Interleukin 8 modulates interleukin-1β, interleukin-6 and tumor necrosis factor-α release from normal human mononuclear cells

Recombinant human interleukin 8 (IL-8) enhanced the release of inflammatory cytokines including interleukin 1β (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) from normal human mononuclear cells in a dose-related manner (from 1 ng/ml to 10 ng/ml with a maximal effect at 5 ng/ml( when the cells incubated with IL-8 for 24 h. This cytokine-releasing activity of IL-8 is temperature-dependent and required protein synthesis since low temperature (4°C) and cycloheximide (100 μg/ml) minimized the cytokine release from MNC. However, when IL-8 concentration was greater than 20 ng/ml, the cytokine release was supressed. For further investigating the subcellular mechanism of the adverse effect of high dose IL-8 (20 ng/ml) in cytokine synthesis, human mononuclear cells (1 × 10⁶/ml) were stimulated with PHA (1 μg/ml) in the presence of 20 ng/ml IL-8 for 3 days. We found not only [³H]thymidine incorporation of MNC was tremendously inhibited but DNA fragmentation appeared. Subsequently, the cell cycle of PHA-stimulated MNC retarded in the phase of G₀/G₁. These results suggest that in low concentration (5-10 ng/ml) IL-8 not only activated neutrophil phagocytosis but facilitated the release of inflammatory cytokines from mononuclear cells. Higher dose of IL-8 (more than 20 ng/ml) conversely suppressed these cytokine release from damaged cells by its cytotoxic effect. This newly found cytokine-releasing activity of IL-8 may play a role in the modulation of inflammation.