OBJECTIVE: 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). METHODS: Expression of IL-12 receptor (IL-12R) β1, β2, and IL-18Rα 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-γ production, the proliferative response, and the induction of IL-2R, IL-12R, and IL-18R of LPLs. RESULTS: IL-12Rβ2 expression was significantly greater in LPL-CD compared with LPL-NL. LPL-NL demonstrated a proliferative response and a significant increase in interferon-γ production and IL-2Rα 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-2Rα monoclonal antibody. Furthermore, IL-12 was observed to upregulate IL-18Rα expression in LPL-CD. CONCLUSIONS: 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.
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