TEMPORAL CASCADE OF PLASMA-LEVEL SURGES IN ACTH, CORTICOSTERONE, AND CYTOKINES IN ENDOTOXIN-CHALLENGED RATS

The present study was designed to investigate the coupling mechanisms linking the immune and the neuroendocrine corticotropic systems in an integrated defense response triggered by an infectious aggression. The experimental paradigm used consisted of the exploration in individual conscious rats of the temporal pattern of increased plasma concentrat ions of the two stress hormones, adrenocorticotropic hormone (ACTH) an d corticosterone (Cort), and of three cytokines known as ACTH stimulat ors, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, and IL-6, after intraarterial infusions of lipopolysaccharide (LPS) g iven at three doses, 5 mu g/kg (LPS-5), 25 mu g/kg (LPS-25), and 1 mg/ kg (LPS-1,000). Blood samples were taken 30 min and immediately before LPS injection (t(0)) and at 15, 30, 60, 120, 300, and 480 min post-LP S. The three doses of LPS induced ACTH and Cort surges, starting after 30 min for LPS-5 and LPS-25 or 15 min for LPS-1,000 and peaking with a similar amplitude at 60 min before receding slowly to baseline at 48 0 min for the two lower LPS doses. On the other hand, whatever the LPS dose, none of the three cytokines rose above undetectable basal level s before 60 min. They increased thereafter to culminate 10- to 30-fold above baseline at 60 min (TNF-alpha) or 120 min (IL-1 beta and IL-6) after LPS and declined back to basal levels at 300 min (TNF-alpha, all doses, and IL-6 for LPS-5 and LPS-25). After LPS-25, only IL-1 beta h ad not regressed to baseline levels at 480 min. The data indicate that although none of the three cytokines at levels measurable in the syst emic circulation may act as a direct trigger for the initial stage of the corticotropic stress response to LPS, they may nevertheless strong ly contribute to the timing and amplitude of the ACTH and Cort peaks a nd in the hours-long sustained post-LPS activation of the corticotropi c axis.