ROLE OF CIRCULATING ENDOTOXIN AND INTERLEUKIN-6 IN THE ACTH AND CORTICOSTERONE RESPONSE TO INTRAPERITONEAL LPS

Peripheral administration of lipopolysaccharide (LPS) may activate the hypothalamus-pituitary-adrenal (HPA) axis by way of both neural and h umoral mechanisms. We have investigated whether biologically active en dotoxin appears in the general circulation after intraperitoneal admin istration of LPS (5 or 100 mu g/kg) to rats and whether this is a prer equisite for activation of this HPA axis. Within 15 min, endotoxin app eared in the general circulation, whereas elevations of plasma adrenoc orticotropic hormone (ACTH), corticosterone, and interleukin (IL)-6 co ncentrations were not detected until 90 min after LPS injection. At th is time, a marked interindividual variation was observed in plasma con centrations of endotoxin, ACTH, corticosterone, and IL-6. Elevated lev els of plasma endotoxin were associated with elevated levels of ACTH, corticosterone, and IL-6. Intravenous administration of the LPS antago nist cationic antimicrobial protein 18 (5 mg/kg), which did not affect cytokine production in the peritoneal cavity, markedly reduced plasma ACTH, corticosterone, and IL-6 levels after 5 mu g/kg LPS. Our result s suggest that circulating endotoxin is required for the activation of the HPA axis. They also favor a role for circulating IL-6 in this res ponse.