ACUTE STIMULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS BY IL-1-BETA, TNF-ALPHA AND IL-6 - A DOSE-RESPONSE STUDY

We investigated the effects of iv and intracerebroventricular (icv) ad ministration of increasing doses of recombinant human IL-1 beta, TNF a lpha and IL-6 on plasma corticosterone (B) levels in rats. Rats were e quipped with a jugular cannula for repeated blood sampling and a subgr oup of rats also received an icy implanted cannula. Iv administration of IL-1 beta, TNF alpha or IL-6 and icy administration of IL-1 beta an d IL-6 induced a significant dose-dependent increase in plasma B level s, whereas icy injection of TNF alpha in doses up to 1000 ng/rat was n ot effective. Iv pretreatment of rats with anti-CRH antiserum had no s ignificant overall effect on the plasma B response to iv administered IL-1 beta (500 and 3000 ng/rat), whereas the plasma B response to iv T NF alpha or IL-6 administration (3000 ng/rat) were significantly reduc ed. Iv pretreatment of the animals with recombinant human IL-1 recepto r antagonist (IL-1ra) significantly blocked the plasma B response to i v treatment with IL-1 beta, whereas the TNF alpha- and IL-6-induced in creases in plasma B levels were not affected. Our data show that: 1) i v administration of IL-1 beta, TNF alpha or IL-6 and icy administratio n of IL-1 beta or IL-6 dose-dependently stimulate the HPA axis; 2) whe n given iv or icy, IL-1 beta is more powerful than TNF alpha and IL-6 in activating the HPA axis; 3) endogenous CRH is involved in the activ ation of the HPA axis by acute iv administration of TNF alpha and IL-6 . It is most likely that in case of iv treatment with IL-1 beta a CRH- independent mechanism is involved. This study provides no arguments fo r the involvement of endogenous IL-1 in TNF alpha- or IL-6-induced act ivation of the HPA axis.