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Am J Physiol Gastrointest Liver Physiol 292: G253-G261, 2007. First published September 28, 2006; doi:10.1152/ajpgi.00134.2006
0193-1857/07 $8.00
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INFLAMMATION/IMMUNITY/MEDIATORS

Short-form Ron receptor is required for normal IFN-{gamma} production in concanavalin A-induced acute liver injury

Cynthia C. Wetzel,1,4 Mike A. Leonis,1,4 Arlene Dent,1,4 Meredith A. Olson,1,4 Angela M. Longmeier,1,4 Paul A. Ney,5 Greg P. Boivin,2 Sarah A. Kader,3 Charles C. Caldwell,3 Sandra J. F. Degen,1,4 and Susan E. Waltz3

Departments of 1Pediatrics, 2Pathology, and 3Surgery, University of Cincinnati College of Medicine and 4Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio; and 5Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee

Submitted 24 March 2006 ; accepted in final form 20 September 2006

Abrogation of Ron receptor tyrosine kinase function results in defects in macrophage activation and dysregulated acute inflammatory responses in vivo. Several naturally occurring constitutively active alternative forms of Ron have been identified, including from primary human tumors and tumor cell lines. One of these alternative forms, short-form (SF) Ron, is generated from an alternative start site in intron 10 of the Ron gene that eliminates most of the extracellular portion of the receptor and is overexpressed in several human cancers. To test the physiological significance of SF-Ron in vivo, mice were generated that solely express the full-length form of Ron (FL-Ron). Our results show that elimination of the capacity to express SF-Ron in vivo leads to augmented production of IFN-{gamma} from splenocytes following stimulation ex vivo with either concanavalin A or anti-CD3/T cell receptor monoclonal antibody. Moreover, in a concanavalin A-induced murine model of acute liver injury, FL-Ron mice have increased production of serum INF-{gamma} and serum alanine aminotransferase levels and worsened liver histology and overall survival compared with wild-type control mice. Taken together, these results suggest for the first time that SF-Ron impacts the progression of inflammatory immune responses in vivo and further support a role for the Ron receptor and its various forms in liver pathophysiology.

receptor tyrosine kinases; regulation of cytokine production; animal models of liver injury


Address for reprint requests and other correspondence: S. E. Waltz, Dept. of Surgery, Univ. of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267 (e-mail: susan.waltz{at}uc.edu)






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