Regulation of TLR4 signaling in macrophages by Macrophage Stimulating Protein, the ligand for the Ron receptor tyrosine kinase (134.20)

Abstract

Abstract The Ron receptor tyrosine kinase regulates the balance between classical (M1) and alternative (M2) macrophage activation. The ligand for Ron, macrophage stimulating protein (MSP), inhibits the expression of iNOS, while promoting the expression of arginase I in primary murine macrophages. Ron-/- mice express elevated levels of IL-12 following endotoxin administration, resulting in increased serum IFNγ levels and enhanced susceptibility to septic shock. Here, we demonstrate that MSP inhibits LPS-induced IL-12p40 expression in primary macrophages. MSP does not inhibit the MyD88-independent activation of IRF3 and production of IFNβ in response to LPS, but limits the IFNβ-dependent phosphorylation of Stat1 following LPS stimulation. While MSP does not inhibit LPS-induced Tak1 phosphorylation or Map kinase activation in primary macrophages, the induction of IκB kinase (IKK) activity, IκB degradation and DNA binding of NFκB following LPS stimulation are delayed in the presence of MSP. In addition, Ron inhibits serine phosphorylation of p65 and NFκB transcriptional activity induced by LPS stimulation of TLR4. Finally, MSP inhibits the NFκB-dependent upregulation of the nuclear IκB family member, IκBζ, while inducing expression of the Stat3-regulated nuclear IκB family member, Bcl-3. LPS also induces expression of Ron and Sf-Ron in primary macrophages, suggesting that the upregulation of Ron by LPS could play a role in limiting subsequent LPS responses in macrophages.