Inhibition of TLR4-Induced I kappa B Kinase Activity by the RON Receptor Tyrosine Kinase and Its Ligand, Macrophage-Stimulating Protein

Department of Veterinary and Biomedical Science, The Pennsylvania State University, University Park, PA 16802, USA.
The Journal of Immunology (Impact Factor: 4.92). 11/2010; 185(12):7309-16. DOI: 10.4049/jimmunol.1000095
Source: PubMed


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.

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    • "TMPRSS11D plays an important role in the activation of the pro-macrophage-stimulating protein [43], which induces macrophage spreading, migration, phagocytosis, and cytokine production. It also inhibits the lipopolysaccharide-induced production of inflammatory mediators [44-46]. DCK has a functional role for drug resistance and sensitivity [47] and IGJ regulates the structure and function of IgM polymers secreted by B cells [48] and helps to bind immunoglobulins with secretory components [49]. "
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