Short-form Ron receptor is required for normal IFN-gamma production in concanavalin A-induced acute liver injury.
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.
Wetzel
Cynthia C
CC
Department of Pediatrics, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA.
Leonis
Mike A
MA
Dent
Arlene
A
Olson
Meredith A
MA
Longmeier
Angela M
AM
Ney
Paul A
PA
Boivin
Greg P
GP
Kader
Sarah A
SA
Caldwell
Charles C
CC
Degen
Sandra J F
SJ
Waltz
Susan E
SE
D000818:Animals; D001483:Base Sequence; D056486:Chemical and Drug Induced Liver Injury; D003208:Concanavalin A / Q000633:toxicity*; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D005786:Gene Expression Regulation / Q000276:immunology; D005822:Genetic Vectors; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000187:drug effects; D008099:Liver / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D008107:Liver Diseases / Q000235:genetics / Q000473:pathology*; D051379:Mice; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D015183:Restriction Mapping; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D017931:DNA Primers; D018076:DNA, Complementary; D003208:Concanavalin A; D012313:RNA; D007371:Interferon-gamma; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases