Macrophage-stimulating protein, the ligand for the stem cell-derived tyrosine/ RON receptor tyrosine kinase, inhibits IL-12 production by primary peritoneal macrophages stimulated with IFN-γ and lipopolysaccharide

J. Immunol. 172: 1825- 1832, 2004

Speaker：李秀儀                             Time：2004/11/24 15:00~16:00 Commentator：王志堯 老師                    Place：Room 601

Abstract

Macrophage-stimulating protein (MSP) is an 80-kDa serum growth factor that promotes macrophage movement, chemotaxis and spreading. Previous studies showed that MSP via RON receptor tyrosine kinase, could inhibit NO production from macrophages in response to IFN-γ. IL-12, produced by macrophage, is a pro-inflammatory cytokine and stimulates IFN-γ production in both NK and γdT cells. Using RON^-/- mice model, the authors demonstrated that RON, the receptor of MSP, played an important role in regulating IL-12 production which was involved in inflammatory response. Both ELISA and RT-PCR results showed that MSP-pretreated peritoneal macrophage before stimulation with IFN-γ and lipopolysaccharide (LPS) could inhibit IL-12 production by repressing the expression of IL-12 p40 subunit. MSP-pretreated peritoneal macrophage in RON^-/- mice demonstrated that MSP could inhibit IL-12 production via RON receptor. Previous studies have demonstrated the significance of STAT-1-related signal pathways in regulating IL-12 production. MSP could inhibit STAT-1 phosphorylation via RON receptor and then affected the expression of a transcription factor, IFN consensus sequence binding protein (ICSBP), in downstream of STAT-1. The influence of ICSBP is not only on IL-12 p40 promoter activity, but also on the transcriptional level of IL-15 and IL-18. In addition, the authors ruled out the possibility of IL-10, an inhibitor of IL-12, in MSP-mediated inhibitory mechanism for inflammatory-involved IL-12 production. Take together, MSP-mediated IL-12 production and its related signaling is via RON receptor in an IL-10-independent manner. This is the first study to demonstrate that MSP-RON signaling pathway regulates the expression of IL-12 by APCs as well as by limiting IFN-γ production.

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