Interleukin-1β and interferon-γ regulate interleukin-6 production in cultured human intestinal epithelial cells

Recent studies suggest that interleukin-6 (IL-6) is produced in the intestinal mucosa during sepsis and endotoxemia and that the enterocyte may be a source of IL-6 in these conditions. The regulation of IL-6 production in the enterocyte is not fully understood. We tested the hypothesis that IL-6 production in the enterocyte is regulated by proinflammatory cytokines. This was done by treating cultured Caco-2 cells, a transformed human intestinal epithelial cell line, with different concentrations of tumor necrosis factor-α (TNF-α), IL-1β, IL-6 or interferon-γ (IFN-γ). IL-6 production by the Caco-2 cells was determined by ELISA. The expression of IL-6 mRNA was determined by reverse-transcriptase polymerase chain reaction. IL-6 was not produced in unstimulated Caco-2 cells. Treatment of the Caco-2 cells with IL-1/3 resulted in a dose- and time-dependent stimulation of IL-6 production with a maximal effect noted at an IL-1β concentration of .5 ng/mL at 24 h. IFN-γ alone did not stimulate IL-6 production but potentiated the effect of IL-1β in a synergistic fashion. Treatment of the Caco-2 cells with IL-1β induced expression of IL-6 mRNA with a response noticed after 30 min. TNF-α and IL-6 did not influence the production of IL-6 in the Caco-2 cells. The results suggest that enterocyte IL-6 production is stimulated by IL-1β and that this effect is potentiated by IFN-γ. The regulation of IL-6 production in the enterocyte may be specific for IL-1β, since neither TNF nor IL-6 stimulated IL-6 production.