AJP - Regulatory, Integrative and Comparative Physiology, Vol 270, Issue 3 518-R524, Copyright © 1996 by American Physiological Society

ARTICLES

Interleukin-6 (IL-6) is secreted from the brain after intracerebroventricular injection of IL-1 beta in rats

L. I. Romero, I. Kakucska, R. M. Lechan and S. Reichlin
Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.

To test the hypothesis that the brain is a source of the interleukin-6 (IL-6) that appears in the peripheral circulation of rats after intracerebroventricular (icv) injection of IL-1 beta, the concentration of bioactive IL-6 in superior sagittal sinus (SSS) blood plasma was compared with aortic plasma 4 h after icv injection of 100 ng of recombinant human IL-1 beta at a time at which cerebrospinal fluid (CSF) IL-6 concentration was found to be markedly elevated. In three separate experiments, CSF IL-6 concentration (pg/ml; values are means +/- SE) was significantly elevated after icv IL-1 beta compared with saline control injections (25,879 +/- 11,472 vs. 35.5 +/- 5; 32,323 +/- 4,945 vs. 128 +/- 29; 114,410 +/- 33,563 vs. 848 +/- 250, respectively). The concentration of plasma IL-6 (pg/ml) in the aortas of rats injected intracerebroventricularly with IL-1 was greater than in controls [252 +/- 93 vs. 36.7 +/- 8.3, P = 0.0037; 361 +/- 95 vs. 57 +/- 13, P = 0.02; 2,254 +/- 550 vs. 1,239 +/- 666, P = 0.26 (NS)]. In IL-1-injected animals, SSS venous plasma IL-6 (pg/ml) was greater than in the aorta in all three studies (1,617 +/- 357 vs. 252 +/- 93, P = 0.0011; 3,754 +/- 1,188 vs. 361 +/- 95, P = 0.024; 8,208 +/- 1,388 vs. 2,254 +/- 550, P = 0.0054). The concentration difference (pg/ml) between SSS and aorta was significantly greater after IL-1 beta injection than in diluent-injected animals (1,365 +/- 369 vs. 48.3 +/- 13, P = 0.0083; 3,393 +/- 1,203 vs. 126 +/- 59, P = 0.035; 5,954 +/- 1,260 vs. 494 +/- 774, P = 0.0042). Suppression of peripheral sympathetic activation by preganglionic cholinergic blockade (chlorisondamine, 250 micrograms sc) did not prevent the usual IL-1-induced elevation in aortic blood IL-6 (3,272 +/- 1,174 vs. 244 +/- 74 pg/ml, P = 0.0012) nor the increased SSS-aortic gradient (2,541 +/- 1,134 vs. 165 +/- 48, P = 0.0142 by Mann-Whitney comparison). Injection of rat/human corticotropin-releasing hormone (CRH; 10.0 micrograms) icv did not change IL-6 concentration in CSF or in peripheral blood. These studies demonstrated that the brain and/or its supporting structures are activated by icv IL-1 beta to release IL-6 into the blood and that the effect is not dependent on peripheral sympathetic activity or central mobilization of CRH. Direct secretion of IL-6 and possibly of other cytokines from the brain is postulated to be a pathway of neuroimmunomodulation.

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