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Mechanisms by Which Blood Levels of Interleukin-6 (IL-6) Are Elevated after Intracerebroventricular Injection of IL-1ß in the Rat: Neural Versus Humoral Control¹

Department of Medicine, University of Arizona Medical College, Tucson, Arizona 85724-5099

Address all correspondence and requests for reprints to: Dr. Seymour Reichlin, Department of Medicine, University of Arizona Medical College, Tucson, Arizona 85724-5099.

Intracerebroventricular (icv) injection of interleukin-1ß (IL-1ß) 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), ß-adrenergic receptors (propanalol, butoxamine), and -adrenergic receptors (phentolamine) did not prevent the IL-6 response. That the peripheral response was due to passage of the injected IL-1ß into blood from the brain was supported by several observations. Immunoreactive IL-1ß appeared in peripheral blood by 10 min after icv injection and remained constant between 10–100 min after injection; values after icv injection were virtually identical to those after iv injection at 60 and 80 min. Radioiodine-labeled IL-1ß 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-1ß infused iv in a 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 icv injection. Sustained levels of IL-1ß 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 icv injection of IL-1ß are best explained by the reservoir function of the brain IL-1ß pool and the self-priming effect of IL-1ß in peripheral tissues.

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