Biological signals最新文献

The most studied endocrine product of the pineal gland, melatonin, has been reported to be involved in the feedback between neuroendocrine and immune functions and to exert oncostatic action, at least in certain experimental conditions. Melatonin seems to be an integral part of the immune system, by exerting direct and/or indirect stimulatory effects on both cellular and humoral immunity. Likewise, an antitumor activity of melatonin has been shown in several experimental models in vivo and in vitro. The means by which melatonin exerts its effects on immunity and neoplastic growth have not been elucidated. The different putative mechanisms of action of melatonin investigated so far are here briefly discussed.

A bidirectional flow of informations exists between the central nervous system and the immune system. Cytokines play a crucial role in this communication and exert several neuromodulatory actions. This short review considers some data concerning the effects of several cytokines, interleukin (IL)-1, IL-2, IL-6 and granulocyte-macrophage colony-stimulating factor on scopolamine-induced amnesia for a passive avoidance response, and on hippocampal neurotransmitter amino acid levels in mice. We interpret these behavioral and biochemical observations to indicate that the cytokine-to-brain communication can result in alterations in brain functions.

To obtain further information on the mode of action of interleukin (IL)-1 in modulating gonadotropin secretion, a series of in vivo and in vitro studies has been performed with the beta-isoform of IL-1. IL-1 beta injected in a lateral ventricle of 3-week-castrated female rats resulted in the expected decrease in serum levels of gonadotropins luteinizing hormone (LH), and follicle-stimulating hormone (FSH), accompanied by a decrease in the number of LH-releasing hormone (LHRH) receptors. These results may indicate that the inhibition of gonadotropin release may result from a decrease in the number of LHRH pituitary receptors either through a direct effect on the pituitary or by modulating the release of LHRH from hypothalamic neurons able to induce a reduction in pituitary LHRH receptors. In vitro studies using the GT1-1 cell line, which specifically produces and secretes LHRH, demonstrated that IL-beta stimulates LHRH release but does not influence intracellular levels of LHRH mRNA. These results seem to indicate that IL-1 beta may act at several levels of the nervous machinery leading to gonadotropin secretion, with a series of effects more complex than previously anticipated.

The effect of Freund's adjuvant injection on 24-hour variation in circulating ACTH, prolactin, growth hormone (GH) and thyroid-stimulating hormone (TSH) levels, and of hypothalamic norepinephrine (NE) content and dopamine (DA) and serotonin (5HT) turnover was examined in adult rats. In control rats, serum ACTH and prolactin exhibited peak values at the light-dark transition while the maximum in TSH was found in the late afternoon. GH levels did not vary on a 24-hour basis. In Freund's-adjuvant-injected rats, 24-hour variations in TSH levels became blunted while 24-hour variations in prolactin and ACTH persisted. Freund's adjuvant treatment augmented serum ACTH and prolactin levels, and decreased GH and TSH levels. Hypothalamic NE content, and turnover of DA and 5HT varied on a 24-hour basis in rats receiving adjuvant's vehicle. The NE content of the anterior, medial and posterior hypothalamus peaked at 04.00 h, while that of the median eminence attained its maximum at 16.00-20.00 h. Maxima in hypothalamic DA and 5HT turnover ocurred at 04.00 h regardless of the region examined. In Freund's-adjuvant-injected rats, reduced amplitude of daily variations of NE content in the median eminence and anterior and medial hypothalamus, as well as a phase advance in the 24-hour rhythm of the posterior hypothalamic NE content were seen. Mycobacterial adjuvant injection also reduced the amplitude of circadian rhythm in hypothalamic 5HT turnover, shifted the maximum in median eminence DA turnover towards light-dark transition, and decreased the amplitude of DA turnover rhythm in the anterior, medial and posterior hypothalamus. Administration of the immunosuppressant drug cyclosporine restored the augmented ACTH and prolactin levels and the depressed GH and TSH levels found in Freund's-adjuvant-injected rats. Cyclosporine was also effective to restore 24-hour rhythmicity of serum ACTH and TSH, but not of prolactin levels. Immunosuppression restored rhythmicity of NE content and of DA and 5HT turnover in anterior, medial and posterior hypothalamic regions. Cyclosporine did not modify the effect of Freund's adjuvant on median eminence but in was able to counteract the changes in the DA and 5HT turnover in the median eminence found after immunization. The results are in accord with a significant effect of immune-mediated inflammatory response at an early phase after Freund's adjuvant injection on ACTH, GH, prolactin and TSH release mechanisms, which was partially sensitive to immunosuppression induced by cyclosporine.

Immune system alterations coexist with modifications in the reproductive axis. The bacterial endotoxin lipopolysaccharide (LPS) has inflammatory effects and stimulates cytokine release in the hypothalamus where LHRH neurons are located. LPS inhibition of LHRH release at hypothalamic level appears to be associated with modifications in the cerebral immune system. Central and peripheral LPS administration induces the expression and release of several cytokines in the central nervous system. Hence the present study was designed to investigate a possible function of the interleukin-6 (IL-6) stimulated by LPS in the regulation of LHRH secretion. Male rats were decapitated, and the preoptic mediobasal hypothalamic area (PO/MBH) was dissected and superfused with Earle's balanced salt solution. Superfusate fractions were collected at 15-min intervals after a 60-min stabilization superfusion period. LPS (100 ng/ml) and IL-6 receptor antagonist (IL-6ra) were then added to the superfusion medium over 1 h in two different experimental designs: (1) LPS only and (2) LPS followed by IL-6ra, performed in different experiments. This was followed by a washout period. The PO/MBH fragments were then subjected to a 56 mM K+ stimulus. Control PO/MBH fragments were continuously superfused with Earle's solution. As expected, LHRH release was significantly reduced (p < 0.05) during and following exposure to LPS. At the same time, IL-6 concentrations significantly increased in the superfusion medium compared with the control group. IL-6ra significantly (p < 0.01) potentiated the inhibitory effect of LPS on LHRH secretion. On the bases of previous papers indicating a stimulatory effect of IL-6 on LHRH release it could be considered that the potentiation of IL-6ra of the inhibitory effect of LPS on LHRH could be the consequence of the lack of the stimulatory effect of IL-6 on LHRH produced by the receptor antagonist. IL-6ra also increased IL-6 levels measured in medium probably due to a decrease in the metabolization induced by the blockage of the receptors and the consequent accumulation of IL-6 in the media. These results could indicate that IL-6 partly attenuates the inhibitory effect of LPS on LHRH release. These observations indicate that there is an increase in IL-6 release that becomes significant at the same time when LHRH release is decreased. Also, depolarizing concentrations of K+ (56 mM) did not increase IL-6 release, while LHRH release from the hypothalamic fragments was significantly increased. These data suggest that the inhibitory effect of LPS on LHRH release may be explained by the stimulation of other cytokines than IL-6, meanwhile the augmented levels of IL-6 probably released via a nonneuronal source was shown to be higher when LHRH was decreased. This could confirm the stimulatory role of IL-6 on LHRH release.

Male rats were grafted an anterior pituitary within breast muscles or received a sham operation on day 5 of life. At the 60th day of life, the sympathetic denervation of rat submaxillary lymph nodes was achieved by a bilateral sympathetic superior cervical ganglionectomy (SCGx; at 15.00 h). Rats were killed either 18 h later (acute SCGx) or after 12 days (chronic SCGx) to measure lipopolysaccharide (LPS)- and concanavalin A (ConA)-induced cell proliferation in submaxillary lymph nodes, submaxillary lymph node cellularity and serum prolactin levels. In control rats, acute SCGx significantly augmented LPS or ConA activity on lymph cells while chronic SCGx had no effect. In pituitary-grafted rats, acute SCGx depressed the mitogenic effect of LPS or ConA whereas chronic SCGx augmented it. A global inhibitory effect of surgical stress on submaxillary lymph node cellularity was found in rats subjected to SCGx or its sham operation 18 h earlier. Serum prolactin levels increased significantly in pituitary-grafted rats, particularly in those subjected to chronic SCGx. In pituitary-grafted rats, a significant effect of acute SCGx was apparent, with serum prolactin levels augmenting about twice in sham-SCGx rats, and to a significantly less extent in acute SCGx rats. The results provide further evidence of the immunomodulatory role of local sympathetic nerves in submaxillary lymph nodes.

The data reviewed in this study show that immune-active molecules, such as infectious agents and their components, and cytokines, may induce profound alterations in several neurotransmitters in the CNS. The activation of the immune system elicits fever, behavioral and neuroendocrine changes and may be involved in neuropathological changes occurring in CNS conditions. These effects may be achieved through and accounted for by the changes induced in central neurotransmitters and in the neuroendocrine system by immune challenges. The present review will summarize the available evidence of the reciprocal interactions between cytokines and neurotransmitters in the CNS.

We aimed to explore whether and how the pineal influences the adrenal medulla, the area postrema and the brain water content; and is influenced by sham pinealectomy (SPX) in its structures and melatonin secretion. Quantitative morphological methods were mainly used in rats and golden hamsters. Experimental results showed: (1) Pineal effects on the A cell system of the adrenal medulla were inhibitory to the synthesis and secretion of epinephrine into the perivascular space and stimulatory to the opioid synthesis, and augmented by SPX. Time-of-day changes were also influenced by SPX and PX. (2) The sizes of a part of the nuclei of nerve and glia cells in the area postrema and the brain water content increased by SPX depending on the presence of the pineal, suggesting the pineal's stimulatory effects on these following SPX. (3) SPX caused morphological changes suggesting an increased activity of pinealocytes. However, corresponding consistent increases in plasma melatonin levels were not seen following SPX. Possible interpretations of these observations were discussed.

Free-running circadian rhythms in melatonin secretion persist in dissociated chick pineal cells. Calcium and cyclic AMP interact at several levels in the regulation of melatonin biosynthesis and secretion. Extracellular Ca2+ is required for optimal stimulation of melatonin secretion by cAMP analogues and protagonists. Increased Ca2+ influx during the circadian night is thought to play a role in the circadian clock regulation of melatonin secretion. We have recently described a nonselective cationic channel, ILOT, in chick pineal cells that is regulated by the intrinsic circadian oscillator. Active ILOT channels are detected only during the nighttime and may explain the nocturnal increase in Ca2+ influx. The mechanism by which the activity of ILOT is regulated by the circadian oscillator is not known. In the present study, the effect of the translational inhibitor anisomycin (10(-6) M) on the nighttime activity of ILOT channels was examined. The results show that protein synthesis is required for the detection of ILOT channel activity during the nighttime in cells maintained on light-dark cycles or constant dark conditions.