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H Besedovsky

Publications and source records attributed to H Besedovsky.

At least 19 recordsLinked to original sources
PubMed2004

Cortisol and dehydroepiandrosterone affect the response of peripheral blood mononuclear cells to mycobacterial antigens during tuberculosis.

The effect of cortisol and/or dehydroepiandrosterone (DHEA) on the immune response to antigens obtained from Mycobacterium tuberculosis was studied in vitro by using peripheral blood mononuclear cells obtained from patients at various stages of lung tuberculosis (TB) and from healthy control people (HCo). The results obtained show for the first time that addition of cortisol within concentrations of physiological range can inhibit the mycobacterial antigen-driven proliferation of cells from HCo and TB patients and the production of interferon-gamma (IFN-gamma), indicating that endogenous levels of cortisol may contribute to the decreased lymphoid cell response to mycobacterium antigens observed in TB patients. DHEA did not affect lymphoid cell proliferation, IFN-gamma production and the cortisol-mediated inhibitory effects. Interestingly, we found that DHEA, but not cortisol, suppressed the in vitro transforming growth factor-beta production by lymphoid cells from TB patients with an advanced disease, which is indicative of a selective direct effect of this hormone.

Adjuvants, Immunologic↗
PubMed1997

Induction of cytokine transcripts in the central nervous system and pituitary following peripheral administration of endotoxin to mice.

The regional distribution and inducibility of cytokines in the normal brain is still a matter of controversy. As an attempt to clarify this issue, we studied the constitutive and induced expression of interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma mRNAs in the brain, pituitary, and spleen of mice using qualitative and semiquantitative reverse-transcription polymerase chain reaction. The contribution of nonbrain cells to the cytokine transcripts detected was considered. With the exception of IFN-gamma mRNA, transcripts for the other cytokines were found to be constitutively present in the brain. Following i.p. injection of lipopolysaccharide (LPS) at a dose below those described to disrupt the blood-brain barrier (BBB), cytokine mRNA expression was increased in the spleen, the pituitary, and the brain. In the brain, the onset of transcription varied from 45 min (IL-1beta, TNF-alpha) to 4 hr (IFN-gamma), and the peak of mRNA accumulation was observed at different times depending on the cytokine and the brain region studied. IL-1 and IL-6 were highly expressed in the hypothalamus and hippocampus, while TNF-alpha expression was more marked in the thalamus-striatum. The cortex was the region in which cytokines were less inducible. The inducible expression of cytokine mRNAs in the brain was paralleled by stimulation of the hypothalamus-pituitary-adrenal axis. These results show the capacity of brain cells to synthesize different cytokine mRNAs in vivo and define the kinetics of their expression in several brain areas and in the periphery in parallel to the activation of a neuroendocrine pathway by endotoxin.

Animals↗
PubMed1997

Endotoxin impedes vasoconstriction in the spleen: role of endogenous interleukin-1 and sympathetic innervation.

Processes relevant for an appropriate immune response such as immune cell traffic and recirculation require a tight control of blood supply to lymphoid organs. Interactions between endogenous cytokines and sympathetic nerve fibers in lymphoid organs can contribute to this control. The results reported in this paper show that 1) administration of low doses of lipopolysaccharide (LPS), an endotoxin derived from gram-negative bacteria, causes an increase in splenic blood flow (SBF); 2) this increase is mediated by the production of endogenous interleukin-1 (IL-1); 3) the effect of LPS on SBF requires an intact splenic sympathetic innervation; 4) the LPS-induced increase in SBF is exerted at the postganglionic level; 5) the endotoxin inhibits the vasoconstriction induced by the in vivo stimulation of the splenic nerve but does not affect the vasoconstriction induced by norepinephrine (NE); and 6) although IL-1 and LPS stimulate general sympathetic activity as reflected by increased peripheral vascular resistance, they do not increase NE concentration in splenic dialysates. Together these in vivo results indicate that endogenous IL-1 affects blood supply to the spleen by inhibiting the sympathetic vasoconstrictor tonus at a postganglionic, prejunctional level. This effect is expected to be relevant for immune cell recirculation, homing, and traffic as well as antigen trapping in the spleen, an organ specialized in the control of these processes during immune responses.

Administration, Topical↗
PubMed1991

On the mechanism of antiinflammation induced by tumor transplantation, surgery, and irritant injection.

Tumor transplantation, major surgery, and injection of nonspecific irritants elicit inflammation locally while suppressing inflammation induced subsequently and at distant sites. Such systemic antiinflammation in rodents occurs via corticosterone-independent and -dependent pathways. Based upon hormone measurements and the response to adrenalectomy, antiinflammation induced by irritants and certain surgical procedures is corticosterone independent while that which follows tumor transplantation is corticosterone dependent. However, injection of tumorous ascites stimulates both pathways since it contains two antiinflammatory factors: Factor A (molecular weight less than 2,000) does not alter hormone balance while Factor B (molecular weight 30,000-100,000) increases corticosterone levels and is corticosterone dependent. Desensitization of systemic antiinflammation develops rapidly regardless of whether it is corticosterone dependent (Factor B) or independent (Factor A or irritants). However, tumor transplantation resists desensitization possibly by inducing an immune response since lymphocytic mitogens prevent development of and break established desensitization. Nevertheless, abolition of tumor-induced antiinflammation follows injection of tumorous ascites by a mechanism that involves Factor B suppression of the corticosterone response to the tumor while Factor A apparently raises the threshold at which physiological increases in corticosterone inhibit leukocyte emigration. We conclude that systemic antiinflammation is a general consequence of a localized inflammatory reaction and that desensitization of such antiinflammation develops rapidly. Recent evidence indicates that certain mediators of inflammation are proinflammatory when administered intradermally but antiinflammatory when given intravenously. Thus, systemic antiinflammation may arise when chemical mediators of inflammation generated by a local reaction gain access to the circulation.

Adrenalectomy↗
PubMed1989

Antidiabetic effects of interleukin 1.

Interleukin 1 (IL-1), a cytokine released mainly by activated macrophages-monocytes, affects glucose homeostasis and may mediate some of the metabolic derangements observed during certain inflammatory and infectious processes. In this report, it is shown that IL-1 acts as a hypoglycemic agent not only in normal animals but also in mice at early stages of alloxan-induced diabetes and in genetically diabetic, insulin-resistant C57BL/Ks db/db mice and C57BL/6J ob/ob mice. In these animal models, a single injection of a low dose of human recombinant IL-1 normalized glucose blood levels for several hours. This effect was not mediated by possible insulin secretagogue actions of the cytokine. Furthermore, IL-1 markedly reduced the levels of triglycerides in blood of streptozotocin-induced diabetic mice at later stages of the disease. Although the final mechanism of action is at present unknown, the results showed that IL-1 is a hormone with powerful antidiabetic properties. Defective production of this cytokine associated with diabetes could contribute to aggravate the course of the disease during infectious and inflammatory processes.

Animals↗
PubMed1989

Host endocrine responses during tumor growth.

Transplantation of the EL-4 lymphoma to syngeneic recipients caused significant endocrine changes which occurred very early as well as late after transplantation. Among the hormonal changes induced were a biphasic increase in the level of serum corticosterone, a biphasic decrease in serum insulin levels, an early decrease in prolactin and a terminal severe deficiency in thyroxine. The mechanism by which corticosterone levels are increased immediately following tumor transplantation appears to involve post-thymic T cells. In addition, the corticosterone response after tumor transplantation seems to be restricted to syngeneic recipients and does not seem to occur with allogeneic tumor transplantation. Further, the phenomenon may require an immunogenic tumor since the relatively nonimmunogenic mammary tumor virus (MTV) induced adenocarcinoma did not increase corticosterone in syngeneic C3H/He mice. Such data are consistent with the proposition that recognition of tumor antigen by mature T cells occurs within hours of tumor transplantation. This recognition appears to be MHC restricted. Whereas mitogen stimulation of T cells produces a glucocorticoid increasing factor designated GIF (Besedovsky et al., 1985b), it is reasonable to suggest that GIF is produced in vivo as part of the T cell response to tumor antigen. GIF in turn stimulates hypophyseal release of ACTH with a subsequent release of corticosterone from the adrenal gland. The biological relevance of this physiological increase in serum levels of corticosterone was examined with respect to the anti-inflammatory phenomenon often observed after tumor transplantation. First, a concordance was noted following tumor transplantation between elevated corticosterone levels and anti-inflammation. Similarly, transplantation of the MTV induced mammary adenocarcinoma which failed to increase serum levels of corticosterone did not exhibit anti-inflammation. Consistent with the concept that corticosterone levels increase following T cell recognition of tumor antigens, it is known that anti-inflammation does not occur with weakly immunogenic tumors but does follow transplantation of moderately immunogenic tumors (Normann, 1985b; Normann et al., 1985a). Second, adrenalectomy prevented the corticosterone response to tumor transplantation and eliminated tumor associated anti-inflammation. Additional studies are necessary to determine if the increase in serum levels of corticosterone alters other parameters of the host response to tumors. Anti-inflammation was shown to occur following tumor transplantation via a corticosterone dependent pathway.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Hormonal changes following tumor transplantation: factors increasing corticosterone and the relationship of corticosterone to tumor-induced anti-inflammation.

EL-4 lymphoma cells transplanted to syngeneic C57BL/6J mice induced a biphasic decrease in inflammation and a bi-phasic increase in serum levels of corticosterone. In addition, this tumor altered serum levels of 3 other hormones, resulting in a biphasic decrease in insulin, an early decrease in prolactin, and a terminal severe deficiency in thyroxine. Early changes occurred 16 to 48 hr after tumor transplantation and were of variable duration, while late-phase defects developed during the last few days of life. Soluble factors associated with tumor growth may mediate certain hormonal changes since serum levels of corticosterone increased and insulin decreased following injection of tumorous ascites into normal mice. Further, injection of cell-free tumor culture supernatants increased corticosterone levels. Hormonal changes following injection of soluble factors occurred after a delay of 16 hr indicating that the factors acted indirectly. Surgical adrenalectomy blocked the corticosterone increase induced by tumor transplantation or ascites injection and eliminated the anti-inflammatory effect of tumor transplantation while significantly decreasing the effect associated with injection of tumorous ascites. Thus, the physiologically induced increase in serum levels of corticosterone reached anti-inflammatory levels. Further, elevated levels of corticosterone are a major contributing factor to anti-inflammation induced by tumorous ascites injection and constitute the principal mechanism of anti-inflammation following tumor transplantation.

Animals↗
PubMed1988

Interactions between endogenous glucocorticoids and inflammatory responses in normal and tumor-bearing mice: role of T cells.

Appropriately stimulated lymphocytes and macrophages produce factors in vitro that increase serum corticosterone levels when injected in vivo. In this study, we used euthymic and congenitally athymic mice on a BALB/c background to explore the role of T cells in controlling corticosterone levels and the leukocyte response to inflammation. Adult athymic mice had more intense inflammatory reactions than euthymic mice despite higher basal corticosterone levels. This latter condition may be due to interleukin-1 (IL-1) since macrophages from athymic mice when stimulated in vitro by lipopolysaccharide produced more IL-1 than macrophages from euthymic mice. In response to mitogen stimulation, however, splenocytes from athymic mice produced a factor (not IL-1), which, upon injection, increased corticosterone levels and suppressed inflammation. Production of this factor was enhanced by T cells since splenocyte supernatants from euthymic mice were more potent in eliciting both effects. Evidence for in vivo participation of T cells in regulating corticosterone levels was obtained by tumor transplantation. Injection of syngeneic tumor cells or cell-free tumorous ascites rapidly increased corticosterone levels in euthymic but not athymic mice. Anti-inflammation correlated with increased corticosterone levels but was observed also in athymic mice receiving syngeneic tumor transplants. These studies demonstrate that T cells enhance production of a lymphokine that increases corticosterone levels and are required for the corticosterone response to tumor transplantation. In addition, the data suggest two pathways of anti-inflammation in tumor-bearing hosts: a corticosterone-independent, T cell-independent mechanism and a T cell-dependent mechanism that involves a lymphokine-mediated increase in corticosterone blood levels.

Animals↗
PubMed1987

Corticotropin-releasing factor-producing neurons in the rat activated by interleukin-1.

Intraperitoneal administration of human recombinant interleukin-1 (IL-1) to rats can increase blood levels of corticosterone and adrenocorticotropic hormone (ACTH). The route by which IL-1 affects pituitary-adrenal activity is unknown. That the IL-1-induced pituitary-adrenal activation involves an increased secretion of corticotropin-releasing factor (CRF) is indicated by three lines of evidence. First, immunoneutralization of CRF markedly attenuated the IL-1-induced increase of ACTH blood levels. Second, after blockade of fast axonal transport in hypothalamic neurons by colchicine, IL-1 administration decreased the CRF immunostaining in the median eminence, indicating an enhanced release of CRF in response to IL-1. Third, IL-1 did not stimulate ACTH release from primary cultures of anterior pituitary cells. These data further support the notion of the existence of an immunoregulatory feedback circuit between the immune system and the brain.

Adrenal Glands↗
PubMed1987

Neuroendocrine and metabolic responses induced by interleukin-1.

We have previously demonstrated that Interleukin-1 (IL-1), a cytokine mainly produced by activated monocytes, stimulates the pituitary-adrenal axis and affects glucose homeostasis. Comparative studies revealed that a beta form of recombinant human IL-1, similar to the mature peptide secreted naturally, is more powerful than other preparations of this monokine in stimulating adrenocorticotrophic hormone (ACTH) and corticosterone output. Another monokine, tumor necrosis factor (TNF), does not share with IL-1 the capacity to induce such effects. In extending our studies to rats, we showed that increased ACTH and blood corticosterone levels are also induced by IL-1 in this species. Another in vivo activity of IL-1 relates to its capacity to induce a reduction in blood glucose levels. Our studies strongly suggest that, as opposed to other effects elicited by IL-1, blockade of prostaglandin synthesis does not affect the capacity of IL-1 to stimulate insulin output and produce hypoglycemia. Administration of IL-1 to adrenalectomized mice, which are defective in counterregulatory mechanisms of glucose homeostasis, resulted in marked hypoglycemia. In contrast to the response observed in normal mice, in adrenalectomized animals this effect was paralleled by decreased blood insulin levels. IL-1 was also injected into alloxan-diabetic mice. A marked reduction in blood glucose levels occurred in these animals. This effect was already noticeable 1 hr after injection. After 2 hr and for at least another 6 hr, glucose levels of alloxan-treated mice injected with IL-1 remained within the normal range.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1987

Interleukin 1 affects glucose homeostasis.

Alterations in glucose metabolism are known to occur during certain types of inflammation and infectious diseases. Interleukin 1 (IL 1), an immune-derived cytokine released during these processes, is proposed to function as a mediator of such alterations, since administration of low subpyrogenic doses of human rIL 1 to mice and rats produced hypoglycemia. In mice this effect was paralleled by increased insulin, glucagon, and corticosterone blood levels. When IL 1 was repeatedly injected, mice remained hypoglycemic for at least 14 h after the last injection. Furthermore, these animals responded normally to a challenge with glucose, thus suggesting that the proper function of the pancreas was preserved. A moderate hypoglycemia, paralleled by increased glucagon and corticosterone blood levels, was also observed in IL 1-injected rats, but no increase in insulin levels was detected. IL 1 administration to adrenalectomized rats resulted in a more marked hypoglycemia and in a profound hypoinsulinemia. The results suggest that IL 1 causes hypoglycemia by increasing insulin blood levels and probably also by mechanisms independent of the insulin secretagogue action of this cytokine.

Adrenalectomy↗
PubMed1986

Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones.

The production and action of immunoregulatory cytokines, including interleukin-1 (IL-1), are inhibited by glucocorticoid hormones in vivo and in vitro. Conversely, glucocorticoid blood levels were increased by factors released by human leukocytes exposed to Newcastle disease virus preparations. This activity was neutralized by an antibody to IL-1. Therefore the capacity of IL-1 to stimulate the pituitary-adrenal axis was tested. Administration of subpyrogenic doses of homogeneous human monocyte-derived IL-1 or the pI 7 form of human recombinant IL-1 to mice and rats increased blood levels of adrenocorticotropic hormone (ACTH) and glucocorticoids. Another monokine, tumor necrosis factor, and the lymphokines IL-2 and gamma-interferon had no such effects when administered in doses equivalent to or higher than those of IL-1. The stimulatory effect of IL-1 on the pituitary-adrenal axis seemed not to be mediated by the secondary release of products from mature T lymphocytes since IL-1 was endocrinologically active when injected into athymic nude mice. These results strongly support the existence of an immunoregulatory feedback circuit in which IL-1 acts as an afferent and glucocorticoid as an efferent hormonal signal.

Adrenocorticotropic Hormone↗
PubMed1984

Endogenous blood levels of corticosterone control the immunologic cell mass and B cell activity in mice.

An inverse relation between endogenous levels of glucocorticoids and splenic mass and cellularity was detected. Decreased endogenous corticosterone blood levels result in an increased number of immunoglobulin-secreting cells in the spleen, a fact that cannot be attributed only to the expansion of the lymphoid cell mass. The opposite phenomenon was observed in animals with high corticosterone blood levels, which showed reduced numbers of immunoglobulin-secreting cells. It is concluded that endogenous glucocorticoid levels contribute to the control of B cell activity and possibly to the interaction of these cells with other immunologic cells.

Adrenalectomy↗
PubMed1983

The immune response evokes changes in brain noradrenergic neurons.

A decreased noradrenaline turnover in the hypothalami of rats was observed at the peak of the immune response to sheep red blood cells. The decrease in noradrenergic neuronal activity was mimicked by injection of soluble r mediators released by immunological cells activated in vitro. Noradrenaline also tended to decrease in the brainstem but not in the residual brain. It is suggested that products released from activated immunological cells during the immune response may induce the previously described autonomic and endocrine mechanisms that contribute to immunoregulation.

Animals↗