Neuroimmunomodulation
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Neuroimmunomodulation · Jan 2000
Natural killer cell activity and resistance to tumor metastasis in prepubescent rats: deficient baselines, but invulnerability to stress and beta-adrenergic stimulation.
Although young children and animals exhibit high rates of tumor development, little is known about natural killer (NK) cell activity in the very young. We recently provided direct evidence that reduced levels of NK activity in prepubescent rats underlie higher levels of susceptibility to metastasis. The aim of the current study was to further characterize NK activity and tumor resistance in prepubescent rats, specifically with respect to the effects of stress and sex, as these factors have been shown to modulate tumor development in adult populations. ⋯ Metaproterenol (0.8 mg/kg, 1 h before testing) resulted in a large suppression of NK activity and resistance against MADB106 metastasis in mature males and females, but not in prepubescent animals. In mature, but not in young animals, males exhibited higher baseline levels of NK activity. Taken together, these findings indicate that NK cells of prepubescent rats are resistant to beta-adrenergic stimulation, and suggest that prepubescent rats are markedly less responsive to SNS-induced suppression of NK activity, which may underlie their invulnerability to the effects of surgery on MADB106 metastasis.
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Neuroimmunomodulation · Sep 1999
Role of several mediators of inflammation on the mouse hypothalamo-pituitary-adrenal axis response during acute endotoxemia.
Cytokines secreted by bacterial endotoxin-activated immune cells are substances known to stimulate the hypothalamo-pituitary-adrenal (HPA) axis function. The present study was designed to better understand the effect of different mediators of inflammation, such as cytokines and histamine, on the acute HPA axis response induced by administration of a single dose of bacterial lipopolysaccharide (LPS) in adult, male, BALB/c mice. Two different experimental designs were set up. ⋯ The blockade of histaminergic pathway functions did not impede the LPS-induced ACTH and B release regardless of the product employed. The present results indicate that TNF-alpha, and to a lesser extent IL-1beta, are the most relevant cytokines involved in HPA axis response to endotoxin administration. Our data also suggest that, in mice, HPA axis activation after infection appeared to be independent of stimulation of the histaminergic pathway.
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Neuroimmunomodulation · Jul 1999
Comparative StudyDifferential effects of one and repeated endotoxin treatment on pituitary- adrenocortical hormones in the mouse: role of interleukin-1 and tumor necrosis factor-alpha.
The role of endogenous interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) in modulating the hypothalamic-pituitary-adrenal (HPA) axis response was examined in male C57BL/6 mice injected with endotoxin (lipopolysaccharide, LPS) or saline at 24-hour intervals for 4 or 8 consecutive days. The mice were divided into four groups: (1) LPS injections for 4 or 8 days and LPS injection on day 5 or 9, respectively (LPS-LPS); (2) LPS injections for 4 or 8 days and saline injection on day 5 or 9, respectively (LPS-saline); (3) saline injections for 4 or 8 days and LPS injection on day 5 or 9, respectively (saline-LPS), and (4) saline injections for 4 or 8 days and saline injection on day 5 or 9 (saline-saline). The mice were sacrificed by decapitation 2 h after the last injection and plasma levels of hormones and cytokines and tissue levels of IL-1beta were measured. ⋯ Furthermore, [125I]IL-1alpha binding was markedly reduced in the LPS-LPS group compared with the saline-LPS group. There was a significant positive correlation between plasma ACTH and IL-1beta after a single and repeated LPS treatment for 4 days, while a significant correlation was seen between plasma ACTH and TNFalpha following one but not repeated LPS treatment. These data demonstrate a differential regulation of IL-1beta and TNFalpha by repeated endotoxin treatment and suggest that while TNFalpha may be important modulating the attenuated pituitary adrenocortical response following the 4-day endotoxin treatment, IL-1beta appears to be the primary regulator of the response following the 8-day endotoxin treatment in the regulation of the HPA axis.
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Neuroimmunomodulation · Nov 1998
ReviewHypothalamic-pituitary-adrenal axis suppression and inhaled corticosteroid therapy. 2. Review of the literature.
In the first part of this two-part review it was noted that inhaled corticosteroids had become the mainstay of treatment for chronic asthma and yet the effects of long-term use of these compounds on the hypothalamic-adrenal-pituitary (HPA) axis were largely being determined by testing methods of limited reliability, especially by morning plasma cortisol measurements. It was established in our examination of the published literature and in our presentation of current knowledge of the structure and function of the HPA axis that safe, accurate and discriminating techniques to assess the functional status of the HPA axis were available. It was concluded that two state-of-the-art tests that have been insufficiently used were the ACTH stimulation test and measurement of the 24-hour integrated serial plasma cortisol concentrations. ⋯ We present our analysis of this limited number of studies to determine what accurately can be known of the HPA axis safety profile of three of the most commonly used and investigated inhaled corticosteroids - beclomethasone dipropionate, budesonide and fluticasone propionate. The first finding of significance was that only 50 reports were identified in which information on the HPA axis safety effects of orally inhaled steroids in asthma patients or in clinical pharmacological studies met our inclusion requirements. By analysis of the data presented in these reports we were able to reach the following conclusions: (1) inhaled corticosteroids administered chronically, and prudently, within recommended dose ranges do not endanger the functioning of the HPA axis, (2) the increasing tendency to use higher doses of inhaled corticosteroids on the assumption that there are clear dose-response benefits and no adverse HPA axis effects from long-term high-dose regimens is misguided and not supported by reliable published information, (3) the corollary - that higher corticosteroid potencies (as measured, for example, by skin-blanching activity) can have greater therapeutic effect in lung tissue without greater concomitant systemic activity - is a flawed concept, and (4) the limited clinical and pharmacological data support our part 1 conclusions that discriminating techniques to assess the functional HPA axis status should be an integral part of the drug development process and that further HPA axis function studies are required on existing inhaled corticosteroids - if they lack a rigorous testing history or long-term record of clinical safety.
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Neuroimmunomodulation · Mar 1997
Sexual dimorphism in the mouse hypothalamic-pituitary-adrenal axis function after endotoxin and insulin stresses during development.
Bidirectional communication between the immune and the endocrine systems is now widely accepted as essential for the survival of the organism. Since a classical nonresponsive period of the hypothalamic-pituitary-adrenal (HPA) axis takes place shortly after birth and because endogenous sex hormones modulate immune function, the aim of the present work was to determine whether sex steroids regulate the PHA axis response to immune (bacterial, lipopolysaccharide, LPS) and nonimmune (insulin, INS) stressors in mice during development. For this purpose 7-, 15-, 30-, 45- and 60-day-old mice of both sexes were intraperitoneally injected with either vehicle alone (basal) or containing LPS (2 mg/kg body weight) or INS (12 IU/kg body weight). ⋯ Plasma samples were assayed to measure corticosterone concentrations. The results indicated that: (a) there was a transient increase in basal plasma corticosterone levels during development, with a peak value at the juvenile age, regardless of sex; (b) a higher basal plasma corticosterone concentration in females than in males characterized the adult age; (c) the infantile age is a period of the HPA axis function nonresponsive to purely neuroendocrine but not to inflammatory stimuli; (d) during the juvenile age, females showed a hyporesponsive HPA axis to neurendocrine and immune stress, whereas male mice were fully unresponsive to both challenges; (e) animals of both sexes showed a maximal HPA axis response to purely neuroendocrine stress at the prepubertal age; this response to the immune stimulus was also maximal in 30-day-old males, while it was found in females after puberty (45-day-old mice); (f) sexual dimorphism in the HPA axis response to a purely neuroendocrine stimulus was found at 30 days of age or later, while this characteristic of the response to endotoxin was not present until puberty. These data clearly suggest that these are gender-dependent characteristics of the ontogeny of the HPA and HP-gonadal axes that are responsible for the sexual dimorphism of HPA axis function in mice.