Brain-IL-1beta induces local inflammation but systemic anti-inflammatory response through stimulation of both hypothalamic-pituitary-adrenal axis and sympathetic nervous system.

It is well established that systemic inflammation induces a counter-regulatory anti-inflammatory response particularly resulting in deactivation of monocytes/macrophages. However, recently we demonstrated a systemic anti-inflammatory response without preceding signs of systemic inflammation in patients with brain injury/surgery and release of cytokines into the cerebrospinal fluid (CSF). In order to analyze the mechanisms and pathways of systemic immunodepression resulting from sterile cerebral inflammation we established an animal model using continuous intra-cerebroventricular (i.c.v.) or intra-hypothalamic (i.h.) infusion of rat recombinant (rr) tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta for 48 h. Controls received intra-venous (i.v.) cytokine administration. Interestingly, i.c.v. and i.h. infusion of IL-1beta but not TNF-alpha produced distinct signs of central nervous system (CNS) inflammation. Correspondingly, i.c.v. infusion of IL-1beta particularly diminished the TNF-alpha but increased the IL-10 concentration in whole blood cultures after endotoxin stimulation. All parameters normalized within 48 h after termination of the infusion. Blocking the hypothalamic-pituitary-adrenal (HPA) axis by hypophysectomy (HPX) led to complete recovery of the diminished TNF-alpha concentration and temporarily inhibited the IL-10 increase. Blocking the sympathetic nervous system (SNS) transmission by application of the beta2-adrenoreceptor antagonist propranolol not only inhibited the increase but further downregulated the endotoxin induced IL-10 concentration in the media of whole blood cell cultures, whereas the TNF-alpha decrease was only partially prevented. Interestingly, HPX and propranolol also diminished the cell invasion into the CSF. In summary, activation of both the HPA axis and the SNS plays an important role in systemic anti-inflammatory response resulting from cytokines in brain and cerebral inflammation.

Differences in immune cell invasion into the cerebrospinal fluid and brain parenchyma during cerebral infusion of interleukin-1beta.

Cytokine-mediated inflammatory cell recruitment into the brain is a critical step in the response to diverse insults, including infection, trauma, and stroke. Hence, continous intra-cerebroventricular infusion of interleukin (IL)-1beta leads to an impressive cell invasion into the cerebrospinal fluid, as well as the brain parenchyma. Neither tumor necrosis factor-alpha nor IL-6 induced any significant cell invasion at all. However, the diverse immune cells (granulocytes, monocytes/macrophages) showed a different time course of invasion. Moreover, there was an association between the number of infiltrating immune cells and the infused IL-1 concentration. By analyzing intra-brain immune events, we demonstrated a time- and dose-dependent induction of intercellular adhesion molecule (ICAM)-1, whereas there were no differences for P-selectin, vascular cell adhesion molecule (VCAM)-1, and monocyte-chemotractant protein (MCP)-1, comparing vehicle and IL-1-infused animals. In conclusion, we assume IL-1beta to be a key cytokine for the granulocyte and monocyte recruitment into the central nervous system after various insults. However, granulocytes anticipate monocyte invasion.

Brain IL-1beta increases neutrophil and decreases lymphocyte counts through stimulation of neuroimmune pathways.

Leukocytosis after cerebral injury is well described and may participate in the generation of cerebral damage. However, the mechanisms of brain-induced leukocytosis are still speculative. Since it is known that proinflammatory cytokines are involved in neuroimmunomodulation and since others and we have demonstrated high cytokine levels in the cerebrospinal fluid following injury, we supposed that brain cytokines may also influence leukocyte counts. In order to evaluate this hypothesis, we established an animal model using continuous intracerebroventricular (i.c.v.), intrahypothalamic (i.h.), or intravenous infusion of the proinflammatory cytokines tumor necrosis factor (TNF)-alpha and IL-1beta. Controls received vehicle solution. With this experimental paradigm we could show that i.c.v. and i.h. infusion of IL-1beta but not TNF-alpha dramatically increased neutrophil counts, whereas lymphocytes dropped. Blocking the hypothalamic-pituitary-adrenal (HPA) axis by hypophysectomy abolished the neutrophilia, whereas the lymphopenia remained unchanged. Furthermore, application of the beta2-adrenoreceptor antagonist propranolol prevented the decrease of lymphocytes and diminished the neutrophilia. All parameters normalized within 48 h after termination of infusion. So, our results demonstrate that brain IL-1beta can modify blood leukocyte counts through stimulation of both the sympathetic nervous system (SNS) and the HPA axis.