PubMed Health⌕ Search

Biomedical subjects

H O Besedovsky

Publications and source records attributed to H O Besedovsky.

At least 37 records · Page 2Linked to original sources
PubMed1996

Alterations in the pituitary-adrenal axis of adult mice following neonatal exposure to interleukin-1.

Interleukin-1 (IL-1), a cytokine mainly derived from activated cells of the macrophage lineage, can stimulate the hypothalamus-pituitary-adrenal (HPA) axis. Acute and long-lasting effects on the HPA axis were induced by the administration of low doses of IL-1 to mice during the first 5 days of life. In 5-day-old mice, corticosterone blood levels were markedly elevated 2 h following the last injection of IL-1. IL-1-treated mice grew normally. When studied during adulthood, however, these animals showed a reduction in morning values of corticosterone and the ACTH/corticosterone ratio was increased. Furthermore, an inverse correlation between ACTH and corticosterone levels in blood and between ACTH content in the pituitary gland and corticosterone levels was observed in IL-1-treated mice. Lower blood levels of corticosterone were not due to a reduced sensitivity of the adrenal glands, because these animals responded normally to exogenous ACTH. Another alteration observed in IL-1-exposed adult mice was a reduction in ACTH-like immunoreactivity in the pituitary gland following acute cold and restraint stress. It is concluded that exposure of mice to IL-1 early in life causes long-lasting alterations in the HPA axis. Spleen cells from adult mice treated with IL-1 at birth also developed a stronger response to allogeneic antigens than did cells from control mice. This observation indicates the relevance of immune-neuroendocrine interactions during development.

Adrenocorticotropic Hormone↗
PubMed1996

Metabolic and endocrine effects of interleukin-1 in obese, diabetic Zucker fa/fa rats.

IL-1, a cytokine produced predominantly by cell from the macrophage lineage, can affect multiple neuroendocrine and metabolic functions. We report here effects of this cytokine in obese, diabetic Zucker fa/fa rats. These animals are modestly hyperglycemic, hyper-lipemic, and markedly hyperinsulinemic. Changes in the levels of glucose, lactate, triglycerides, free fatty acids, insulin, glucagon, and corticosterone were detected following a single intraperitoneal or intravenous injection of IL-1 into fa/fa rats. No comparable changes were observed following administration of insulin. In fa/fa rats, the diabetic status is particularly manifested by an abnormal glucose tolerance. Administration of a bolus injection of IL-1 normalized the response of diabetic fa/fa rats to a glucose load. These rats not only returned to their basal glucose levels quicker, but reached glucose concentrations in blood which were comparable to, or even lower than those of Fa/? rats. Although the mechanism underlying the effects of IL-1 in fa/fa rats are presently not clear, the results obtained suggest that this cytokine tends to normalize glucose homeostasis and stimulate fat mobilization in these animals.

Animals↗
PubMed1995

Interleukin-1 increases splenic blood flow by affecting the sympathetic vasoconstrictor tonus.

The possibility that interleukin-1 (IL-1), a cytokine involved in immune and inflammatory mechanisms, can affect the blood flow of the spleen was considered because changes in spleen perfusion can affect immune cell recirculation, traffic, and homing. The results indicate that administration of a subpyrogenic dose of IL-1 induced a pronounced increase in splenic blood flow. This was not a general effect, because no change in blood flow of skeletal muscle was noticed. The studies also show that 1) the increase in splenic perfusion induced by IL-1 is to a large extent independent from the secondary induction of nitric oxide (NO), 2) the splenic blood flow in the rat is under sympathetic control, and 3) the effect of IL-1 on splenic blood flow is completely abrogated after surgical interruption of the splenic nerve, which is predominantly composed of sympathetic fibers. It is concluded that the IL-1-mediated increase in splenic blood flow is most likely based on the inhibition of the sympathetic vasoconstrictor tonus in the rat spleen. These results show that a cytokine released by activated immune cells can regulate the blood flow of a main lymphoid organ, the spleen, by affecting mechanisms under neural control.

Animals↗
PubMed1992

Interleukin-1 stimulates aldosterone secretion: involvement of renin, ACTH, and prostaglandins.

Interleukin-1 (IL-1), a cytokine produced during infection and inflammation, mediates some of the endocrinological alterations that parallel these processes. The purpose of this study was to determine whether human recombinant IL-1 (hrIL-1) affects aldosterone output as well as renin and adrenocorticotropic hormone (ACTH) release, two key factors in the regulation of mineralocorticoid secretion. We observed that intravenous administration of hrIL-1 into conscious unrestrained rats elicited a marked and rapid rise in aldosterone plasma levels in a dose-dependent manner. The hrIL-1-induced increase in aldosterone levels was associated with enhanced renin activity and increased ACTH levels in plasma. Furthermore, aldosterone levels of IL-1-injected rats were positively correlated with plasma renin activity (PRA), suggesting that the renin-angiotensin system contributes to the changes observed in the levels of the mineralocorticoid hormone. ACTH seems also to be implicated in the aldosterone response to hrIL-1 because the profile of the kinetic curves of changes in the levels of the pituitary hormone and aldosterone was similar. Pretreatment with the cyclooxygenase inhibitor indomethacin markedly reduced the increase in aldosterone plasma levels and PRA induced by IL-1, indicating that prostaglandins are involved in these effects of the cytokine. These results suggest that IL-1 may play an important role in the control of homeostasis during infectious and inflammatory diseases.

Adrenocorticotropic Hormone↗
PubMed1992

Metabolic and neuroendocrine effects of pro-inflammatory cytokines.

Immune-neuroendocrine interactions occur during physiological and pathological situations. Pro-inflammatory cytokines such as IL-1, IL-6 and TNF alpha play a role in mediating these interactions. Although all three cytokines can stimulate ACTH and glucocorticoid output, IL-1 has the highest potency. It is known that increased glucocorticoid levels result in hyperglycemia. However, administration of low doses of lipopolysaccharide (LPS), an inducer of several cytokines including those mentioned above, causes a profound and long lasting hypoglycaemia. This effect seems to be dissociable from that of insulin, since the same effect was observed in insulin-resistant db/db mice. The data reported here show that IL-1 plays a crucial rôle in the mediation of the hypoglycaemia induced by LPS, since other cytokines released following inoculation of endotoxin, such as TNF alpha and IL-6, have only marginal effects or do not induce hypoglycaemia when administered in doses similar to those of IL-1. The effect of IL-1 seems to be integrated at least in part at CNS level since i.c.v. administration produces hypoglycaemia in spite of the concomitant release of corticosterone. The data reported here reinforce the concept that IL-1 and related cytokines participate in the mediation of immune-neuroendocrine interactions.

Adrenocorticotropic Hormone↗
PubMed1992

Immune-neuroendocrine circuits: integrative role of cytokines.

Several efficient autoregulatory mechanisms confer a certain degree of autonomy to the immune system. However, increasing evidence shows that immune processes operate in a coordinated fashion with other body systems. In this article, we discuss concepts and facts concerning interactions between immune and neuroendocrine mechanisms. There are clear examples that immune cells can be influenced by hormones, neurotransmitters, and neuropeptides and also by alterations in brain functions. Conversely, immune-derived products such as lymphokines and monokines can affect endocrine, autonomic, and central mechanisms. Neuroendocrine responses occur during the activation of the immune system. These responses can be elicited by innocuous antigens; they can also be detected during pathological conditions involving immune activation, and in many cases are dissociable from the effects of the disease itself and from the stress of being sick. On this basis, we emphasize the multidirectional nature of the communication processes between the immune, endocrine, and nervous systems. The role of lymphokines and monokines as messengers able to convey information to neuro and endocrine structures about the present state of activity of the immune system is stressed. The relevance of immune-neuroendocrine interactions for immunoregulation and host defenses is discussed as well as the active role of the immune system in mediating metabolic and homeostatic adjustments or derangements during the course of certain infectious, inflammatory, and neoplastic processes. The evidence available suggests that complex immune-neuroendocrine networks operate under both physiological and pathological conditions.

Animals↗
PubMed1991

Cytokines as modulators of the hypothalamus-pituitary-adrenal axis.

The hypothalamus-pituitary-adrenal (HPA) axis is stimulated during the course of certain immune, inflammatory and neoplastic processes. IL-1 is an important immunologically derived cytokine mediating the stimulation of this axis, although not the only one. We have compared the relative potencies of the cytokines IL-1, IL-6 and tumor necrosis factor (TNF), which share several biological actions, for stimulating ACTH and corticosterone output in freely-moving rats. Although all three cytokines can stimulate the HPA axis, IL-1 was the most potent. This effect of IL-1 was also present during the neonatal period, when the response of the HPA axis to acute stress is reduced in rodents. The results support the existence of an immune-HPA axis circuit. The biological and clinical relevance of this circuit is discussed.

Adrenocorticotropic Hormone↗
PubMed1991

Selective depletion of macrophages prevents pituitary-adrenal activation in response to subpyrogenic, but not to pyrogenic, doses of bacterial endotoxin in rats.

The mechanisms by which bacterial endotoxin [lipopolysaccharide (LPS)] stimulates the hypothalamo-pituitary-adrenal axis (HPAA) have not been elucidated. The present study was designed to investigate the involvement of macrophages in plasma ACTH and corticosterone responses to LPS administration in rats using selective in vivo macrophage depletion. Intraperitoneal administration of subpyrogenic doses of LPS to normal rats resulted in elevated plasma ACTH and corticosterone concentrations, measured 2 h later. The response showed a remarkable steep dose relationship, with minimal effective doses between 0.5-1.5 micrograms (ACTH) and 0.5 micrograms or less (corticosterone)/kg BW. Plasma PRL, LH, and catecholamine (norepinephrine, epinephrine) levels were not significantly changed under the conditions used. Only at 6 h after LPS administration was a small elevation of norepinephrine noted. To deplete macrophages, rats were injected with liposomes encapsulated with dichloromethylene diphosphonate (Cl2MDP). Histochemical (acid phosphatase) and immunocytochemical techniques (monoclonal antibodies to rat macrophages coded ED1 and ED3) were applied to examine the efficiency of macrophage elimination by the Cl2MDP liposomes in cytospins of peritoneal exudates and in sections of the liver and spleen. Since cells of the macrophage lineage are considered to be the main source of IL-1 in the circulation, we also measured circulating levels of immunoreactive interleukin-1 beta (IL-1) concentrations in control and Cl2MDP liposome-treated rats by the use of a newly developed RIA. Reduced numbers of macrophages were seen in peritoneal lavages of Cl2MDP liposome-treated animals, whereas the morphological appearance and numbers of mast cells, granulocytes, and T-cells were unaffected. Similarly, macrophages were effectively eliminated in the spleen, mesenteric lymph nodes, and liver, as inferred from the reduction of macrophage staining in these organs. Plasma IL-1 concentrations could only be detected in response to a pyrogenic (2.5 mg/kg, iv) and not to a subpyrogenic (0.025 mg/kg, ip) dose of LPS. The increase in plasma IL-1 concentrations in response to the pyrogenic dose of LPS, reaching levels of 20-40 ng/ml in control rats, was blunted in animals treated with the Cl2MDP liposomes. Macrophage depletion by Cl2MDP liposomes did not affect either resting plasma corticosterone levels or the corticosterone response to ether exposure. At subpyrogenic doses of LPS, plasma ACTH and corticosterone responses were completely prevented by macrophage depletion. In contrast, at pyrogenic doses of LPS, plasma ACTH and corticosterone responses were not significantly affected by depleting macrophages. These data demonstrate that activation of the HPAA by a subpyrogenic dose of LPS is macrophage dependent. However, macrophage-independent mechanisms mediate activation of the HPAA in response to a pyrogenic dose of LPS.

Adrenal Glands↗
PubMed1991

Feed-back interactions between immunological cells and the hypothalamus-pituitary-adrenal axis.

There is now increasing evidence that complex networks of interactions between immunological cells and endocrine, autonomic and brain structures operate during physiological and pathological conditions. Such interactions imply the existence of afferent messengers derived from the immune system, such as lymphokines and monokines, capable of integrating immune-neuroendocrine circuits. The operation of a glucocorticoid-associated immunoregulatory circuit is discussed as an example of these interactions. Under basal conditions, in non-overtly immunized animals, endogenous levels of glucocorticoids affect the number of immunoglobulin-secreting cells. At the time of the peak of the immune response to innocuous antigens, as well as following inoculation of infective agents, endotoxins or tumour cells, immunological cells release cytokines which can stimulate the pituitary-adrenal axis. The acute effect of these cytokines is mediated by stimulation of the release of corticotropin-releasing factor from the hypothalamus. Thus, immunological cells are not only influenced by glucocorticoids but their products can also control the activity of the hypothalamus-pituitary-adrenal axis. The possible relevance of these findings for immunoregulation and their implications for pathology are discussed.

Feedback↗
PubMed1989

Mechanism of virus-induced stimulation of the hypothalamus-pituitary-adrenal axis.

Increased blood levels of glucocorticoids are observed during certain viral infections. In this paper, we report data obtained from a model in rodents showing that the pituitary-adrenal axis is stimulated following inoculation of Newcastle Disease Virus (NDV). No evidence for an ectopic, lymphoid source of ACTH-like immunoreactive material capable of inducing this effect was obtained. Administration of virus-free supernatants from cocultures of human peripheral blood leukocytes with NDV also stimulated ACTH and glucocorticoid output in normal mice. This observation showed the immunological cell origin of the mediator of the hormonal effect. Pretreatment of the supernatant with anti-IL-1 sera neutralized its capacity to induce an increase in glucocorticoid and ACTH levels in blood. Furthermore, injection of IL-1 in nanogram amounts also increased ACTH and glucocorticoid blood levels. Thus, we conclude that IL-1 is the most likely mediator of the stimulation of the pituitary-adrenal axis during viral infection. The reported data are also discussed in the general context of the postulated glucocorticoid-associated immunoregulatory circuit.

Adrenocorticotropic Hormone↗
PubMed1989

Neuroendocrine, sympathetic and metabolic responses induced by interleukin-1.

Effects on turnover of vasopressin (AVP) in the hypothalamus and on secretion of pituitary hormones, catecholamines and insulin after intraperitoneal injection of recombinant interleukin-1 (beta) (IL-1) were investigated in male wistar rats. Intraperitoneal administration of IL-1 in a dose (1 microgram) that maximally activated pituitary-adrenal activity failed to alter plasma concentrations of prolactin, luteinizing hormone and melanocyte-stimulating hormone. Rats chronically cannulated in the right jugular veins showed a time-related increase in plasma corticosterone concentrations in response to intraperitoneal administration of IL-1 that lasted up to 4 h. In the same rats, plasma epinephrine (E) and norepinephrine (NE) concentrations were only slightly elevated (2-fold increase) at 30 min and at 1 h after IL-1 administration. Unlike in endotoxin-resistant C3H/HeJ mice, where IL-1 induces hypoglycemia, IL-1 did not affect plasma concentrations of glucose and insulin in Wistar rats. In the zona externa of the median eminence, IL-1 stimulated corticotropin-releasing factor (CRF) turnover at an approximate rate of 15%/h, but did not cause a concomitant change in AVP turnover as can be observed after insulin-induced hypoglycemia. Since half of the hypothalamic CRF neurons have been shown to costore AVP, the data favor the view of a selective effect of IL-1 on a subtype of CRF neurons. We conclude that pituitary-adrenal activation in response to Il-1 is caused by CRF secretion from a subtype of CRF neurons (not storing AVP) in the rat hypothalamus.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1989

Interleukin-1 and glucose homeostasis: an example of the biological relevance of immune-neuroendocrine interactions.

Interleukin-1 (IL-1), a cytokine mainly produced by monocytes-macrophages, plays a crucial role in immunological and inflammatory processes. We have recently demonstrated that IL-1 can also affect neuroendocrine mechanisms. In this paper, we refer to the capacity of IL-1 to affect glucose homeostasis. In normal mice, low doses of IL-1 induce a long-lasting hypoglycemia which is not dependent on possible insulin-secretagogue actions of this cytokine. The hypoglycemic effect of IL-1 is also observed in insulin-resistant diabetic mice. Furthermore, IL-1 seems to adjust the 'set point' for glucose regulation to a lower level. The effects of IL-1 on glucose homeostasis constitute a clear example of the biological relevance of immune-neuroendocrine interactions.

Animals↗
PubMed1988

Interleukin-1 induces changes in norepinephrine metabolism in the rat brain.

Interleukin-1 (IL-1) is a hormone that, apart from playing a key role in immune and inflammatory processes, can also affect mechanisms under brain control. To gain a better understanding of the action of this cytokine on the CNS, its effects on the contents of norepinephrine (NE), dopamine (DA) and serotonin (5-HT), and their main metabolites and precursors, were evaluated in different regions of the forebrain, brain stem, and spinal cord. Following administration of human recombinant IL-1 (beta form) to rats, a modest decrease in the content of NE was observed in the hypothalamus as well as in the dorsal posterior brain stem. However, the most relevant finding was that 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), the main NE metabolite, and the relation MHPG/NE were increased in all the regions studied, revealing a stimulatory effect of IL-1 on NE metabolism in the CNS. This effect seems to be specific for NE since no comparable changes in the brain content of DA, 5-HT, or its metabolite, 5-hydroxyindole acetic acid, were detected after administration of the cytokine. However, tryptophan was significantly increased in all brain regions and in the cervical spinal cord. The capacity of IL-1 to affect the metabolism of NE, a neurotransmitter involved in the control of a variety of brain functions, provides further proof for the relevance of this cytokine in brain-immune interactions.

Animals↗
PubMed1987

T lymphocytes affect the development of sympathetic innervation of mouse spleen.

We investigated whether the development of sympathetic innervation of the spleen is affected by lymphoid cells. Splenic noradrenaline (NA) levels of athymic nude mice (nu/nu) and normal thymus-bearing littermates (nu/+) were determined at different times during ontogeny. While no differences were detected at birth, higher splenic NA levels were found in 7-, 11-, and 21-day-old athymic mice. Thymus transplantation or thymocyte injection to newborn nude mice resulted in splenic NA levels comparable to those of normal nu/+ mice. Histochemical studies fully confirmed such differences. Taken together with previous studies, these results suggest that T lymphocytes or their products exert an inhibitory influence on sympathetic nerve fibers, thus leading to decreased NA content in the spleen. The data also illustrate the capacity of a nonneuronal cell in a peripheral organ to affect the process of autonomic innervation of this organ.

Aging↗
PubMed1985

Changes in plasma hormone profiles after tumor transplantation into syngeneic and allogeneic rats.

Transplantation of 2 chemically (DMBA, MCA)-induced tumors into syngeneic female or male DA strain rats elicited hormonal changes during tumor growth. Plasma levels of 7 different hormones were studied. Tumor cells in syngeneic recipients produced a biphasic decrease in insulin, an early increase in prolactin, and a late-phase decrease in thyroxine. Corticosterone decreased in female tumor bearers but increased in males. This difference may reflect differences in the tumors transplanted. Male rats had a decrease in testosterone during the late phase of tumor growth, while females had a biphasic decrease in progesterone and a late-phase increase in growth hormone. The tumors used were moderately immunogenic in syngeneic recipients. However, tumor transplantation to allogeneic recipients produced an early decrease in growth hormone and no change in insulin, corticosterone or thyroxine. Further, transplantation of normal liver cells to syngeneic or allogeneic recipients produced no hormonal abnormalities. This study demonstrates that hormonal changes which are not observed with normal cells or allogeneic tumor transplantation can occur within 2 days of syngeneic tumor transplantation. Progressive tumor growth is characterized by a worsening endocrine imbalance which involves multiple hormone systems.

9,10-Dimethyl-1,2-benzanthracene↗