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Biomedical subjects

A Del Rey

Publications and source records attributed to A Del Rey.

13 recordsLinked to original sources
PubMed2001

Complex phenotype of mice homozygous for a null mutation in the Sp4 transcription factor gene.

BACKGROUND: Sp4 is a zinc finger transcription factor which is closely related to Sp1 and Sp3. All three proteins recognize the same DNA elements and can act as transcriptional activators through glutamine-rich activation domains. Unlike Sp1 and Sp3, which are ubiquitous proteins, Sp4 is highly abundant in the central nervous system, but also detectable in many other tissues. RESULTS: We have disrupted the mouse Sp4 gene by a targeted deletion of the exons encoding the N-terminal activation domains. Sp4 knockout mice show a complete absence of Sp4 expression. They develop until birth without obvious abnormalities. After birth, two-thirds die within 4 weeks. Surviving mice are growth retarded. Male Sp4null mice do not breed. The cause for the breeding defect remains obscure since they show complete spermatogenesis. In addition, pheromone receptor genes in the vomeronasal organ appear unaffected. Female Sp4null mice have a smaller thymus, spleen and uterus. In addition, they exhibit a pronounced delay in sexual maturation. CONCLUSIONS: The phenotype of the Sp4null mice differs significantly from those described for Sp1-/- and Sp3-/- mice. Thus, the structural similarities, the common recognition motif and the overlapping expression pattern of these three transcription factors do not reflect similar physiological functions.

Alleles↗
PubMed2000

Endocrine host responses during early and late phases of tumor development.

It is well established that hormones affect tumor growth. Conversely, inoculation of cells obtained from tumors that had been transplanted for many generations causes changes in the concentration of different hormones before and after tumor detection. We aimed at answering the question of whether hormonal alterations also occur during the development of primary tumors and following transplantation of tumors from early generations. Primary tumors were induced in mice by either the carcinogenic agent 3-methylcholanthrene, which produces fibrosarcomas, or the milk-transmitted mammary tumor virus, which induces adenocarcinomas. The results showed that (i) in both models, an early reduction in plasma insulin and prolactin levels occurred, and in the case of insulin, this reduction was sustained for a prolong period prior to tumor detection, indicating that recognition by the host of emergent tumor cells triggers an endocrine response; (ii) in contrast with multiply transplanted tumors, cells from early transplant generations produced no significant endocrine changes during latency; (iii) irrespective of whether they were primary or transplanted, large tumor burdens caused similar hormonal alterations, consisting of increased corticosterone and growth hormone and decreased insulin, thyroxin, prolactin and sex steroid levels in blood. Our comprehensive longitudinal study demonstrates host endocrine responses during different stages of neoplastic development.

Animals↗
PubMed2000

Increased sensitivity of the baroreceptor reflex after bacterial endotoxin.

Lipopolysaccharide (LPS), an endotoxin that elicits the production of several cytokines, induces cardiovascular changes characterized by increased perfusion of immune organs and compensatory sympathetic vasoconstriction in other tissues. We therefore hypothesized that to adapt to altered blood flow distribution following LPS administration, changes in the sensitivity of reflexes that control blood pressure would occur. Our data show that the sensitivity of the baroreceptor reflex increases significantly two and three hours after the intravenous administration of a subpyrogenic dose of the endotoxin. This change in sensitivity that could occur at peripheral or central levels may underlie necessary adjustments of cardiovascular mechanisms during the course of certain immune responses.

Animals↗
PubMed2000

Not all peripheral immune stimuli that activate the HPA axis induce proinflammatory cytokine gene expression in the hypothalamus.

Administration of low doses of lipopolysaccharide (LPS) that do not disrupt the blood-brain barrier (BBB) results in the expression of interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF alpha) in the hypothalamus in parallel to stimulation of the hypothalamus-pituitary-adrenal (HPA) axis. This endocrine response is triggered by peripheral cytokines, and we recently obtained evidence that brain-borne IL-1 contributes to its maintenance. LPS preferentially stimulates cells of the macrophage lineage and B lymphocytes. The possibility that primarily stimulation of other types of peripheral immune cells also results in the expression of proinflammatory cytokines in the brain and in the activation of the HPA axis was investigated. Our results showed that, in contrast to LPS, administration of the superantigen staphylococcal enterotoxin B (SEB), which stimulates T cells by binding to appropriate V beta domains of the T-cell receptor, did not result in induction of IL-1 beta, IL-6, and TNF alpha expression in the hypothalamus. Furthermore, although IL-2 transcripts in the spleen were highly increased, expression of this gene was not detected in the brain. However, as with LPS, SEB administration also results in elevated levels of glucocorticoids in blood. Therefore, our data suggest that increased expression of proinflammatory cytokines in the brain is not a necessary step in the stimulation of the HPA axis by SEB.

Animals↗
PubMed2000

Sympathetic innervation affects superantigen-induced decrease in CD4V beta 8 cells in the spleen.

The stimulation by superantigens of T cells expressing an appropriate V beta chain results in a strong proliferative response that is followed by a state of energy specific for the antigen used. This model was used to continue our studies on immunoregulatory host neuroendocrine responses. We have recently found that four days after administration of the superantigen staphylococcal enterotoxin B (SEB) into mice, that is, at an early stage of the anergic phase, the decrease in the percentage of splenic CD4V beta 8 was accompanied by a decrease in the splenic concentration of the sympathetic neurotransmitter noradrenaline (NA) as compared to vehicle-injected mice. No comparable changes were detected in the kidney. At this point, blood levels of NA, adrenaline, and corticosterone were comparable in SEB- and vehicle-injected mice. We have also found that the decrease in splenic CD4V beta 8 cells was not observed in animals that had been chemically sympathectomized prior to the administration of the superantigen. These results indicate that the sympathetic response induced by SEB may have immunoregulatory implications.

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

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↗
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↗
PubMed1985

Lymphoid cells produce an immunoregulatory glucocorticoid increasing factor (GIF) acting through the pituitary gland.

Products are released in vitro by mitogen stimulation of human peripheral blood mononuclear cells or rat spleen cells which increase corticosterone blood levels when injected into normal rats. We report that an almost pure population of human peripheral blood lymphocytes in mixed lymphocyte culture stimulated with phytohaemagglutinin also produces a glucocorticoid increasing factor(s). The product equivalent to the amount released by 5 X 10(5) cells increased corticosterone levels four-fold and also increased ACTH levels. When rats were hypophysectomized or treated with dexamethasone to block ACTH output, no corticosterone increase was noted following administration of glucocorticoid increasing factor(s) (GIF). Similar results were obtained with supernatants of rat spleen cells stimulated with concanavalin A. We conclude that GIF has no direct action on the adrenals in vivo and that a functional pituitary gland is essential for its action. The presented data taken together with those described earlier suggest the existence of a glucocorticoid associated immunoregulatory feedback circuit.

Adrenocorticotropic Hormone↗
PubMed1979

Antigenic competition between horse and sheep red blood cells as a hormone-dependent phenomenon.

Various mechanisms for understanding antigenic competition have been proposed, such as macrophage availability, suppressor cells and their soluble products. In view of the regulatory function of some hormones on the immune system, the role of immunosuppressive adrenal corticosteroids in antigenic competition was investigated. When horse red blood cells (HRBC) were injected into rats a five-fold increase in corticosterone blood levels was measured by day 6 and a strong decrease was noted on day 11. In animals injected with HRBC and on day 6 with a second antigen (sheep red blood cells, SRBC), the corticosteroid level was high on day 11. Such high levels are immunosuppressive. To impede such increases in adrenal hormone levels, rats were adrenalectomized. Adrenalectomized or sham-operated animals receiving SRBC only showed no difference in plaque-forming cell (PFC) numbers. All sham-operated rats injected first with HRBC and 5 days later with SRBC showed the expected antigenic competition. Adrenalectomized rats also injected with both antigens sequentially had a five fold increase in number of PFC when compared with the sham-operated controls which had received both antigens. A detailed analysis of these data revealed that a proportion of adrenalectomized animals had PFC numbers within the normal range. In vitro, hydrocortisone enhances the response of spleen cells when only one antigen (SRBC) is present. Prior addition of the unrelated antigen (HRBC) impedes this enhancement. Thus, in a hydrocortisone-enriched culture medium, the presence of the first antigen can interfere with the immune response to the second unrelated antigen, mimicking in vitro a condition of antigenic competition. These findings indicate that hormones may have a role in antigenic competition.

Adrenal Cortex Hormones↗