ISSN:1021-7401    

DOI:10.1159/000097140

出版商:S. Karger AG    

年代:1994

数据来源: Karger

ISSN:1021-7401    

DOI:10.1159/000095948

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

African sleeping sickness (SS) is a severe, potentially lethal parasitic disease. The treatments of choice are the antiparasitic agents suramin, which is adrenotoxic, and/or melarsoprol. We evaluated the functional integrity of the hypothalamic-pituitary-adrenal (HPA) axis of patient with SS before, during, and after therapy with suramin and/or melarsoprol, in two sequential stages. First, we employed the standard adrenocorticotropic hormone (ACTH) 1-24 stimulation test (250 μg i.v.) to assess the maximal adrenocortical responsiveness of 69 patients with SS and 38 normal controls. We demonstrated paradoxically subnormal Cortisol responses before suramin therapy [net Cortisol response 60 min after stimulation: 10.5 ± 2.9 (mean ± SE) vs. 17.5 ± 1.0 μg/dl for controls, p = 0.004], with 27% of the patients falling within the adrenal insufficiency range (stimulated cortisol concentration <20 μg/dl). These responses subsequently and unexpectedly improved with suramin and/or melarsoprol therapy. Second, we performed a human corticotropin-releasing hormone (hCRH) test (100 μg i.v.) in 68 additional patients with SS and 14 control subjects to examine whether the glucocorticoid deficiency observed was primary and/or secondary. Compared to controls, the ACTH and Cortisol responses to hCRH were blunted (ACTH after 60 min: 29 ± 7 vs. 58 ± 8 pg/ml in controls, p = 0.014; cortisol: 15.2 ± 1.5 vs. 19.6 ± 0.7 μg/dl, p = 0.018), suggesting the presence of secondary adrenal insufficiency. There was improvement of both ACTH and cortisol responsiveness to hCRH with therapy, with cortisol recovery occurring before ACTH, suggesting an additional primary component of adrenal dysfunction in these patients. Plasma concentrations of tumor necrosis factor (TNF)-α (16.0 ± 4.1 vs. 2.9 ± 1.4 pg/ml in controls, p = 0.003) and interleukin (IL)-6 (19.2 ± 7.3 vs. 1.3 ± 0.2 pg/ml, p = 0.0001), but not IL-1β (2.0 ± 0.2 vs. 0.9 ± 0.2, p = NS), were elevated when adrenocrotical function impairment and disease activity were at their maximum, but gradually decreased into the normal range with therapy. We found a negative correlation between baseline cytokine concentrations and maximal Cortisol concentrations during hCRH testing (TNF-α: r = –0.31, p = 0.003; IL-6: r = –0.34, p = 0.002). We conclude that unmedicated SS is associated with significant impairment of adrenocortical function which is reversed with suramin and/or melarsoprol therapy in the majority of patients. This impairment may be due to the elevated plasma cytokine concentrations, and may represent a natural adaptation of the HPA axis in inflammatory states. A controlled therapeutic trial is necessary to demonstrate whether supplemental glucocorticoids could be beneficial in SS.

ISSN:1021-7401    

DOI:10.1159/000095930

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

It has previously been shown that interleukin (IL)-1-like bioactivity is released from rat hypothalamic explants in short-term incubations. Experiments conducted with antiserum against IL-1α or IL-1β showed that IL-1α is released more abundantly under basal conditions. For the present study, we developed a specific radioimmunoassay to investigate the release of immunoreactive (ir) IL-1α from the rat hypothalamus in short-term experiments, and observed that release of irIL-1α increased with time and was significantly increased by high KCI concentrations. The stimulatory effect of 28 mM KCI was significantly inhibited by verapamil. Subsequent investigation of the effects of putative modulators of IL-1α secretion, bacterial lipopolysaccharide (LPS) and the prostaglandins E2 (PGE2) and F2α) (PGF2α), showed that irIL-1α release was stimulated by 100 ng/ml LPS, but not by higher concentrations, PGE2 had no effect and PGF2α caused dose-dependent inhibition. However, the latter did not seem to exert a tonic inhibitory influence on irIL-1α release, since blockade of cyclo-oxygenase activity by indomethacin had no effect on cytokine release under basal conditions. We conclude that LPS stimulates and PGF2α inhibits basal release of hypothalamic IL-1α, the characteristics of the secretion of which suggest that it may be, at least in part, of neuronal origin.

ISSN:1021-7401    

DOI:10.1159/000097086

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

α-Melanocyte-stimulating hormone (α-MSH) modulates inflammatory processes in models of acute inflammation and in models of sepsis/septic shock/ adult respiratory-distress syndrome (ARDS). Because this neuropeptide inhibits actions of cytokines and other mediators of inflammation that are also believed to underlie aspects of chronic inflammation, tests were performed to compare the effects of repeated administration of the peptide with those of prednisolone and saline on the development of adjuvant arthritis in rats. α-MSH (50 μg), injected i.p. twice daily, markedly inhibited the clinical and histological signs of experimental arthritis and moderated the weight loss observed in control animals. Prednisolone (100 mg/kg), given twice per day, prevented development of arthritis but caused marked and progressive weight loss. The results confirm the potent anti-inflammatory influence of α-MSH, in this case in a model of chronic inflammation that has immune components.

ISSN:1021-7401    

DOI:10.1159/000097087

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

Leukocytes synthesize a variety of hormones that were once thought to be unique products of endocrine tissues. Understanding the regulation of leukocyte-derived hormone synthesis requires an accurate means for measuring steady-state expression of specific mRNA transcripts. Here we describe a competitive reverse transcriptase-polymerase chain reaction (RT-PCR) technique to accurately quantitate macrophage-derived insulin-like growth factor-I (IGF-I) mRNA, and demonstrate the utility of this approach for measuring expression of leukocyte-derived hormone transcripts. A riboprobe was constructed to generate approximately 1 kb of synthetic competitor IGF-I RNA (exons 1 and 3-6) that differed from cellular IGF-I RNA by insertion of 122 bp of β-actin RNA. One set of oligonucleotide primers could thus be used to simultaneously reverse transcribe and amplify both 144 bp of cellular (exons 3 and 4) and 266 bp of competitor IGF-I RNA. Densitometric scanning of the PAGE-separated PCR products revealed that the ratio of competitor to cellular amplified DNA bore a linear relationship (r2≥. 0.98) to the amount of competitor RNA for both rat liver and splenocytes. However, rat liver contained 104 x 106 IGF-I molecules per microgram of total cellular RNA compared to only 2 x 106 IGF-I molecules for splenocytes. Competitive RT-PCR using as little as 0.5 μg cellular RNA, coupled with [α-32P]dCTP incorporation in the amplification step and phosphorimager analysis of the resulting gel, was then used to show that colony-stimulating factor-1 (CSF-1) induces an increase from 2 x 106 to 110 x 106 IGF-I molecules per microgram RNA as bone-marrow-derived progenitors differentiate into macrophages in vitro. Quantitation of these same transcripts by RNase protection assays revealed that CSF-1 induced a similar 60-fold increase in IGF-I mRNA, but 15 μg target RNA was used for this assay. These data confirm that IGF-I transcripts are coordinately expressed during macrophage differentiation induced by CSF-1. They also show the utility and broad application of using synthetic, competitor RNA derived from an expression vector as an internal standard in RT-PCR for quantitating steady-state transcripts for leukocyte-derived hormones.

ISSN:1021-7401    

DOI:10.1159/000097088

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

There is increasing evidence that cytokines contribute to the immunopathogenesis of human immunodeficiency virus (HIV) infection. It may be, therefore, that compensatory rises in circulating cytokine antagonists also occur in HIV infection and that such changes mark disease progression. To test this idea, plasma concentrations of the cytokine antagonists Ormelanocyte-stimulating hormone (α-MSH), interleukin-1 receptor antagonist (Il-lra), and soluble tumor necrosis factor receptor (sTNFr) were measured in patients of different Centers for Disease Control (CDC) categories of HTV infection and in seronegative controls. Plasma levels of all these cytokine antagonists were higher in HIV-infected patients. Hl-ra and sTNFr concentrations were correlated with indicators of disease activity: positively with plasma neopterin and negatively with CD4+ T lymphocyte counts. α-MSH and sTNF r were greater in CDC groups III and IV, whereras IL-lra was elevated only in the latter group. Because cytokines activate the hypothalamic-pituitary-adrenal axis and adrenal steroids inhibit cytokine production, we measured circulating adrenocorticotropic hormone (ACTH) and Cortisol in HIV-infected patients and investigated relations among these hormones, cytokine antagonists, and markers of disease progression. It appears that these physiological modulators of cytokine activity are not closely linked to sTNFr, IL-lra and α-MSH: there were no significant correlations between plasma concentrations of ACTH or Cortisol and those of cytokine antagonists, nor were there correlations between hormones and markers of disease progression such as neopterin or CD4+ T cell counts. It is notable that severe adrenal insufficiency was extremely rare (3%) in HIV-infected patients; it was confined to the AIDS group and was consistently secondary to ACTH deficiency. Finally, because of the recent expansion of the AIDS case definition to include all patients with CD4+ T cell counts less than 200/μl, we examined cytokine antagonists, hormones and neopterin in a subset of patients included in the AIDS group because of low CD4+ T cells in the absence of clinical criteria formerly required for AIDS case definition. Cytokine antagonists and neopterin concentrations in patients with low CD4+ T cells were similar to those of patients with the clinical complications of AIDS. The results indicate that: (1) plasma concentrations of cytokine antagonists are increased in HIV infection particularly in later stages of the disease, and (2) the recent expansion of the AIDS case definition to one including a low CD4+ T cell count results in the inclusion of patients who have disease markers similar to those of patients who meet the clinical criteria for AIDS.

ISSN:1021-7401    

DOI:10.1159/000097089

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

Our previous work has shown that cells of the immune system produce a growth hormone (GH) molecule similar to that secreted by the pituitary. In the present studies, we evaluated the possibility that normal spleen cells producing GH transferred to dwarf mice could stimulate their growth. The results showed that normal spleen cells alone or spleen cells treated with growth-hormone-releasing hormone (GHRH) did not appear to significantly stimulate the growth of dwarf mice. Spleen cells activated in vitro with concanavalin A or lipopolysaccharide and then transferred to dwarf mice, or thymus cells alone, were also without effect, whereas GH alone stimulated growth as expected. Serum levels of insulin-like growth factor-I (IGF-I) and IGF-I liver RNA were undetectable in control dwarf mice and dwarf mice receiving spleen cells, whereas serum levels of IGF-I increased after treatement of dwarf mice with GH. The immune system of dwarf mice receiving spleen cells, however, was significantly altered. Spleen cells from dwarf animals showed enhanced immunoglobulin, interleukin (IL)-6, IL-2, and interferon-γ production whereas no significant change was apparent in natural killer cell activity. Despite the absence of the pit-1 protein in dwarf mice, their spleen and thymus cells retained the ability to produce almost as much lymphocyte GH as normal. Overall, the findings support the idea that the pit-1 protein in lymphocytes of dwarf mice may not be obligatory for the expression of lymphocyte GH. Further, the transfer of spleen cells to dwarf mice appears to have an autocrine/paracrine effect on the immune system rather than a pronounced endocrine effect on the growth of dwarf mice under the conditions studied.

ISSN:1021-7401    

DOI:10.1159/000097090

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

The L-tryptophan eosinophilia myalgia syndrome (L-Trp-EMS), related to ingestion of impure L-Trp, occurred in epidemic proportions in the United States in 1989. Epidemiologic studies implicated 1,1′-ethylidenebis[L-tryptophan] (EBT) as the impurity most highly associated with development of human L-Trp-EMS. We have previously shown that Lewis (LEW/N) rats fed L-Trp implicated in the L-Trp-EMS epidemic (case-associated L-Trp) develop fasci itis and perimyositis which is associated with a reduction in corticotropin-releasing hormone (CRH) mRNA expression in the hypothalamic paraventricular nucleus (PVN). In this study, we report the effects of EBT- and case-associated L-Trp on CRH mRNA expression in the hypothalamic PVN and secretion of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) into the plasma over a time course of 1-6 weeks in the same rats in which we have found fascial thickening and immune cell activation induced by these compounds. Both control L-Trp and EBT stimulated the secretion of ACTH and CORT at 1-2 weeks, whereas case-associated L-Trp did not. EBT and case-associated L-Trp decreased CRH mRNA expression in the PVN at 2–6 weeks, while control L-Trp had no effect. The striking contrast in the effects of case-associated L-Trp and EBT on the HPA axis suggests that the reduction in CRH mRNA levels in the PVN seen in each case may be related to different mechanisms. It is possible that EBT suppresses CRH mRNA expression directly, in the absence of inflammation, while case-associated L-Trp may act through multiple mechanisms, including that associated with inflammation. The different effects of case-associated L-Trp and EBT on both peripheral blood mononuclear cell activation and suppression of hypothalamic CRH mRNA levels suggest that case-associated L-Trp may contain additional compounds besides EBT which may contribute to and/or amplify the inflammatory responses to contaminated L-Trp.

ISSN:1021-7401    

DOI:10.1159/000097091

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

Lewis (LEW/N) and Fischer (F344/N) rats represent two extremes of the spectrum of corticosterone responses to stressful stimuli, from the chronical hypo-responsiveness of LEW/N to the chronical hyperresponsiveness of F344/N. It might be expected that the amount of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) binding, and the levels of their corresponding mRNAs in various tissues in LEW/N and F344/N rats might reflect the overall integrated levels of corticosterone to which these receptors have been exposed. We have found that while the binding affinity (Kd) of MR and GR varies between tissues, there was no strain difference in any tissue. Receptor binding number (Bmax), however, varied not only between tissues, but also between strains. MR Bmaxin the hippocampus and pituitary was lower in LEW/N than in F344/N, whereas the GR Bmaxin the LEW/N thymus was greater than that found in F344/N rats. The hippocampal levels of MR mRNAs in Adx LEW/N and F344/N rats were in good agreement with, and paralleled, the functional levels of these receptors as determined by binding assays. On the other hand, the number of hippocampal GR binding sites and the level of GR nRNA while similar were not identical in the two strains: the hippocampal GR Bmaxdid not differ between strains, while the hippocampal GR mRNA level was slightly, but significantly, lower in Adx LEW/N compared to F344/N rats.

ISSN:1021-7401    

DOI:10.1159/000097092

出版商:S. Karger AG    

年代:1994

数据来源: Karger