Th1-MEDIATED INTESTINAL INFLAMMATION IN CROHNS DISEASE M AY BE INDUCED BY ACTIVATION OF LAMINA PROPRIA LYMPHOCYTES THROUGH SYNERGISTIC STIMULATION OF INTERLEUKIN-12 AND IN TERLEUKIN-18 WITHOUT T CELL RECEPTOR ENGAGEMENT
- Th1-MEDIATED INTESTINAL INFLAMMATION IN CROHN�S DISEASE MAY BE INDUCED BY
ACTIVATION OF LAMINA PROPRIA LYMPHOCYTES THROUGH SYNERGISTIC STIMULATION OF
INTERLEUKIN-12 AND INTERLEUKIN-18 WITHOUT T CELL RECEPTOR ENGAGEMENT
The development of T helper type 1 (Th1) CD4+ T cells in the intestinal
mucosa is driven by interleukin (IL)-12 produced from activated macrophages
and IL-18 produced from activated macrophages and epithelial cells. Each of
these two cytokines is important for the mucosal response during intestinal
inflammation, but their synergistic effect is not fully understood. To
characterize the synergistic effect of IL-12 and IL-18 with respect to human
intestinal inflammation, we assessed the effect of IL-12 and IL-18 on lamina
propria lymphocytes from normal control subjects (LPL-NL) and patients with
Crohn�s disease (LPL-CD).
Expression of IL-12 receptor (IL-12R) ?1, ?2, and IL-18R? in LPLs was
analyzed by flow cytometry. The functional activity of IL-12 and IL-18 was
assessed by the effect of recombinant IL-12 and recombinant IL-18 on
interferon-? production, the proliferative response, and the induction of
IL-2R, IL-12R, and IL-18R of LPLs.
IL-12R?2 expression was significantly greater in LPL-CD compared with LPL-NL
LPL-NL demonstrated a proliferative response and a significant increase in
interferon-? production and IL-2R? expression when exposed to both IL-12 and
IL-18, but neither IL-12 nor IL-18 were able to induce this response on
their own. However, IL-12 and IL-18 produced this response in LPL-CD when
administered alone. Moreover, a more pronounced synergistic effect of IL-12
and IL-18 was observed in LPL-CD. The response normally observed after
administration of IL-12 and IL-18 was significantly inhibited by anti-IL-2
and anti-IL-2R? monoclonal antibody. Furthermore, IL-12 was observed to
upregulate IL-18R? expression in LPL-CD.
These findings suggest that a combination of IL-12 and IL-18 in the absence of T cell receptor engagement may serve as a potent regulatory factor for LPL and contribute to the maintenance and enhancement of chronic inflammation in CD.