Background: Interleukin (IL)-15 is overexpressed in intestinal tissue with active Crohn's disease (CD). However, its role in the pathogenesis of the disease remains uncertain. We studied the effects of IL-15 on colonic mucosal proinflammatory cytokine response in vitro using organ culture of human colonic explants.
Methods: Colonic tissue was obtained from (1) resections in pediatric CD patients (inflamed and noninflamed) and (2) rectal biopsies in patients with CD undergoing colonoscopy (n = 31) and controls (n = 9). In preliminary experiments, explants from the resections were cultured in the presence or absence of a simulated T(H)1 stimulation using ionomycin (Io) and phorbol-myristate-acetate (PMA), with or without IL-15, or in medium alone. Rectal biopsies were cultured in the same conditions as above, with or without adding a monoclonal anti-IL-15 neutralizing antibody (mAb). Levels of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and IL-2R alpha were measured by enzyme-linked immunosorbent assay.
Results: IL-15, in the absence of Io + PMA, did not induce the expression of IFN-gamma, TNF-alpha, or IL-2R alpha. Only inflamed explants from resections stimulated with Io + PMA expressed IFN-gamma, TNF-alpha, and IL-2R alpha. This T(H)1 stimulatory effect was inhibited by IL-15 in a dose-dependent fashion. In rectal biopsy explants, inflamed, noninflamed CD, and control tissue responded to stimulation with Io + PMA (P < 0.05) with increased IFN-gamma and TNF-alpha (P < 0.05). This response was again inhibited by IL-15. The inhibitory effect of IL-15 was specifically reversed by anti-IL-15 mAb (P < 0.05). The data for the CD group were also analyzed according to the severity of colonic inflammation and medication use.
Conclusions: Our results suggest a possible anti-inflammatory role for IL-15 in CD. We postulate that its overexpression in CD potentially represents a protective mechanism against the exaggerated T(H)1 immune response.