Submitted on March 24, 2006
Accepted on September 20, 2006
Short Form Ron Receptor Is Required For Normal IFN-
Production In Concanavalin A-Induced Acute Liver Injury
Cynthia C. Wetzel1, Mike A. Leonis1, Arlene Dent1, Meredith A. Olson1, Angela M. Longmeier2, Paul A. Ney3, Greg P. Boivin4, Sarah A. Kader5, Charles C. Caldwell5, Sandra J. F. Degen1, and Susan E Waltz5*
1 Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States; Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, United States
2 Pediatrics, University of Cincinnati College of Medicine, 45229, Ohio, United States
3 Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee, United States
4 Pathology, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
5 Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
* To whom correspondence should be addressed. E-mail: susan.waltz{at}uc.edu.
Abrogation of Ron receptor tyrosine kinase function results in defects in macrophages activation and disregulated 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 over-expressed in several human cancers. To test the physiologic 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 interferon-
(IFN-) from splenocytes following stimulation ex vivo with either conconavalin A (conA) or anti-CD3/T cell receptor monoclonal antibody. Moreover, in a conA-induced murine model of acute liver injury, FL-Ron mice have increased production of serum INF- and serum alanine aminotransferease levels, and worsened liver histology and overall survival compared to 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 supports a role for the Ron receptor and its various forms in liver pathophysiology.
