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The RON Receptor Tyrosine Kinase Regulates IFN- Production and Responses in Innate Immunity

Caleph B. Wilson^1,*, Manujendra Ray^1,, Michael Lutz^*, Daniel Sharda^*, Jie Xu^* and Pamela A. Hankey^2,*,

^* Graduate Program in Pathobiology and Integrative Biosciences Graduate Program, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802

Receptor tyrosine kinases are emerging as a class of key regulators of innate immune responses. We have shown previously that the RON receptor tyrosine kinases (murine Stk), expressed on tissue-resident macrophages, inhibit classical macrophage activation while promoting hallmarks of alternative activation, thus regulating the critical balance between the inflammatory and wound-healing properties of activated macrophages. We have also shown previously that RON^–/– mice are more susceptible to in vivo endotoxin challenge than wild-type mice, suggesting that the expression of this receptor confers a degree of endotoxin resistance to these animals. Here we demonstrate that, in response to in vivo LPS challenge, RON^–/– mice harbor significantly increased systemic levels of IFN- and IL-12p70 and increased levels of IL-12p40 transcript in their spleen. This elevation of IFN- can be attributed to splenic NK cells responding to the elevated levels of IL-12. Analysis of RON and IFN- receptor double-knockout mice indicates that the enhanced susceptibility of RON^–/– mice to endotoxin challenge is dependent on IFN--mediated signals. In vitro studies demonstrate that stimulation of primary peritoneal macrophages with macrophage-stimulating protein, the ligand for RON, inhibits IFN--induced STAT1 phosphorylation and CIITA expression, resulting in reduced surface levels of MHC class II. Further studies demonstrating the induction of suppressor of cytokine signaling 1 via macrophage-stimulating protein/RON signaling provide a potential mechanistic insight into this regulatory pathway. These results indicate that the RON receptor regulates both the production of and response to IFN-, resulting in enhanced susceptibility to endotoxin challenge.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ C.B.W. and M.R. contributed equally to this work.

² Address correspondence and reprint requests to Dr. Pamela A. Hankey, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, 115 Henning Building, University Park, PA 16802. E-mail address: phc7{at}psu.edu

³ Abbreviations used in this paper: NKT, NK T cell; TAM, tyrosine-based activation motif; MSP, macrophage-stimulating protein; SOCS, suppressor of cytokine signaling; rm, recombinant murine (as prefix); m, murine (as prefix); WT, wild type; DKO, double knockout; D-GalN, D-galactosamine; iNOS, inducible NO synthase.