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

Abstract

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.

Sleep Apnea and Daytime Sleepiness and Fatigue: Relation to Visceral Obesity, Insulin Resistance, and Hypercytokinemia

“…Furthermore, there are several ways that peripheral cytokines can communicate and signal the brain to elicit central nervous system manifestations, e.g. sleepiness, including acting in areas outside the blood-brain barrier (periventricular organs), crossing the blood-brain barrier (18,19), and through peripheral autonomic afferent nerves (20). Indeed, even small doses of IL-1 administered peripherally in rats can produce sleep (20).…”

The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection

“…67 It has been recently demonstrated by Reichlin and colleagues, that the brain and/or its supporting structures are activated by intracerebroventricular IL-1␤ to release IL-6 into the blood and that such an 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 has been postulated to be a pathway of neuroimmunomodulation 78 in much the same way that the hormonal cascade released from the hypothalamic-pituitary-adrenal axis modulates peripheral endocrine effects. Thus, the relationship between peripheral and central cytokines is such that peripheral cytokines, originating from immune cells, affect the functioning of the brain, and central cytokines may be secreted by the brain to modulate peripheral immune function.…”

Anti-inflammatory effect by lentiviral-mediated overexpression of IL-10 or IL-1 receptor antagonist in rat glial cells and macrophages

“…Peripheral or central administration of LPS or IL-1b induces a clear activation of microglial and astroglial cells, and the production of, for example, interleukin-6 (IL-6), tumor necrosis factor a (TNFa) and nitric oxide. [6][7][8] Although inflammatory mediators are of importance for their restorative actions under restricted inflammatory conditions in the brain, 9 they become detrimental in a situation of uncontrolled production by activated glial cells and infiltrated monocytes. 10 Indeed, cognitive impairments, demyelination, disturbances in, for example, sensory and motor movement function and eventually neuronal cell death have been reported.…”

“…10 Indeed, cognitive impairments, demyelination, disturbances in, for example, sensory and motor movement function and eventually neuronal cell death have been reported. 1,11 To balance the pro-inflammatory cascade of responses, an enhanced anti-inflammatory response is found in the brains of LPS or IL-1-treated rats 8,12,13 as well as in experimental models for MS and Alzheimer's disease.…”