The RON Receptor Tyrosine Kinase Regulates IFN-γ Production and Responses in Innate Immunity
| Autor: | Pamela A. Hankey, Daniel R. Sharda, Michael A. Lutz, Caleph B. Wilson, Jie Xu, Manujendra Ray |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Lipopolysaccharides
Immunology Suppressor of Cytokine Signaling Proteins Receptor tyrosine kinase Interferon-gamma Mice Suppressor of Cytokine Signaling 1 Protein CIITA Animals Immunology and Allergy Macrophage Genetic Predisposition to Disease STAT1 Receptor Cells Cultured Receptors Interferon Mice Knockout Mice Inbred BALB C Innate immune system biology Suppressor of cytokine signaling 1 Receptor Protein-Tyrosine Kinases Interleukin-12 Shock Septic Immunity Innate Up-Regulation Cell biology Mice Inbred C57BL Protein Subunits Suppressor of Cytokine Signaling 3 Protein biology.protein Phosphorylation Signal Transduction |
| Zdroj: | The Journal of Immunology. 181:2303-2310 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.181.4.2303 |
| Popis: | 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-γ and IL-12p70 and increased levels of IL-12p40 transcript in their spleen. This elevation of IFN-γ can be attributed to splenic NK cells responding to the elevated levels of IL-12. Analysis of RON and IFN-γ receptor double-knockout mice indicates that the enhanced susceptibility of RON−/− mice to endotoxin challenge is dependent on IFN-γ-mediated signals. In vitro studies demonstrate that stimulation of primary peritoneal macrophages with macrophage-stimulating protein, the ligand for RON, inhibits IFN-γ-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-γ, resulting in enhanced susceptibility to endotoxin challenge. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|