IL-4 gene transfer to the small bowel serosa leads to intestinal inflammation and smooth muscle hyperresponsiveness.
Intestinal mucosal inflammation can lead to altered function of the underlying smooth muscle, which becomes hyperreactive to most contractile stimuli. Through nematode parasite infection models, T helper type 2 (Th2) cytokines have been implicated in intestinal muscle dysfunction; however, the mechanisms involved and the relevance of these findings to other forms of intestinal inflammation are unclear. Through gene transfer, we explored whether the Th2 cytokine IL-4 can mediate changes in longitudinal muscle function in the context of an adenoviral infection. Following abdominal surgery on mice, control beta-galactosidase-encoding recombinant adenoviruses and IL-4-encoding adenoviruses were applied to the serosal surface of the jejunum, leading to infection of cells in the serosa and in the mesentery. Marker transgene expression lasted for 3 wk and was accompanied by the recruitment of macrophages, lymphocytes, and neutrophils into the peritoneal cavity and mild inflammation at the site of infection. IL-4 transgene expression led to a stronger inflammatory response characterized by tissue eosinophilia and increased numbers of peritoneal mast cells and plasma cells. Whereas control virus infection had no effect on intestinal muscle function, infection with the IL-4 virus led to significant jejunal muscle hypercontractility, evident by day 7 postinfection. This modulation of smooth muscle function was shown to be IL-4 specific, since the application of an IL-5-encoding adenovirus induced tissue eosinophilia but did not alter muscle function. These results highlight an important causal role for IL-4 in the pathological regulation of enteric smooth muscle function and identify a novel strategy for gene transfer to the intestine.
Vallance
Bruce A
BA
Division of Gastroenterology, British Columbia's Children's Hospital, ACB, Rm. K4-188, 4480 Oak St., Vancouver, BC, Canada V6H 3V4. bvallance@cw.bc.ca
Radojevic
Nicola
N
Hogaboam
Cory M
CM
Deng
Yikang
Y
Gauldie
Jack
J
Collins
Stephen M
SM
D000260:Adenoviruses, Human / Q000235:genetics; D000818:Animals; D017931:DNA Primers; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007249:Inflammation / Q000276:immunology* / Q000503:physiopathology; D015847:Interleukin-4 / Q000235:genetics*; D007421:Intestine, Small / Q000276:immunology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009130:Muscle, Smooth / Q000276:immunology / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012704:Serous Membrane / Q000276:immunology* / Q000503:physiopathology; D018418:Th2 Cells / Q000276:immunology; D014158:Transcription, Genetic
D017931:DNA Primers; D015847:Interleukin-4