Cytokine and adrenal axis responses to endotoxin.

The push–pull cannula (PPC) technique was applied to examine the kinetics of in vivo concentration changes in male rat brain extracellular fluid (ECF) of endogenous interleukin-1β (IL-1β) and corticotrophin releasing hormone (CRH) after a peripheral injection of lipopolysaccharide (LPS) (25 μg/100 g b.wt. intravenously). In addition, IL-1β, adrenocorticotropin hormone (ACTH) and corticosterone concentrations in plasma were also measured at selected intervals after LPS challenge. Administration of LPS resulted in a progressive increase in the concentrations of IL-1β in brain hypothalamic ECF. A significant increase from the zero time mean value of 77±10 to 393±88 pg/ml at the 15-min interval was recorded. The increase in IL-1β concentration in hypothalamic ECF reached a peak of 883±237 pg/ml at 30 min post-LPS. CRH concentration in the same hypothalamic ECF was 41±17 pg/ml at time zero, 97±15 pg/ml at 15 min and at 30 min was significantly increased (215±56 pg/ml). A time course of significant increases at 30 min in plasma concentrations of IL-1β, ACTH and corticosterone was also recorded in the same animals described above. The data show that a peripherally administered LPS bolus elicited an early (over 15 min post-injection) increase in brain ECF IL-1β concentration; additional significant increases in hormones released from the hypothalamic-pituitary-adrenal (HPA) axis were recorded at 30 min post-LPS injection. These observations support the concept of an early change in hypothalamic ECF concentration of IL-1β preceding LPS-induced activation of the HPA axis.