Search PubMed⌕ Search

Biomedical subjects

E M Sternberg

Publications and source records attributed to E M Sternberg.

At least 37 records · Page 2Linked to original sources
PubMed1997

Intracerebroventricular transplantation of embryonic neuronal tissue from inflammatory resistant into inflammatory susceptible rats suppresses specific components of inflammation.

To more directly define the role of central nervous system factors in susceptibility to peripheral inflammatory disease, we examined the effect of intracerebroventricular transplantation of neuronal tissue from inflammatory resistant into inflammatory susceptible rats on subcutaneous carrageenan-induced inflammation (a measure of innate immunity), and on the relative percentage of naive and memory T helper cells in peripheral blood (a measure of the anamnestic immune response). Female inflammatory disease susceptible Lewis (LEW/N) rats transplanted with hypothalamic tissue from inflammatory resistant Fischer (F344/N) rats exhibited > 85% decrease in carrageenan inflammation compared to naive LEW/N rats, LEW/N rats transplanted with F344/N spinal cord, or sham-operated animals. LEW/N rats transplanted with LEW/N hypothalamic tissue exhibited > 50% decrease in carrageenan inflammation. In contrast, intracerebroventricular transplantation of neuronal tissue did not affect the characteristically twofold higher percentage of naive versus memory T helper cells in LEW/N rats, suggesting that the central nervous system (CNS) and hypothalamus play a greater role in the innate inflammatory response than in the acquired immune processes. Grafted tissue survived well and did not show extensive gliosis or inflammation. Compared to naive LEW/N rats, LEW/N rats transplanted with F344/N or LEW/N hypothalamic tissue expressed significantly greater hypothalamic corticotropin releasing hormone mRNA. LEW/N rats transplanted with F344/N hypothalamic tissue also showed significant increases in plasma corticosterone responses to lipopolysaccharide. These data indicate that intracerebroventricular transplantation of fetal hypothalamic tissue from inflammatory resistant into inflammatory susceptible rats suppresses peripheral inflammation partially through hypothalamic factors. These findings have implications for understanding the contribution of specific neuronal tissue in regulation of components of the immune/inflammatory response and in susceptibility to inflammatory disease. Furthermore, this model could be used in the development of potential new treatments for inflammatory/autoimmune diseases aimed specifically at sites within the CNS.

Animals↗
PubMed1997

Lymphocyte subpopulation expression in women: effect of exercise and circadian rhythm.

It is well established that exercise affects immune responses in men, but little information is available for women. Whether exercise-induced immune responses are affected by circadian rhythm has not been determined. This study examined lymphocyte responses of women to exercise in the morning (AM) and evening (PM). Lymphocytes expressing markers for T, B, and natural killer (NK) cells were identified by FACScan in blood samples collected before (baseline), immediately after, and 40 min after exercise (recovery). Absolute counts of all lymphocyte subpopulations increased immediately after exercise, but at recovery values were below baseline counts. Circadian variations were noted in absolute counts for total T, helper/inducer T cells, and B cells. Although these counts were significantly higher in the PM, the magnitude of the immune response to exercise was the same in the AM and PM. In contrast, natural killer cells, both the relative counts and the magnitude of immune response were higher in the AM. Thus, it appears that despite differences in baseline cell counts the overall exercise-induced response in most lymphocyte subpopulations is similar in the AM and PM.

Adult↗
PubMed1997

Exercise and circadian rhythm-induced variations in plasma cortisol differentially regulate interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF alpha) production in humans: high sensitivity of TNF alpha and resistance of IL-6.

Although we have previously shown that the integrity of inflammatory mediator-induced activation of the hypothalamic-pituitary-adrenal axis is essential for conferring resistance to inflammatory disease in susceptible Lewis rats, the role of endogenous glucocorticoid secretion in human immune function in either health or disease is less clear. To further understand the relevance of physiological variations in plasma cortisol on immune function in humans, we evaluated ex vivo lipopolysaccharide-induced interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF alpha) production in the whole blood of healthy volunteers studied under conditions chosen to approximate either physiological or pharmacological glucocorticoid levels. Administration of a pharmacological dose of hydrocortisone suppressed the production of all three cytokines, whereas administration of a physiological dose of hydrocortisone suppressed only TNF alpha production. Stress-induced levels of glucocorticoids, achieved during exercise at 100% maximal oxygen utilization, suppressed IL-1 beta and TNF alpha production, but were without effect on IL-6 production. In addition, circadian variations of cortisol were associated with decreased TNF alpha production, but were without effect on IL-1 beta or IL-6 production. These studies challenge the generally accepted idea that glucocorticoids consistently suppress cytokine production and indicate a hierarchy of sensitivity, with TNF alpha having the greatest sensitivity, IL-1 beta having intermediate sensitivity, and IL-6 being resistant. The resistance of IL-6 production to glucocorticoid suppression is compatible with data suggesting an antiinflammatory as well as a proinflammatory action for this cytokine.

Adult↗
PubMed1997

Corticosteroid resistance and disease.

Both the unpredictability of side-effects and efficacy of glucocorticoid treatment can be problematic during clinical treatment. Here we discuss the evidence that exists for the hypothesis that individual glucocorticoid sensitivity underlies this problem. We suggest that glucocorticoid sensitivity is actually much more dynamic and common than previously thought. It is postulated that acquired tissue-specific glucocorticoid resistance could play a role in the origin and pathogenesis of depression, autoimmune disorders and AIDS. Moreover, recent genetic research has shown mutations in the glucocorticoid receptor (GR) gene and GR protein which are suggested to play a role in the pathogenesis of leukaemia, hereditary glucocorticoid resistance and Nelson's syndrome. These findings indicate that variations in the GR and in glucocorticoid resistance play a central role in a wide variety of diseases.

Adrenal Cortex Hormones↗
PubMed1996

Pathogenesis of L-tryptophan eosinophilia myalgia syndrome.

Taken together, these studies suggest that many different etiologic agents alone or together may initiate the common final pathways of tissue pathologic response resulting in the clinical syndrome of eosinophilia, myalgias and fasciitis. Tryptophan itself may contribute to some of the scarring features of the illness, while impure L-tryptophan, and one or more of the impurities cause the characteristic features of the illness. The altered tryptophan metabolism in EMS is secondary to inflammation.

5-Hydroxytryptophan↗
PubMed1996

The estrogen antagonist tamoxifen inhibits carrageenan induced inflammation in LEW/N female rats.

Carrageenan induces a measurable inflammatory response in susceptible animals, and mature females are more responsive to carrageenan, than males. In the present study, we tested whether the estrogen antagonist tamoxifen influences carrageenan-induced inflammatory responses. Female LEW/N rats were treated with tamoxifen and compared to a control group of animals injected with vehicle. Tamoxifen significantly reduced estrous phase of estrous cycle during treatment, consistent with its functional anti-estrogen effects. Moreover, tamoxifen significantly decreased exudate volume but did not significantly influence relative white blood cell counts in the exudate. Interestingly, tamoxifen induced differential dose-dependent alterations in peripheral blood lymphocyte subpopulations. Low dose of tamoxifen increased CD25 cells. The high tamoxifen dose significantly increased CD8 blood lymphocytes counts. Our data indicate that tamoxifen treatment decreases carrageenan-induced inflammatory response in female LEW/N rats and suggest therefore that this inflammatory response is, at least in part, estrogen related. Moreover, our results suggest a possible role for tamoxifen in treatment of inflammatory disorders.

Animals↗
PubMed1996

Hippocampal 5-HT1A receptor binding site densities, 5-HT1A receptor messenger ribonucleic acid abundance and serotonin levels parallel the activity of the hypothalamo-pituitary-adrenal axis in rats.

We have previously demonstrated that susceptibility of the Lewis rat to inflammatory disease, compared to the relatively resistant Fischer F344 rat, is related to a hyporesponsive hypothalamopituitary adrenal axis to inflammatory and other stress mediators. Since 5-HT and the 5HT1A receptor are important stimulators of this axis, we have investigated the levels of 5-HT1A receptor binding sites and encoding mRNA, 5-HT and 5-hydroxyindole acetic acid in various brain regions of Lewis, Harlan Sprague Dawley and Fischer F344 rats. Lewis rats expressed significantly less hippocampal and frontal cortical 5-HT1A receptor binding sites and mRNA than Harlan Sprague-Dawley and Fischer F344 rats. Adrenalectomy increased the number of 5HT1A receptor binding sites and mRNA expression in the hippocampus of all three strains. The levels of hippocampal 5-HT in Fischer F344 rats were significantly greater than levels detected in the same regions for the other two strains. Hypothalamic 5-HT and 5-hydroxyindole acetic acid levels in Harlan Sprague-Dawley rats were higher than the same area from the other two strains. Adrenalectomy increased the levels of 5-hydroxyindole acetic acid in the hypothalamus of all three strains. We conclude that hippocampal 5-HT1A receptor densities and 5-HT levels in the rat parallel the the activity and responsiveness of the hypthalamopituitary-adrenal axis. We have published these data in an earlier report.

Adrenalectomy↗
PubMed1996

Lymphocyte subset responses to exercise and glucocorticoid suppression in healthy men.

It is well established that in vivo changes in ratios of lymphocyte phenotype subsets is altered by glucocorticoid administration. To determine whether the lymphocyte response would be further affected by strenuous exercise, since glucocorticoids are released during exercise, 14 physically fit men were randomly given placebo (P), 4 mg of dexamethasone (DEX), or 100 mg of hydrocortisone (HCO) 4 h before high-intensity treadmill running. Blood was drawn pre- and immediately post-exercise; lymphocyte subsets (CD3, CD4, CD8, CD19, and CD56) were determined by flow cytometry. Pre-exercise CD3 and CD4 percentages were lower, whereas CD8 and CD56 were higher with DEX and HCO as compared to P. Exercise induced a lymphocytosis after all treatments, but subsets did not change proportionally. With P, DEX, and HCO, the magnitudes of change were comparable: CD3 and CD4 decreased and CD8 and CD56 increased. Notably, for all treatments exercise induced in approximately 2-fold increase in the percentage of cells expressing CD56 (natural killer cells). Thus, a single oral dose of DEX or HCO did not alter the direction or magnitude of immediate post-exercise changes in lymphocyte subset expression. Whether glucocorticoid pretreatment influences lymphocyte responses during recovery from strenuous exercise remains to be determined.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1996

Adenylate-cyclase-dependent pituitary adrenocorticotropin secretion is defective in the inflammatory-disease-susceptible Lewis rat.

Susceptibility to arthritis in the Lewis rat is associated with a defect of the hypothalamic-pituitary-adrenal axis. We examined the pituitary corticotropes of both intact and dexamethasone-treated male and female inflammatory-disease-susceptible Lewis and inflammatory-disease-resistant Fischer rats. We determined adrenocorticotropin levels in the media from primary cultures of anterior pituitary cells of both strains. In other experiments we have measured intracellular cyclic adenosine monophosphate and inositol monophosphate accumulation. Cells were incubated with corticotropin-releasing hormone, arginine vasopressin, forskolin, phorbol myristate acetate, or thyrotropin-releasing hormone. Corticotropin-releasing hormone stimulated adrenocorticotropin secretion from both male and female Lewis rat pituitary cells in a concentration-dependent manner. Basal and stimulated adrenocorticotropin levels in cells from Lewis rats were lower than those measured in the incubation media of Fischer rat dispersed pituitary cells. Arginine vasopressin, as well as forskolin and phorbol myristate acetate, induced a significant release of adrenocorticotropin from pituitary cells of both strains. Incubation with corticotropin-releasing hormone did not produce a significant accumulation of intracellular cyclic adenosine monophosphate in Lewis rat dispersed pituicytes of both sexes. On the other hand, forskolin induced a significant increase of intracellular cyclic adenosine monophosphate in the same cultures. Finally, inositol monophosphate accumulation was comparable in pituitary cells from both Lewis and Fischer rats of both sexes incubated with thyrotropin-releasing hormone. Adrenocorticotropin secretion from pituitary cells of male Lewis rats treated in vivo with dexamethasone was either reduced or abolished following incubation with different secretagogues. A defect in pituitary adrenocorticotropin secretion could be among the causes of the hyporesponsiveness of the hypothalamic-pituitary-adrenal axis in the Lewis rat. Such a defect appears to be associated with dysfunction of receptor-coupled events related to adenylate cyclase.

Adenylyl Cyclases↗
PubMed1996

Changes in corticosteroid sensitivity of peripheral blood lymphocytes after strenuous exercise in humans.

Although plasma corticosteroid concentrations can be measured accurately, the biological effect on the target tissue is uncertain. The availability of an accurate measure of corticosteroid sensitivity would potentially clarify the putative roles of endogenous glucocorticoids in illnesses such as inflammatory disease and obesity and allow evaluation of an additional regulatory level of glucocorticoid action. To measure corticosteroid sensitivity, we developed an assay based on the inhibition by dexamethasone (Dex) of lipopolysaccharide (LPS)-induced Interleukin-6 (IL-6) production and release in whole unseparated blood in vitro. LPS induced a dose-dependent increase in IL-6 concentrations up to 34 +/- 6.6 ng/mL, reaching plateau levels after 8 h, whereas Dex dose dependently inhibited LPS-induced IL-6 production. Involvement of the glucocorticoid receptor in this response was supported by abrogation of Dex (10(-7) mol/L) inhibition of IL-6 production by the glucocorticoid receptor antagonist RU 38486. To determine whether corticosteroid sensitivity is a dynamic phenomenon, we subjected healthy males to a graded quantifiable exercise associated with increases in plasma ACTH and cortisol. Before exercise, 3 x 10(-8) mol/L Dex inhibited LPS-induced IL-6 production in vitro; after exercise, 3 x 10(-8) and 10(-7) mol/L Dex were unable to inhibit IL-6 production. We conclude that Dex suppression of LPS-induced IL-6 production is an effective means of determining corticosteroid sensitivity, and that corticosteroid sensitivity in human subjects is a dynamic, rather than a static, phenomenon.

Adrenocorticotropic Hormone↗
PubMed1996

Localization of urocortin messenger RNA in rat brain and pituitary.

Pituitary function is regulated by hypothalamic releasing hormones secreted into hypophyseal-portal blood. A new hypothesis is that pituitary function might also be regulated at the local level by releasing hormones synthesized within the pituitary. Here we show that the pituitary expresses high levels of the gene encoding for urocortin. We suggest that urocortin synthesized by the pituitary may modulate pituitary function, and that adrenocorticotropic hormone (ACTH) secretion is dependent on input not only from the hypothalamus as previously described, but it may also be regulated by urocortin synthesized locally. Urocortin binds to the corticotropin-releasing hormone (CRH) receptor type 1 (CRH-R1) with high affinity and potently stimulates pituitary-adrenal function. Our group and others have previously localized high levels of CRH-R1 mRNA in the pituitary. Using a 35S-labeled rat urocortin riboprobe we have now localized urocortin mRNA in rat brain and pituitary. The finding of urocortin gene expression in the pituitary may help explain why proopiomelanocortin (POMC) mRNA levels are not decreased during hypothalamo-pituitary disconnection, and also describes a new level of complexity in the regulation of hypothalamo-pituitary function. Future studies should consider the possibility that pituitary function might be regulated at the local level by urocortin.

Animals↗
PubMed1995

Accumulation of 3-(phenylamino)alanine, a constituent in L-tryptophan products implicated in eosinophilia-myalgia syndrome, in blood and organs of the Lewis rats.

3-(Phenylamino)alanine (PAA), a newly discovered impurity in case-associated L-tryptophan tablets, has been investigated as a possible contributing factor in the etiology of eosinophilia-myalgia syndrome (EMS). We have studied distribution and elimination of PAA in rats which were administered a single 5 mg/kg dose of PAA by gastric gavage. PAA concentrations in blood, brain, kidney and liver were measured by high-performance liquid chromatography (HPLC) with electrochemical detection. The concentration of PAA in each tissue reached a maximum at 5 h, and then gradually declined. A high level of PAA still remained at 24 h, indicating gradual elimination. The concentration of PAA in brain at 5 h was 2139 ng/g tissue, demonstrating passage through the blood-brain barrier. Consecutive administration of PAA (5 mg/kg) for 4 days resulted in approximately double the concentration in all tissues. Chronic treatment using PAA incorporated into food pellets for 6 weeks resulted in similar accumulations in each tissue, and following 12 days on a PAA free diet, levels of this drug were still detectable in all tissues.

Alanine↗
PubMed1995

Neuroendocrine factors in susceptibility to inflammatory disease: focus on the hypothalamic-pituitary-adrenal axis.

Communication between the central components of the stress response and the immune system plays an important role in susceptibility to inflammatory disease. This communication occurs through hormonal and neuronal mechanisms. Hormonal mechanisms involve activation of the hypothalamic-pituitary-adrenal (HPA) axis by immune system products, e.g. cytokines. The stimulated HPA axis regulates immune responses through the immunosuppressive effects of glucocorticoids. Neuronal mechanisms include direct innervation of immune organs. Cytokine activation of the HPA axis and the resultant glucocorticoid-induced suppression of immune and inflammatory responses represent an important mechanism whereby the central stress response modulates peripheral inflammation. Interruption of this communication is associated with exacerbation of inflammatory disease. Conversely, intracerebroventricular transplantation of hypothalamic tissue from inflammatory resistant rats into susceptible rats reduces peripheral inflammation by more than 85%.

Animals↗
PubMed1994

Corticosteroid action and neuroendocrine-immune interactions.

Glucocorticoid feedback during inflammation depends on several factors, including effective corticosteroid concentrations, the temporal coordination between the immune system and the HPAA, and sensitivity of the target organ to corticosteroids. In the case of LEW/N rats, several lines of evidence indicate that CRH is aberrantly regulated, and as a consequence, the circulating corticosterone concentrations are blunted. In addition, basal ACTH and corticosterone responses differ compared to SD and F344/N rats. Therefore glucocorticoid feedback during inflammation is impaired leading to uncontrolled inflammation as observed in various models. We found that in the LEW/N rat, the regulation of the GR and MR, at least in the hippocampus, is different from F344/N rats. A similar impaired upregulation of the GR has been described in aged rats, and this has been postulated to be the cause of the altered HPAA reactivity after various stimuli in these rats. Moreover, adult LEW/N rats exhibit HPAA responses which resemble those observed during the stress hyporesponsive period of immature SD or F244/N rats. These latter data suggest that in the LEW/N rat the ontogeny and/or regulation of the HPAA is disturbed. Taken together, the impaired regulation of HPAA reactivity observed in LEW/N rats could be due to an impaired regulation of the central MR and/or GR. Although no data of GR dynamics in the context of local inflammation are available yet, this could be an additional factor determining tissue sensitivity and immune responses to corticosteroids. In humans, determination of the role of the HPAA in inflammation is more complex due to the much higher intrinsic variability between subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗