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Negative Regulation of Macrophage Activation in Response to IFN- and Lipopolysaccharide by the STK/RON Receptor Tyrosine Kinase¹

Qing-Ping Liu^*, Kristy Fruit, Jennifer Ward and Pamela H. Correll^2,*,,

^* Department of Veterinary Science, Graduate Program in Pathobiology, and Women in Science and Engineering Research Program, Pennsylvania State University, University Park, PA 16802

IFN- primes macrophages for antimicrobial activity, increased killing of intracellular pathogens, and Ag processing and presentation to lymphocytes by cooperating with a second signal (provided by LPS or endogenous TNF-) to promote increased proinflammatory cytokine production, NO production, and MHC class II expression. Macrophage-stimulating protein (MSP) suppresses NO production by activated peritoneal macrophages in vitro. Furthermore, targeted deletion of the receptor for MSP, stem cell-derived tyrosine kinase receptor (STK/RON), resulted in increased production of NO by activated macrophages both in vitro and in vivo. Here we demonstrate that expression of STK in RAW264.7 cells resulted in suppression of NO production following IFN-^+/- LPS stimulation in the presence of MSP, reflecting a decrease in the levels of inducible NO synthase (iNOS) mRNA and protein, which was confirmed by decreased trans-activation of an iNOS reporter. The iNOS expression is regulated by the coordinate activity of the inducible transcription factors STAT-1, IFN response factor-1, and NF-B. The presence of the STK receptor did not significantly alter the expression of the IFN- receptor, STAT1 phosphorylation, or the up-regulation of IFN response factor-1 expression following IFN- stimulation. However, nuclear translocation of NF-B following stimulation of RAW cells with IFN- and LPS was reduced in the presence of the MSP/STK signaling pathway. These results suggest that the negative regulation of macrophage responses by MSP/STK occurs at least in part via inhibition of costimulatory signals, resulting in NF-B activation, that cooperate with IFN- to promote activation.