title: Inhibition of TLR4-induced IκB kinase activity by the RON receptor tyrosine kinase and its ligand, macrophage-stimulating protein.
abstract: The RON receptor tyrosine kinase regulates the balance between classical (M1) and alternative (M2) macrophage activation. In primary macrophages, the ligand for Ron, macrophage-stimulating protein (MSP), inhibits the expression of inducible NO synthase, a marker of classically activated macrophages, whereas promoting the expression of arginase I, a marker of alternative activation. Ron(-/-) mice express increased levels of IL-12, a product of classically activated macrophages, after endotoxin administration, resulting in increased serum IFN-γ levels and enhanced susceptibility to septic shock. In this study, we demonstrate that MSP inhibits LPS-induced IL-12p40 expression, and this inhibition is dependent on the docking site tyrosines in Ron. To further define this inhibition, we examined the effect of Ron on signaling pathways downstream of Ron. We found that MSP does not inhibit the MyD88-independent activation of IFN regulatory factor 3 and production of IFN-β in response to LPS, nor does it inhibit MyD88-dependent TGF-β-activated kinase phosphorylation or MAPK activation in primary macrophages. However, the induction of IκB kinase activity, IκB degradation, and DNA binding of NF-κB after LPS stimulation is delayed in the presence of MSP. In addition, Ron inhibits serine phosphorylation of p65 and NF-κB transcriptional activity induced by LPS stimulation of TLR4. Finally, MSP inhibits the NF-κB-dependent upregulation of the nuclear IκB family member, IκBζ, a positive regulator of secondary response genes including IL-12p40. LPS also induces expression of Ron and an N-terminally truncated form of Ron, Sf-Ron, in primary macrophages, suggesting that the upregulation of Ron by LPS could provide classical feedback regulation of TLR signaling.
authors.affiliation: Department of Veterinary and Biomedical Science, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Manujendra
authors.initials: M
authors.lastname: Ray
authors.forename: Shan
authors.initials: S
authors.lastname: Yu
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Sharda
authors.forename: Caleph B
authors.initials: CB
authors.lastname: Wilson
authors.forename: QingPing
authors.initials: Q
authors.lastname: Liu
authors.forename: Naveen
authors.initials: N
authors.lastname: Kaushal
authors.forename: K Sandeep
authors.initials: KS
authors.lastname: Prabhu
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Hankey
mesh_terms: D000818:Animals; D002460:Cell Line; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D050838:Interferon Regulatory Factor-3; D053762:Interleukin-12 Subunit p40; C494233:Irf3 protein, mouse; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011518:Proto-Oncogene Proteins; C498144:Rela protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; D016899:Interferon-beta; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D051550:I-kappa B Kinase