition of NfkB signaling (24)(25)(26)(27). Interestingly, increased NfkB signaling activity, as well as increased levels on NO and expression of IL-12p40, have all been observed in the inflamed mucosa of patients with IBD (48)(49)(50).…”

“…MSP is the only known ligand for the MST1R, also known as RON receptor, a disulphide-linked heterodimer composed of an extracellular α chain and a transmembrane β chain with intrinsic kinase activity, expressed predominantly on tissue resident (differentiated) macrophages and epithelial cells (40). Signaling through the MSP/ MST1R has been shown to inhibit LPS or cytokine mediated production of inflammatory mediators by macrophages (24)(25)(26)(27), through the inhibition of NfkB signaling, while mice deficient in MST1R show increase susceptibility to septic shock following LPS challenge (41,42). We have also observed, from publicly available microarray datasets, that MST1 gene expression is elevated during intestinal enterocyte differentiation in Caco-2 cells and in the biopsies from non-inflamed ileum of Crohn's disease patients (data not shown).…”

“…We then narrowed the associated interval to 336 Kb region and identified a non-synonymous coding variant (R689C) in the macrophage stimulating 1 gene (MST1) that is a common risk factor for IBD. MSP, the protein encoded by MST1, and its receptor MST1R have been reported to be involved in macrophage chemotaxis and activation (22,23), as well as regulation of inflammatory responses (such as NO and IL12p40 production) following proinflammatory signals (24)(25)(26)(27). Taken together these data suggest a role for MST1 in IBD pathogenesis.…”

Macrophage-stimulating protein polymorphism rs3197999 is associated with a gain of function: implications for inflammatory bowel disease

“…3,39 In resident peritoneal macrophages stimulated by LPS (lipopolysaccharide) and IFN-g, MSP was reported to suppress IL-12/IL-23 p40 and TNF-a release independent from IL-10. 40 Deficient down-regulation of IL-12/IL-23 release by macrophages of the inflammatory phenotype induces T-helper cell differentiation (Th1, Th17) and/or stabilization of the differentiation status, 41 which is essential for the activation of the adaptive immune response in IBD. 3.…”

Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma

“…MST1R encodes a cell surface receptor for macrophage-stimulating 1 (MST1, also known as MSP) with tyrosine kinase activity. Previous studies show that MST1R plays a critical function in host defense: (i) It is predominantly expressed in the tissue-resident macrophages, which promote tissue repair and inhibit inflammation by repressing the production of proinflammatory molecules induced by pathogens (14)(15)(16)(17) and (ii) MST1R expression is detected in the ciliated epithelial cells in the normal nasal mucosa, and activation of MST1R signaling can increase the ciliary motility to prevent chronic infection (18). Previous studies and our WES data strongly support the role of MST1R as an NPC susceptibility gene.…”