INTERLEUKIN-8 MODULATES INTERLEUKIN-1-BETA, INTERLEUKIN-6 AND TUMOR-NECROSIS-FACTOR-ALPHA RELEASE FROM NORMAL HUMAN MONONUCLEAR-CELLS

Recombinant human interleukin 8 (IL-8) enhanced the release of inflamm atory cytokines including interleukin Ip (IL-1 beta), interleukin 6 (I L-6) and tumor necrosis factor-alpha (TNF-alpha) from normal human mon onuclear 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 2 4 h. This cytokine-releasing activity of IL-8 is temperature-dependent and required protein synthesis since low temperature (4 degrees C) an d cycloheximide (100 mu g/ml) minimized the cytokine release from MNC. However, when IL-8 concentration was greater than 20 ng/ml, the cytok ine release was suppressed. For further investigating the subcellular mechanism of the adverse effect of high dose IL-8 (20 ng/ml) in cytoki ne synthesis, human mononuclear cells (I x 10(6)/ml) were stimulated w ith PHA (1 mu g/ml) in the presence of 20 ng/ml IL-8 for 3 days. We fo und not only [H-3]thymidine incorporation of MNC was tremendously inhi bited but DNA fragmentation appeared. Subsequently, the cell cycle of PHA-stimulated MNC retarded in the phase of G(0)/G(1). These results s uggest that in low concentration (5-10 ng/ml) IL-8 not only activated neutrophil phagocytosis but facilitated the release of inflammatory cy tokines from mononuclear cells. Higher dose of lL-8 (more than 20 ng/m l) 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.