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and Lipopolysaccharide by the STK/RON Receptor Tyrosine Kinase1


,
*
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.
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