Interleukin-6 (IL-6)--a molecule with both beneficial and destructive potentials.

Interleukin-6 (IL-6), a member of the neuropoietic cytokine family, initially was described in terms of its activities in the immune system and during inflammation. Accumulating evidence supports an essential role of IL-6 in the development, differentiation, regeneration and degeneration of neurons in the peripheral and central nervous system. Major sites of IL-6 synthesis are neurons and glial cells. Interleukin-6 functions are mediated by a specific receptor system composed of a binding site and a signal transducer. This receptor system can be modulated by a complex of IL-6 and soluble IL-6 receptor acting as agonist. The IL-6 can exert completely opposite actions on neurons, triggering either neuronal survival after injury or causing neuronal degeneration and cell death in disorders such as Alzheimer's disease. Development of selective IL-6 agonists and antagonists, as well as the usage of soluble IL-6 receptors, offers new possibilities for the treatment of neurodegenerative disorders. Furthermore, optimized genetic mouse models, including transgenic and knockout animals, should help to define the physiological and pathophysiological role of IL-6 in the nervous system.

Basophil priming by neurotrophic factors. Activation through the trk receptor.

There is increasing evidence that nerve growth factor (NGF) acts on cells of the immune system, apart from its neurotrophic effects. In human basophils, NGF potentiates mediator release and primes the cells to produce leukotriene C4 in response to C5a. It is, however, unknown whether other homologous neurotrophins also act outside the nervous system, and whether activation of basophils by NGF requires interaction with trk tyrosine kinase receptors, the low affinity NGF receptor (LNGFR), or both. A triple mutant NGF designed to interrupt binding to the LNGFR was found to activate basophils with equal efficacy as wild-type NGF, demonstrating that the LNGFR is not necessary. Despite a 10 times lower potency of mutant NGF, no LNGFR expression was detected by FACS analysis. Brain-derived neurotrophic factor, which interacts with trkB, was inactive at concentrations up to 1000 ng/ml (> 30,000-fold lower potency than NGF), while neurotrophin-3, which is thought to interact with trkC, trkB, and more weakly with trk, induced a threshold effect at 300 ng/ml (approximately 10,000-fold lower potency), demonstrating that 1) the LNGFR cannot deliver a direct signal; and 2) basophils do not express functional trkB and trkC receptors. In agreement with the functional data, basophils (in contrast to other granulocyte types) expressed mRNA for trk, but not trkB or trkC, and no or minimal mRNA for LNGFR. These data demonstrate that human blood basophils express functional trk receptors that do not require the participation of LNGFR, and that, among the neurotrophin family, NGF is unique in priming basophils.

Neuronal properties and trophic activities of immortalized hippocampal cells from embryonic and young adult mice.

The hippocampal formation elaborates trophic factors such as nerve growth factor (NGF) to support the cholinergic innervation it receives from the septal region. To further study the trophic interactions of this pathway, hippocampal cells from embryonic day 18 and postnatal day 21 mice were immortalized via somatic cell fusion to N18TG2 neuroblastoma cells. The hippocampal cell lines exhibit morphological and cytoskeletal features which are typical of their neuronal parents but which are not expressed by the neuroblastoma parent. When differentiated with retinoic acid, the hippocampal cell lines exhibit electrophysiological features similar to cultured hippocampal neurons. Many of the lines constitutively express high levels of NGF, and at least one cell line exerts a non-NGF trophic effect on the expression of choline acetyltransferase by septal neurons in vitro. These cell lines are potentially useful for investigating the neurochemical and excitable properties of hippocampal neurons and identifying novel trophic activities that promote the development and maintenance of the septohippocampal pathway.

Importance of the adrenal cortex for development and maintenance of hypertension in spontaneously hypertensive rats.

Adrenal regeneration following complete bilateral adrenalectomy in spontaneously hypertensive rats (SHR) was used to study the significance of glucocorticoid and mineralocorticoid hormones for the development and maintenance of hypertension. Pre-hypertensive (5 weeks of age) and hypertensive (10 and 16 weeks of age) male SHR underwent adrenalectomy (ADN) and were kept on 0.9% NaCl. The rats were ether stressed at various intervals to assess adrenal steroid production. Following ADN of all three age groups the development or maintenance of hypertension depended on the presence of adrenal regenerates. Animals without signs of adrenal regeneration remained or became normotensive. There was a significant correlation between plasma corticosterone levels following ether stress and blood pressure. Aldosterone and corticosterone production of regenerates and of adrenal cortex of intact SHR was studied in vitro. Under basal condition and following ACTH stimulation both tissues produced similar amounts of corticosterone, however considerably less aldosterone was secreted by regenerates. Betamethasone substitution in adrenalectomized rats caused a dramatic increase of blood pressure which was attenuated by L-propranolol. Aldosterone had no significant effect on blood pressure. It is concluded that glucocorticoids play a permissive role in the development of hypertension presumably via alteration of sympathetic neurotransmission.

Long-term effects of betamethasone on blood pressure and hypothalamo-pituitary-adrenocortical function in spontaneously hypertensive and normotensive rats.

An enhanced hypothalamo-pituitary-adrenocortical (HPA) activity has been described during onset of elevated blood pressure in spontaneously hypertensive rats (SHR). An instability of the HPA axis could thus contribute to the development of hypertension in these animals. Glucocorticoid effects on blood pressure and HPA function were studied therefore in SHR and normotensive Wistar-Kyoto (WKY) and Wistar rats. Beginning at 4 weeks of age, the rats were treated with 0.1 and 0.5 microgram betamethasone per milliliter drinking water for 7 weeks. SHR and WKY responded with a significant elevation in average blood pressure. In SHR, mean blood pressure rose from 181.4 +/- 3.9 (mean +/- SEM) to 203.1 +/- 2.8 mm Hg in response to the lower dose of betamethasone and to 209.2 +/- 4.0 mm Hg in response to 0.5 microgram betamethasone per milliliter drinking water. In WKY, blood pressure increased from 134.4 +/- 3.3 to 148.2 +/- 3.0 and 157.9 +/- 4.5 mm Hg in response to the lower and higher dose of betamethasone, respectively. No significant effect was seen in Wistar rats, where the mean blood pressure values changed insignificantly from 133.8 +/- 2.1 to 136.3 +/- 3.2 and 135.6 +/- 2.4 mm Hg. Stress-induced secretion of corticosterone was significantly suppressed in a dose-dependent manner in all three strains. Stress-induced secretion of adrenocorticotropin was markedly reduced by 0.5 microgram betamethasone per milliliter in SHR and by both doses in WKY. No significant effect, however, was seen in Wistar rats. A predisposition to the hypertensiogenic actions of glucocorticoids was found therefore in SHR and WKY, but not in Wistar rats.

Stress-induced secretion of ACTH and corticosterone during development of spontaneous hypertension in rats.

Plasma ACTH and corticosterone response to ether inhalation was examined in spontaneously hypertensive rats (SHR) and in normotensive Wistar-Kyoto (WKY) and Wistar control rats at 4, 8, 12 and 16 weeks of age. In SHR, blood pressure rose to hypertensive levels (above 150 mm Hg) between 5 and 8 weeks, whereas, in control animals, it did not exceed 140 mm Hg. Maximum plasma ACTH concentrations were measured 5 min after exposure to ether and plasma corticosterone values attained their maximum at 20 min. Stress-induced ACTH release was significantly elevated in SHR at 4 and 8 weeks. At 16 weeks of age, no difference in the ACTH response between the three strains could be detected. Correspondingly, 4-week-old SHR showed a more pronounced corticosterone release than Wistar and WKY, whereas 16-week-old SHR and control rats responded similarly. Hypothalamo-pituitary-adrenocortical response to ether stress is thus markedly enhanced in SHR during early development of hypertension.