Interleukin 10 gene transfer prevents experimental colitis in rats

Abstract

Background: The development of colitis in interleukin 10 (IL-10) deficient mice, together with the known anti-inflammatory and immunomodulatory properties of this cytokine have prompted consideration of IL-10 as a treatment for inflammatory bowel disease (IBD). However, studies using hrIL-10 in IBD models have yielded inconsistent results.

Aims: To examine the therapeutic potential of overexpressing the IL-10 gene before and after the induction of experimental colitis in rats.

Methods: Gene transfer was achieved by intraperitoneal injection of non-replicating human type 5 adenovirus bearing the IL-10 gene, either 24 hours before or one hour after intrarectal administration of dinitrobenzene sulphonic acid in rats. Colonic damage and inflammation was assessed macroscopically and by measuring myeloperoxidase activity and leukotriene B4 concentrations.

Results: Gene transfer increased IL-10 protein in serum for up to six days. IL-10 gene transfer prior to colitis improved colitis macroscopically and histologically, and significantly reduced colonic myeloperoxidase activity and leukotriene B4 concentrations. In contrast, IL-10 gene transfer after the onset of colitis had no beneficial effect.

Conclusions: Gene therapy using an adenovirus-IL-10 construct was successful in preventing but not in reversing experimental colitis in the rat.

Figure 1

Luciferase activity following administration of Ad5Luc3 or Ad5IL-10. Results represent mean (SEM) from each group (n=8 rats for each group).

Figure 2

Serum IL-10 protein concentrations after administration of HBSS, Ad5LacZ, or Ad5IL-10. Results represent mean (SEM) from each group (HBSS, n=4; Ad5LacZ, n=4; Ad5IL-10, n=8). **Significantly different from controls (p<0.01).

Figure 3

Macroscopic damage scores six days after dinitrobenzene sulphonic acid (DNB) induced colitis. Results represent mean (SEM) from each group (ethanol group, n=6; HBSS, Ad5LacZ, and Ad5IL-10, n=8). *Significantly different from Ad5LacZ (p<0.05).

Figure 4

Histological damage scores six days after dinitrobenzene sulphonic acid (DNB) induced colitis. Results represent mean (SEM) from each group (ethanol group, n=6; HBSS, Ad5LacZ, and Ad5IL-10, n=8). *Significantly different from Ad5LacZ (p<0.05).

Figure 5

Myeloperoxidase activity six days after dinitrobenzene sulphonic acid (DNB) induced colitis. Results represent mean (SEM) from each group (ethanol group, n=6; HBSS, Ad5LacZ, and Ad5IL-10, n=8). *Significantly different from Ad5LacZ (p<0.05).

Figure 6

Effect of pretreatment of rats with Ad5IL-10 gene transfer on leukotriene (LT) B4 concentrations in the distal colon of rats six days after dinitrobenzene sulphonic acid (DNB) induced colitis. Results represent mean (SEM) from each group (ethanol group, n=6; HBSS, Ad5LacZ, and Ad5IL-10, n=8). *Significantly different from Ad5LacZ (p<0.05).