title: The RON receptor tyrosine kinase regulates IFN-gamma production and responses in innate immunity.
abstract: Receptor tyrosine kinases are emerging as a class of key regulators of innate immune responses. We have shown previously that the RON receptor tyrosine kinases (murine Stk), expressed on tissue-resident macrophages, inhibit classical macrophage activation while promoting hallmarks of alternative activation, thus regulating the critical balance between the inflammatory and wound-healing properties of activated macrophages. We have also shown previously that RON(-/-) mice are more susceptible to in vivo endotoxin challenge than wild-type mice, suggesting that the expression of this receptor confers a degree of endotoxin resistance to these animals. Here we demonstrate that, in response to in vivo LPS challenge, RON(-/-) mice harbor significantly increased systemic levels of IFN-gamma and IL-12p70 and increased levels of IL-12p40 transcript in their spleen. This elevation of IFN-gamma can be attributed to splenic NK cells responding to the elevated levels of IL-12. Analysis of RON and IFN-gamma receptor double-knockout mice indicates that the enhanced susceptibility of RON(-/-) mice to endotoxin challenge is dependent on IFN-gamma-mediated signals. In vitro studies demonstrate that stimulation of primary peritoneal macrophages with macrophage-stimulating protein, the ligand for RON, inhibits IFN-gamma-induced STAT1 phosphorylation and CIITA expression, resulting in reduced surface levels of MHC class II. Further studies demonstrating the induction of suppressor of cytokine signaling 1 via macrophage-stimulating protein/RON signaling provide a potential mechanistic insight into this regulatory pathway. These results indicate that the RON receptor regulates both the production of and response to IFN-gamma, resulting in enhanced susceptibility to endotoxin challenge.
authors.affiliation: Graduate Program in Pathobiology, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Caleph B
authors.initials: CB
authors.lastname: Wilson
authors.forename: Manujendra
authors.initials: M
authors.lastname: Ray
authors.forename: Michael
authors.initials: M
authors.lastname: Lutz
authors.forename: Daniel
authors.initials: D
authors.lastname: Sharda
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Hankey
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000097:blood / Q000502:physiology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000097:blood; D008070:Lipopolysaccharides / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021122:Protein Subunits / Q000096:biosynthesis / Q000097:blood; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017471:Receptors, Interferon / Q000502:physiology; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis; D015854:Up-Regulation / Q000276:immunology*; D000096743:Interferon gamma Receptor
chemical_list: D007371:Interferon-gamma; D018664:Interleukin-12; D008070:Lipopolysaccharides; D021122:Protein Subunits; D020794:Receptor Protein-Tyrosine Kinases; D017471:Receptors, Interferon; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000096743:Interferon gamma Receptor; C491590:Socs1 protein, mouse; C491411:Socs3 protein, mouse; C080835:RON protein