Mechanisms by which blood levels of interleukin-6 (IL-6) are elevated after intracerebroventricular injection of IL-1β in the rat:: Neural versus humoral control

Intracerebroventricular (icv) injection of interleukin-1 beta (IL-1 beta) in rats induces elevated IL-6 levels in peripheral blood, exceeding those induced by iv or ip injection. Two hypotheses postulated to explain this phenomenon were tested. Mediation by peripheral sympathetic activation was excluded by showing that agents that blocked preganglionic cholinergic synapses (chlorisondamine), beta-adrenergic receptors (propanalol, butoxamine), and alpha-adrenergic receptors (phentolamine) did not prevent the IL-6 response. That the peripheral response was due to passage of the injected IL-1 beta into blood from the brain was supported by several observations. Immunoreactive IL-1 beta appeared in peripheral blood by 10 min after icy injection and remained constant between 10-100 min after injection; values after icy injection were virtually identical to those after iv injection at 60 and 80 min. Radioiodine-labeled IL-1 beta appeared in blood as early as 5 min, and by phamacokinetic analysis was found to be transferred from the brain at a rate greater than 2% of brain content per min(-1). IL-1 beta infused iv in ct pattern mimicking brain to blood transfer induced IL-6 levels that were more than double the values induced by a single bolus injection and were not significantly different from the values observed after icy injection. Sustained levels of IL-1 beta in blood over time contribute to the high peripheral IL-6 response. This was shown by administering the same total dose iv as a single bolus of 100 ng or in two doses of 50 ng 1 h apart. Rats given a divided dose had 6-10 times higher blood IL-6 levels at 2 h than those given a single injection. The high levels of IL-6 in blood after icy injection of IL-1 beta are best explained by the reservoir function of the brain IL-1 beta pool and the self-priming effect of IL-1 beta in peripheral tissues.