To test the hypothesis that interleukin-6 (IL-6) induced within the brain can be released into peripheral blood, 125I-labeled IL-6 was injected into the lateral cerebral ventricle of rats, and its concentration in peripheral blood followed serially. Acid-precipitable tracer appeared within 5 min of injection and entered the blood following first-order kinetics (fractional rate, 0.0116 +/- 0.0022/min). Comparison of areas under the curve of intracerebroventricular (icv) vs. iv injection showed that 37.1-46.5% of tracer injected into the lateral cerebral ventricle appeared in the blood over a 4-h period. icv IL-6 exits at least in part via venous drainage (superior sagittal sinus/aortic concentration gradient was 1.47 +/- 0.23 and 3.05 +/- 0.87 in two separate groups). Prior icv injection of human IL-1beta (100 ng) did not alter rate of degradation or of exit ofradioiodine-labeled IL-6 from the brain. These studies indicate that a relatively high proportion of IL-6 that arises in the brain enters the peripheral circulation. Direct secretion of IL-6 from brain to blood may be a mechanism by which the brain modifies peripheral metabolic, endocrine, and immune activity.

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Intracerebroventricular (icv) injection of interleukin-1beta (IL-1beta) 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-1beta into blood from the brain was supported by several observations. Immunoreactive IL-1beta 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-1beta 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-1beta 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-1beta 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-1beta are best explained by the reservoir function of the brain IL-1beta pool and the self-priming effect of IL-1beta in peripheral tissues.

LP-BM5 murine leukemia virus infection caused alterations in splenic T cell subsets in adult C57BL/6 female mice. Prolonged infection resulted in increased immunosuppression and a concomitant decreased resistance to Cryptosporidium parvum infection. Significant Cryptosporidium colonization of the intestinal villi was seen 10 days after oral challenge in mice infected with murine retrovirus for 3 months but not in non-virally infected controls. Parasite numbers per villus of retrovirally infected mice were 20-fold higher than in controls, which showed only occasional parasites. Feces from most virally infected mice but none from controls contained oocysts. Cryptosporidium infection in mice after 4 and 5 months of retroviral infection was accompanied by severe immunosuppression and parasite levels 50-5000 times higher than in controls. A high level of infection persisted 21 days after Cryptosporidium challenge in virally infected mice, while controls cleared their transient and marginal infection. These results further characterize LP-BM5 infection as a murine model of retrovirally induced acquired immune deficiency.

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