Intracerebroventricular injection of interleukin-1 stimulates the release of high levels of interleukin-6 and interleukin-1 receptor antagonist into peripheral blood in the primate

Previous studies in the rodent have shown that the cytokine IL-1 can act within the brain to influence peripheral IL-6 secretion. In order to determine if such an interaction occurs in the primate, we have compared the effects of intracerebroventricular vs. intravenous injection of IL-1 beta on the release of IL-6 into the peripheral circulation of the monkey. The effects of i.c.v. IL-1 beta on the release of the IL-1 receptor antagonist (IL-1ra) were studied in parallel. For comparison, we have also measured the release of both IL-6 and IL-1ra into lumbar CSF after i.c.v. IL-1 beta injection. Ten ovariectomized rhesus monkeys with indwelling lateral ventricular and peripheral venous cannulae were studied. Human rIL-1 beta (400 ng) was infused either i.c.v. or i.v. over 30 min and blood samples were collected for IL-6 and IL-1ra measurement by monoclonal human ELISAs. Although both i.c.v. and i.v. IL-1 beta stimulated IL-6 and IL-1ra release into peripheral blood, the stimulation was much more profound after i.c.v, injection (p < 0.001). Peak IL-6 levels were 2010 +/- 590 pg/ml after i.c.v. IL-1 beta compared to 243 +/- 60 pg/ml after i.v. IL-1 beta. Peak IL-1ra levels were 61,310 +/- 16,190 pg/ml after i.c.v. IL-1 beta compared to 18,175 +/- 4270 pg/ml after i.v. IL-1 beta. There was no significant effect of an i.c.v. saline infusion on peripheral IL-6 or IL-1ra levels. In four animals, lumbar CSF was collected 7 h after i.c.v, IL-1 beta injection. The mean concentration of IL-6 in CSF was 103, 570 +/- 13,780 pg/ml after i.c.v. IL-1 beta vs. 224 +/- 190 pg/ml after i.c.v. saline injection; IL-1ra was 47,460 +/- 6290 pg/ml vs. 1040 +/- 550 pg/ml, As expected, both i.c.v. and i.v. IL-beta stimulated ACTH and cortisol release, the stimulation was significantly greater after i.c.v. compared to i.v. administration(p < 0.001). Thus, in the monkey, i.c.v. injection of IL-1 beta stimulates the release of large amounts of IL-6 and IL-1ra into the CSF and the peripheral circulation. Both IL-6 and IL-1ra were released into the peripheral circulation to a much greater extent after i.c.v. compared to i.v. IL-1 beta infusion. These studies provide further support in the primate for a mechanism by which inflammation within the brain could induce a variety of systemic responses. (C) 1999 Elsevier Science B.V. All rights reserved.