Interleukin (IL)-8 and Growth Related Oncogene-α in Severe Endotoxemia and the Effects of a Tumor Necrosis Factor-α/IL-1β Inhibitor on These Chemokines

FR167653 inhibits the production of tumor necrosis factor (TNF)-α and interleukin (IL)-1β, powerful inducers of CXC chemokines IL-8 and growth related oncogene (GRO)-α. The production of IL-8 and GRO-α was investigated and the effects of FR167653 were examined in a rabbit model of endotoxin shock. Male New Zealand rabbits were given endotoxin at a dose sufficient to induce DIC. Three groups of rabbits received FR167653 at different doses. TNF-α, IL-1β, IL-8, and GRO-α levels were measured, several pathologic features were evaluated, and the results were compared with those obtained in control rabbits, which received only endotoxin. Endotoxin increased serum levels of IL-8 and GRO-α, which were associated with hypotension, renal dysfunction, and mortality, peaking at 4 h. FR167653 improved mortality, an event that was associated with decreased levels of not only TNF-α and IL-1β but also IL-8 and GRO-α. TNF-α peaked at 2 h, at a time point before IL-8 and GRO-α reached their peak, and the TNF-α level was tightly correlated with that of IL-8 and GRO-α. Altogether, these data suggest the possible involvement of IL-8 and GRO-α in endotoxin shock, and FR167653 may foster a beneficial outcome in part by modulating the chemokines level by inhibiting TNF-α and IL-1β.