[CELL-MOLECULAR BASIS OFNEUROIMMUNE INTERACTIONS DURING STRESS].

The review represents a modern concept about cells-molecular basis of mechanisms of neuro-immune interactions, the data on the effects of destabilizing factors (electric pain stimulation, rotation, cold and psychoemotional stress) on the functioning of neurons and immune cells. It must be underlined, that under the stress conditions take place the alterations of ligand-receptors interactions on the membrane of lymphocyte. In particular the reaction of these cells to regulating signal - application of Interleikin-1 grow up after mild stress, but it falls down after an influence of severe stress factors. Special attention is paid to the role of the orexinergic system in mechanism of realization of CNS reactions to application of antigens. In the present work the possible methods of correction of imbalance in functional interactions between nervous and immune systems, caused by different destabilizing factors, are reviewed.

[Impairments of rats' behavioral reactions, concentration of corticosterone and expression of cytokine's gene under experimental postviral fatigue].

The aim of the main research was investigated of interaction of neural, endocrine and immune systems under experimental postviral fatigue, behavioral reactions, level of corticosterone, changes of IL-3 and IL-10 gene expression in rats' hypothalamus and INF-α in hypothalamus and spleen were analyzed. It has been shown the decrease of physical activity, increasing of corticosterone's level and gene expression of cytokines after injection of Poly I:C as a model of postviral fatigue. After remedication of Poly I:C increasing of physical activity was shown.

Stress-induced changes in the functional activity of the neuroendocrine system: the modulatory activity of derinat.

Changes in the functional activity of the hypothalamo-hypophyseal-adrenocortical system (HHACS) and hypothalamo-hypophyseal-gonadal system (HHGS) in conditions of different levels of stress and the possibility of correcting them using the native DNA formulation Derinat, which has immunomodulatory properties, were studied. The vectors of changes in hormonal reactions in both systems were found to be independent of the intensity of stress: there were increases in corticosterone levels and decreases in testosterone concentrations in different stress models. Intraperitoneal administration of Derinat at doses of 10 and 50 mg/kg increased HHACS and HHGS activity and reversed the stress-induced reduction in the blood testosterone concentration, which may be evidence that Derinat has stress-protecting effects. Administration of Derinat promoted normalization of stress-induced changes in the production of immunomodulatory cytokines among lymphocyte-activating factors with regulatory influences not only on the functioning of the immune system, but also on the HHACS and HHGS functions.

[Stress-induced changes in functional activity of the neuro-endocrine system: modulatory action of derinat].

Changes in functional activity of HPA and HPG axes under stress influences of different intensity, and possible ways for their correction by native DNA preparation: derinat, possessing immune modulator effects, were studied. It was shown that the vector of changes in hormone's reactions of both axes did not depend on the intensity of stress influences: different models of stress increased corticosterone level and decreased testosterone level in rats' blood. Intraperitoneal injection of 10 and 50 mg/kg BW doses of Derinat to rats enhanced HPA and HPG axes activity, reversed stress-induced decrease of testosterone concentration in blood, that may indicate a stress-protective effect of derinat. Injection of derinat caused normalizing of stress-induced changes in immunomodulatory cytokines production within Lymphocyte Activating Factors, which regulate not only the immune system functions but also the functions of HPA and HPG axes.

[Cellular and molecular mechanisms of interaction between the neuroendocrine and immune systems under chronic fatigue syndrome in experiment].

One of the main mechanisms of chronic fatigue syndrome development involves disturbances of interaction between the immune and neuroendocrine systems. The adequate experimental model for the search of these mechanisms is induction of fatigue in animals via the single intraperitoneal administration of synthetic double-stranded RNA - Poly I : C. Investigation of alterations in cytotoxic and proliferation activities of splenocytcs, the intensity of immunomodulatory cytokines signaling via the sphingomyelin pathways in membrane P2 fraction of the brain cortex, as well as the activity of hypothalamic-pituitary adrenal (HP A) axis in the dynamics of chronic fatigue syndrome in rats has performed. Inhibition of both cytotoxic and proliferative activities of splenocytes during the period of fatigue development has been shown. Priority data concerning the suppression of the activity of neutral sphingomyelinase (nSMase) - the key enzyme of the sphingomyelin cascade - in membranes ofthe cells from the brain cortex on the 3d day after Poly I : C administration to rats have been obtained. It was found that Poly I : C injection to rats led to disturbed HPA axis functions which was manifested by decreased corticosterone concentration in standard functional assays with ACTH and hydrocortisone administration. It is suggested that disturbances in interaction between the immune and neuroendocrine systems during development of chronic fatigue syndrome, including alterations in HPA axis activity, are realized both on the level of changes in the activity of immune-competent cells and immediately on membranes of the brain cells.

Expression of the c-Fos gene in hypothalamic cells and cytotoxic activity of natural killer cells in the spleen of rats after treatment with Cytoxan.

In experiments on rats we studied the effect of cyclophosphamide-containing drug Cytoxan on activation of neurons in hypothalamic structures involved in the regulation of natural killer cell activity in the spleen and changes in cytotoxicity of these cells. Administration of Cytoxan in a dose of 60 mg/kg increased the number of c-Fos-positive cells in the ventromedial hypothalamus and lateral hypothalamic area and reduced interferon-alpha-induced cytotoxic activity of natural killer cells. Our findings attest to the involvement of central mechanisms of regulation of splenic natural killer cells into side effects of Cytoxan.

Production of lymphocyte-activating factors by mouse macrophages during aging and under the effect of short peptides.

Age-specific characteristics of production of lymphocyte-activating factor by mouse peritoneal macrophages and modulation of this production by short synthetic peptides (Vilon, Epithalon, and Cortagen) were studied. The production of lymphocyte-activating factors by macrophages stimulated with lipopolysaccharides in vitro was lower in old animals. The opposite modulating effects of short peptides on the production of lymphocyte-activating factors by resident and lipopolysaccharide-stimulated macrophages in young and old mice were demonstrated for the first time. This is a possible mechanism of immune system dysfunction during aging, which opens new vistas for its correction with short synthetic peptides.

Effects of short peptides on thymocyte blast transformation and signal transduction along the sphingomyelin pathway.

Immunomodulating effects of synthetic peptides Vilon (Lys-Glu), Epithalon (Ala-Glu-Asp-Gly), and Cortagen (Ala-Glu-Asp-Pro) and possible involvement of the sphingomyelin signal transduction pathway in their effects in mouse thymocytes were studied. Vilon produced the most potent comitogenic effect on thymocyte proliferation and modulated comitogenic activity of interleukin-1b. Epithalon was less potent, while Cortagen produced no such effects. Vilon produced a more pronounced stimulatory effect on sphingomyelinase activity in mouse thymocyte membranes compared to Epithalon and Cortagen.

The role of interleukin-1 in stress-induced changes in immune system function.

The cellular-molecular mechanisms of changes in immune system function were studied, including the production of lymphocyte activating factor (LAF) and interleukin-1 (IL-1). the effects of IL-1 on target cells, and subsequent cytokine signal transduction via the sphingomyelin pathway, in different types of stress. These experiments showed that stress of different durations and intensities induced the formation of lymphocyte activating factors by peritoneal macrophages and increased IL-la levels in mouse blood. but led to different changes in the responses of target thymocytes to the committing actions of IL-1beta. which correlated with changes in the level of the humoral immune response. These data coincided with differently-directed stress-induced changes in the activity of membrane-bound neutral sphingomyelinase. the key enzyme in the sphingomyelin cascade, in cerebral cortex membrane fraction P2 from mouse brains. The results obtained here suggest that IL-1 is involved in the physiological mechanisms of stress reactions, operating at the levels of IL-1 production and its biological actions on lymphoid target cells, as well as at the level of cytokine signal transduction via the sphingomyelin pathway in nerve tissue.

The role of neutral sphingomyelinase in interleukin-1beta signal transduction in mouse cerebral cortex cells.

The cytokine interleukin-1 (IL-1) is an important mediator of neuroimmune interactions, though it has not been established precisely how the IL-lbeta signal is transmitted in nerve cells. This study demonstrates the involvement of the sphingomyelin cascade in IL-1beta signal transduction in the P2 membrane fraction of the mouse cerebral cortex. The key role of the membrane enzyme neutral sphingomyelinase in initiating the sphingomyelin signal transduction pathway for this cytokine is supported. The stimulating activity of IL-1beta on sphingomyelinase activity in the P2 fraction of the cerebral cortex was found to be dose-dependent. Studies using this membrane fraction from mice lacking the IL-1 type I receptor due to genomic mutations, along with studies using an IL-1 receptor antagonist. yielded data showing that IL-1beta binding with the type I receptor is a necessary event for activation of neutral sphingomyelinase. The results obtained here lead to the conclusion that the action of IL-1beta in the CNS is mediated by the IL-1 type I receptor and activation of neutral sphingomyelinase as the initiating enzyme of the sphingomyelin cascade.

[Interleukin-1 in realisation of stress-induced changes in functions of the immune system]. / Interleikin-1 v realizatsii stress-indutsirovannykh izmenenii funktsii immunnoi sistemy.

Stress influences of different duration and intensity induce production of a lymphocyte-activating factor (LAF) by murine peritoneal macrophages, and enhancement of Interleukin 1 (IL-1) level in the murine blood, inducing no alterations in the thymocyte reaction to concomitant action of the IL-1 beta which correlates with changes in the value of humoral immune response. The data obtained are in agreement with differently aimed stress-induced alterations in the activity of the membrane neutral sphingomyelinase: the key enzyme of the sphingomyelin cascade, in the membrane P2 fraction of the brain cortex. The IL-1 seems to participate in physiological mechanisms of realisation of stress reactions on the levels of its production and biological action on target cells as well as of the sphingomyelin pathway of its signal transduction in nerve tissue.

[The role of neutral sphingomyelinase in the interleukin-1beta signal transduction in cells of the mouse cerebral cortex]. / Rol' neitral'noi sfingomielazy v transduktsii signala interleikina-1beta v kletkakh kory golovnogo mozga myshei.

Involvement of the sphingomyelin cascade in Interleukin 1 beta (IL-1) signal transduction pathway in membrane fraction P2 of the murine brain cortex, was found. A key role of the membrane enzyme neutral sphingomyelinase (nSMase) in triggering the sphingomyelin pathway for IL-1 beta, was confirmed. The IL-1 beta was shown to activate in a dose-dependent manner nSMase in the P2 fraction of the brain cortex. Employment of both brain cortex membranes from the mice deficient in the type I IL-1 receptor and of IL-1 receptor antagonist made it possible to obtain evidence on the necessity of the IL-1 beta binding to the type I IL-1 receptor for the nSMase activation. It appears that the IL-1 beta effects on the CNS are realized via IL-1 receptor type I and activation of the nSMase as an initiating enzyme of the sphingomyelin cascade.

Activation of neutral sphingomyelinase by IL-1beta requires the type 1 interleukin 1 receptor.

The cytokine interleukin 1beta (IL-1beta) plays an important role in host defence reactions and neuro-immune interactions but it is still not clear which of the two interleukin 1 receptor subtypes is coupled to activation of neutral sphingomyelinase (nSMase) by IL-1beta. To investigate involvement of neutral sphingomyelinase (nSMase) in central IL-1beta effects we used P(2)fractions of brain cerebral cortex from wild-type mice and mice deficient in the type 1 IL-1 receptor. IL-1beta (human, recombinant) was shown to activate, in a dose-dependent manner, nSMase in the P(2)brain fraction of the wild-type mice while in the knock-out mice the stimulatory effect of IL-1beta on nSMase was absent. In the presence of an IL-1 receptor antagonist (IL-1ra), IL-1beta did not activate nSMase either in the cortex of wild-type or knock-out mice. These data suggest that nSMase, a key enzyme of the sphingomyelin signal transduction pathway, might be involved in IL-1beta signalling in the brain and that activation of the enzyme requires the IL-1 receptor type 1.

Interleukin-1 and defensins in thermoregulation, stress, and immunity.

Our previous studies suggested that IL-1 and defensins, which play a critical role in mechanisms of host resistance, participated in the realization of stress reaction. The present report describes functional relations between IL-1 and defensins during stress reactions and the influence of defensins administration on thermoregulation and the IL-1 level in blood. It is shown that stress-induced shifts in the humoral immune response are accompanied by diverse changes in the IL-1 alpha level in blood and LAF production by peritoneal macrophages, which are possibly associated with the intensity and strength of applied stressors. Functional interrelations between actions of defensins and IL-1 during stress reaction and in the conditions of an LPS-induced rise in body temperature was demonstrated. These results suggest that antibacterial peptides defensins may be involved in thermoregulation in case of increased body temperature probably influencing the blood level of IL-1.

Cellular mechanisms of cold stress-related immunosuppression and the action of interleukin 1.

Recent studies of the immunomodulatory cytokines, especially interleukin 1 (IL-1), as the mediators of immunoneuroendocrine links have suggested their important physiological role in the development of host resistance during stress reaction. The present study examined the effects of cold stress (-20 degrees C, 20 min) in rats on the value of humoral immune response, lymphocyte activating factor (LAF) production by peritoneal macrophages, as well as IL-1 beta action on lymphocyte proliferation, and the level of general antibody titers. Cold stress exposure led to a considerable elevation of corticosterone (Cs) in rat blood serum and to pronounced suppression of humoral immune response. This kind of experimental stress induced peritoneal macrophages in rats to release LAF without additional stimulation within 24 h after termination of cooling. At the same time LAF production by macrophages after their additional stimulation by LPS in vivo and heat-killed staphylococcus in vitro was decreased during cold stress reaction. Cold stress exposure suppressed the ability of peripheral blood lymphocytes to proliferate in response to concomitant action of IL-1 beta. Immunoprotective effect of rat recombinant IL-1 beta administrated i.p. to rats before cooling was revealed. It is suggested that IL-1 beta modulates immunological and neuroendocrine responses to stress and plays a critical physiological role in realization of stress reaction.