Elaboration of interleukin 1-receptor antagonist is not attenuated by glucocorticoids after endotoxemia

A. A. Santos, M. R. Scheltinga, E. Lynch, E. F. Brown, P. Lawton, E. Chambers, J. Browning, C. A. Dinarello, S. M. Wolff and D. W. Wilmore
Department of Surgery, Brigham and Women's Hospital, Boston, Mass 02115.

The body's response to infection/inflammation is initiated by the elaboration of cytokines, such as tumor necrosis factor, interleukin 1-beta (IL-1-beta), IL-6, and IL-8. Cytokines, in turn, stimulate the pituitary-adrenal axis, and it has been suggested that the corticosteroids elaborated serve as negative feedback signals to diminish inflammatory events. To test this hypothesis, we administered hydrocortisone shortly before endotoxin administration to normal volunteers. Steroids greatly reduced the clinical response to endotoxin and attenuated the appearance of tumor necrosis factor, IL-6, and IL-8 in the circulation. In contrast, IL-1-receptor antagonist, a competitive antagonist of the IL-1 receptor, was unaffected by steroid administration. These data suggest that IL-1-receptor antagonist may act in synergism with corticosteroids to reduce inflammation. Elevation of concentrations of these two factors, corticosteroids and IL-1-receptor antagonist, in plasma appears to be the mechanism used by the body to overcome the effects of inflammatory cytokines.