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.

[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.

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.

[The reaction of cultured mononuclear cells from the peripheral blood of patients with lepromatous leprosy to rabbit interleukin-1]. / Reaktsiia kul'tiviruemykh mononuklearov perifericheskoi krovi bol'nykh lepromatoznoi leproi na interleikin-1 krolika.

Interleukin-1 (IL-1) obtained from leukocytes of rabbit peritoneal exudate was added to concanavalin A-stimulated cultures of peripheral blood mononuclear cells obtained from healthy donors and patients with lepromatous lepra at the active stage of the process. The comitogenic effect of IL-1, observed in the process of its action on mononuclear donor cells, has been found to be linked with the presence of the state of leprous reaction in the patient and is not manifested in the absence of such state. This indicates that intercellular cooperation processes mediated by IL-1 play some role both in the mechanisms of immunodepression in lepra and in the pathogenesis of leprous reactions connected with the activation of cell immunity.

Altered interleukin-1 production in mice exposed to rotation stress.

This study examined the effects of rotation stress (78 circles per 1 min for 1 h: 10 min rotation + 5 min interval) on peritoneal macrophage release of lymphocyte-activating factors (LAF) and interleukin-1 alpha (IL-1 alpha) concentration in mice (CBA x C57BL6)F1. Rotation stress induced the macrophages' release of LAF with peak reactions in 0-1 h after termination of stress, followed by elevation of plasma IL-1 alpha. Induction of LAF release was accompanied by a higher concentration of corticosterone (Cs) in the blood, most prominent at 0 and 0.5 h after termination of the stressful procedure, and recovering to normal values 1 h later. It is suggested that the stimulating effect of stress on LAF and IL-1 production possibly involves glucocorticoid hormones, as well as other stress-induced neurohumoral shifts accompanying the reaction of glucocorticoids. It is also possible that the activated production of LAF and IL-1 by macrophages has a stress-limiting role in cases of mild stress.

[The combined action of glucocorticoid hormones and interleukin-1 on the development of an immune response]. / Sochetannoe deistvie gliukokortikoidnykh gormonov i interleikina-1 na razvitie immunnogo otveta.

The effect of interleukin-I (IL-I) on glucocorticoid-induced inhibition of the immune response and reactions of cyclic nucleotides to antigen was studied on a model with the use of purified IL-I preparation. Hydrocortisone (HC) in the applied dose caused suppression of the immune response and sharp inhibition of antigen-induced reactions--cAMP in 10 minutes and cGMP on the 6th day after immunization. IL-I administered 10 minutes prior to HC and before immunization prevented the immunosuppressive effect of HC completely. Control administration of heated IL-I and in inactive fraction of the preparation failed to produce a similar effect. IL-I injected 10 minutes after HC also inhibited immunosuppression.

[Interleukin-1 and fibrinolysis. In vivo studies]. / Interleikin-1 i fibrinoliz. Issledovaniia v usloviiakh in vivo.

Distinct decrease in fibrinolytic activity of both whole blood plasma and its euglobulin fraction, occurring due to liberation of an inhibitor of plasminogen activator into circulation, was observed within 2-4 hrs after a single intravenous administration of rabbit interleukin-I into rats at a dose of 50 micrograms/kg, while the activator activity was increased in kidney heart, spleen and lung tissues. The similar data were obtained if the dose was either increased up to 150 micrograms/kg or decreased down to 5 micrograms/kg and 0.5 micrograms/kg, but the effect observed proved to be dose-dependent. Three injections of interleukin-I caused more pronounced increase in concentration of fibrinogen and antiplasmins as compared with controls.

[Effect of interleukin-1 on animals with a fibrinolytic dysfunction]. / Vliianie interleikina-1 na zhivotnykh s disfunktsiei fibrinoliza.

Activating effect of the interleukin-1 on the fibrinolytic system was shown in hypofibrinolysis models. This polypeptide exerted an opposite effect on the fibrinolysis which had been activated with i.v. administration of dihydroergotoxine and thrombin.

[Infectivity of influenza viruses for an organ culture of human embryonic trachea and the change in this trait in recombination]. / Infektsionnost' virusov grippa dlia organnoi kul'tury trakhei émbriona cheloveka i izmenenie dannogo priznaka pri rekombinatsii.

The infecting and reproduction activity of epidemic and vaccine strains of influenza virus as well as their recombinants was studied in human embryo trachea culture. At a certain combination of genes the recombinants showed new qualities: increased tropism to cells of the human upper respiratory tract and intensified virus reproduction in these cells. Of special interest was a recombinant containing the inner proteins of A/Leningrad/9/46 (H0N1) virus and external proteins of A/Brazil/11/78 (H1N1) virus. A possible association of the genes of the internal proteins of influenza A/Leningrad/9/46 virus with the intensity of reproduction, and of the genes of surface glycoproteins with the species specificity of this recombinant is discussed.

[Variability of the virulent properties of influenza A viruses in recombination]. / Izmenchivost' virulentnykh svoistv virusov grippa A pri rekombinatsii.

The pattern of redistribution of human virulence in epidemic strains of influenza viruses in recombination with human avirulent strains was studied. In the course of recombination of epidemic and attenuated influenza virus strains variants with different human virulence were obtained. Some recombinants manifested enforced reactogenic properties as compared with the epidemic strain (X/28, M/35, and 0/26--H1N1, and 2P--H3N2). At the same time, recombinants No 19 (H1N1) and 1P (H3N2) with a similar set of surface antigens were innocuous for man after intranasal administration. Using the observed differences in sensitivity to remantadine as a marker of recombination, we obtained several sets of recombinants which had the antigenic structure of surface proteins of epidemic viruses and remantadine sensitivity of the other parent.

[Biological properties and genome structure of recombinant strains of influenza A virus differing in their degree of human virulence]. / Izuchenie biologicheskikh svoistva i struktury genoma rekombinantnykh shtammov virusa grippa A, razlichaiushchikhsia po stepeni virulentnosti dlia liudei.

The genome structure and some biological properties of parental and recombinant strains of influenza viruses differing by degrees of virulence for man were studied. The vaccine A/Leningrad/9/46 (H0N1) strain was shown to be markedly toxic and pathogenic for mice in contrast to influenza A/Brazil/11/78 and A/Victoria/35/72/50 viruses completely devoid of these properties. The recombinants deriving all 6 genes of the inner proteins of influenza A/Leningrad/9/46 strains and hemagglutinin and neuraminidase of the epidemic A/Brazil/11/78 strain have completely lost their pathogenicity for mice but acquired marked virulence for man. No such effect was observed in recombination of A/Brazil/11/78 with another vaccine strain, A/Victoria/35/72/50. It is suggested that the toxic properties of influenza virus are coded for in genes of internal proteins whereas their manifestation in one or another host species depends on the function of surface polypeptides.