THERAPEUTIC EFFECTS OF INTERLEUKIN-4 GENE-TRANSFER IN EXPERIMENTAL INFLAMMATORY BOWEL-DISEASE

Inflammatory bowel disease (IBD) is characterized by altered immunoreg ulation and augmented intestinal synthesis of nitric oxide. The purpos e of this study was to determine the effects of exogenous IL-4, introd uced by a recombinant human type 5 adenovirus (Ad5) vector, on the tis sue injury associated with an experimental model of colonic immune act ivation and inflammation. Colitis was induced in rats by the intrarect al administration of trinitrobenzene sulfonic acid (TNB) dissolved in 50% ethanol, and control rats received saline via the same route. 1 h later, all rats were randomized into two groups, The first group was i njected intraperitoneally (ip) with 3.0 x 10(6) plaque forming units ( PFUs) of Ad5 transfected with murine interleukin-4 (Ad5IL-4) and the s econd group was injected ip with the same amount of Ad5 expressing the Escherichia call Lac Z gene (Ad5LacZ). One-half of the colitic and co ntrol rats were injected again with 3.0 x 10(6) PFUs of Ad5IL-4 or Ad5 LacZ on day 3 of the 6-d study, When introduced once or twice via the peritoneal route into control rats, Ad5LacZ was localized to the seros al lining of the peritoneal cavity, the diaphragm and the liver on day 6, One or two injections of Ad5IL-4 into rats also produced measurabl e levels of circulating IL-4. TNB-colitis in both Ad5LacZ-treated grou ps was associated With pronounced elevations in serum IFN-gamma, and m ucosal ulceration of the distal colon. Myeloperoxidase and inducible n itric oxide synthase II (NOS II) synthetic activity were also increase d by 30- and fivefold, respectively, above control levels in the dista l colon, However, two injections of Ad5IL-4 into colitic rats caused t he overexpression of IL-4, and significantly inhibited tissue damage, serum and colon IFN-gamma levels and myeloperoxidase activity in the d istal colon, In addition, NOS II gene expression and NOS II nitric oxi de synthesis was significantly Inhibited, No therapeutic effect was ob served in rats Injected once with Ad5IL-4. Thus, IL-4, introduced bg A d5, is therapeutic during acute inflammation in the rat colon, The the rapeutic effect of IL-4 was associated with an inhibition of inducible nitric oxide expression and a reduction in nitric oxide synthesis.