Acne and 'mild' adrenal hyperplasia. A short critical review.
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Acne Vulgaris↗
Biomedical subjects
Christoph A Meier
Publications and source records attributed to Christoph A Meier.
Clinical evaluation of hormonal stress state in medical ICU patients: a prospective blinded observational study.
OBJECTIVE: To evaluate whether classification of patients as having low, moderate, or high stress based on clinical parameters is associated with plasma levels of stress hormone. DESIGN AND SETTING: Prospective, blinded, observational study in an 18-bed medical ICU. PATIENTS: Eighty-eight consecutive patients. INTERVENTIONS: Patients were classified as low (n=28), moderate (n=33) or high stress (n=27) on days 0 and 3 of ICU stay, based on 1 point for each abnormal parameter: body temperature, heart rate, systemic arterial pressure, respiratory rate, physical agitation, presence of infection and catecholamine administration. The stress categories were: high: 4 points or more, moderate 2-3 points, low 1 point. Plasma growth hormone (GH), insulin-like growth factor 1 (IGF-1), insulin, glucagon, cortisol were measured on days 0 and 3. MEASUREMENTS AND RESULTS: Plasma cortisol and glucagon were significantly higher and IGF-1 lower in high vs. low stress patients on days 0 and 3. High stress patients were more likely to have high cortisol levels (odds ratio 5.8, confidence interval 1.8-18.9), high glucagon (8.7, 2.1-36.1), and low IGF-1 levels (5.9, 1.8-19.0) than low stress patients on day 0. Moderate stress patients were also more likely to have high cortisol and glucagon levels than low stress patients. Insulin and GH did not differ significantly. Results were similar for day 3. CONCLUSIONS: Moderate and severe stress was significantly associated with high catabolic (cortisol, glucagon) and low anabolic (IGF-1) hormone levels. The hormonal stress level in ICU patients can be estimated from simple clinical parameters during routine clinical evaluation.
Adolescent↗
Production of chemokines by perivascular adipose tissue: a role in the pathogenesis of atherosclerosis?
OBJECTIVE: Obesity is associated with an increased risk for cardiovascular disease. Although it is known that white adipose tissue (WAT) produces numerous proinflammatory and proatherogenic cytokines and chemokines, it is unclear whether adipose-derived chemotactic signals affect the chronic inflammation in atherosclerosis. METHODS AND RESULTS: Histological examination showed that perivascular WAT (pWAT) is in close proximity to vascular walls, particularly at sites that have a tendency to develop atherosclerosis. In rodents, the amount of pWAT is markedly increased by a high-fat diet. At a functional level, supernatant from subcutaneous and pWAT strongly induced the chemotaxis of peripheral blood leukocytes. The migration of granulocytes and monocytes was mostly mediated by interleukin-8 and monocyte chemoattractant protein-1, respectively, whereas both chemokines contributed to the migration of activated T cells. Moreover, pWAT produces these chemokines, as shown by immunohistochemistry and by explant culture. The accumulation of macrophages and T cells at the interface between pWAT and the adventitia of human atherosclerotic aortas may reflect this prochemotactic activity of pWAT. CONCLUSIONS: Human pWAT has chemotactic properties through the secretion of different chemokines, and we propose that pWAT might contribute to the progression of obesity-associated atherosclerosis.
Adipose Tissue↗
Adipose tissue is a regulated source of interleukin-10.
White adipose tissue (WAT) is the source of pro- and anti-inflammatory cytokines and we have recently shown that this tissue is a major source of the anti-inflammatory interleukin (IL)-1 receptor antagonist (IL-1Ra). We now aimed at identifying additional adipose-derived cytokines, which might serve as regulators of IL-1Ra. We demonstrate here for the first time that the antiinflammatory cytokine IL-10 is secreted by human WAT explants and that it is up-regulated by LPS and TNF-alpha in vitro, as well as in obesity in humans (2- and 6-fold increase in subcutaneous and visceral WAT, respectively) and rodents (4-fold increase).
Adipose Tissue↗
[All is endocrinology].
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Dehydroepiandrosterone↗
Adipose tissue: a regulator of inflammation.
Adipose tissue is a highly active organ. In addition to storing calories as triglycerides, it also secretes a large variety of proteins, including cytokines, chemokines and hormone-like factors, such as leptin, adiponectin and resistin. Intriguingly, many, if not most, of these adipose-derived proteins have dual actions; cytokines have both immunomodulatory functions and act as systemic or auto-/paracrine regulators of metabolism, while proteins such as leptin and adiponectin are regulators of both metabolism and inflammation. The production of pro-atherogenic chemokines by adipose tissue is of particular interest since their local secretion, e.g. by perivascular adipose depots, may provide a novel mechanistic link between obesity and the associated vascular complications.
Adiponectin↗
Decreased fat mass in interleukin-1 receptor antagonist-deficient mice: impact on adipogenesis, food intake, and energy expenditure.
Interleukin (IL)-1 is a regulator of inflammation but is also implicated in the control of energy homeostasis. Because the soluble IL-1 receptor antagonist (IL-1Ra) is markedly increased in the serum of obese patients and is overexpressed in white adipose tissue in obesity, we studied the metabolic consequences of genetic IL-1Ra ablation in mice. We have shown that IL-1Ra-/- mice have a lean phenotype due to decreased fat mass, related to a defect in adipogenesis and increased energy expenditure. The adipocytes were smaller in these animals, and the expression of genes involved in adipogenesis was reduced. Energy expenditure as measured by indirect calorimetry was elevated, and weight loss in response to a 24-h fast was increased in IL-1Ra-/- animals compared with wild-type mice. Lipid oxidation of IL-1Ra-/- mice was higher during the light period, reflecting their reduction in diurnal food intake. Interestingly, IL-1Ra-/- and IL-1Ra+/- mice presented an attenuation in high-fat diet-induced caloric hyperphagia, indicating a better adaptation to hypercaloric alimentation, which is in line with the role of IL-1Ra as a mediator of leptin resistance. Taken together, we show that IL-1Ra is an important regulator of adipogenesis, food intake, and energy expenditure.
Adipose Tissue↗
Peroxisome proliferator-activated receptors (PPARs) and associated transcription factors in colon cancer: reduced expression of PPARgamma-coactivator 1 (PGC-1).
Peroxisome proliferator-activated receptors (PPARs) alpha,beta/delta and gamma are fatty acid sensitive transcription factors that have been implicated in colorectal cancer. To better understand their role, we studied the expression levels of all PPAR-isoforms and transcriptional partners such as the retinoid X receptor alpha (RXRalpha) and PPARgamma-coactivator-1 (PGC-1) by means of real-time PCR in 17 patients with colon cancer. While a heterogeneous pattern was observed for the expression level of the PPAR-isoforms alpha,beta/delta and gamma, the coactivator PGC-1 was significantly decreased in 15 of 17 tumors. Taken together our data suggest that the transcriptional activity of PPARgamma may not only be decreased by mutation but also by downregulation of the coactivator PGC-1 of PPARgamma.
Adult↗
Effect of peroxisome proliferator-activated receptor gamma agonist, rosiglitazone, on dedifferentiated thyroid cancers.
BACKGROUND AND METHOD: As genetic alterations in the gene for the peroxisome proliferator-activated receptor gamma (PPARgamma) have been described and PPAR agonists have been shown to redifferentiate thyroid cancers in animal models, we performed a pilot study in five patients with thyroglobulin-positive and I scan-negative thyroid cancers using the PPARgamma agonist rosiglitazone. RESULTS: Although thyroglobulin levels increased in four of the five patients after 3 months of treatment with rosiglitazone, the I scan remained negative in four patients and became only faintly positive in one patient for two lung metastases that could be correlated with metabolically active lung metastases shown by F-fluorodeoxyglucose positron emission tomography (F-FDG PET) and by computed tomography (CT). F-FDG PET, performed in four patients, revealed metastases of significant size in two patients, including the patient mentioned above and in a second patient confirmed by surgery. CONCLUSIONS: Treatment with rosiglitazone increased the production of thyroglobulin in some patients with thyroid cancers, but only rarely restored scintigraphically significant iodine trapping. It remains to be shown whether longer treatment periods might result in a more efficient redifferentiating effect.
Adult↗
Regulatory effects of interleukin (IL)-1, interferon-beta, and IL-4 on the production of IL-1 receptor antagonist by human adipose tissue.
Adipose tissue is the source of production and site of action of several pro- and antiinflammatory cytokines. We have recently shown that white adipose tissue (WAT) is a major producer of the antiinflammatory IL-1 receptor antagonist (IL-1Ra). Because IL-1Ra serum levels are elevated 7-fold in human obesity and an excess of this protein has been implicated in the acquired resistance to leptin and insulin, we investigated the regulation of IL-1Ra in human WAT. We demonstrate that IL-1Ra is mainly produced by adipocytes, rather than the stromal fraction of WAT, and that IL-1alpha and beta, as well as interferon-beta (IFN-beta), strongly up-regulate the expression and secretion of IL-1Ra in WAT. Moreover, human WAT expresses the receptors and proteins known to be required for the action of IL-1 (IL-1 receptor type I, IL-1 receptor accessory protein) and IFN-beta (IFN-alpha/beta receptor subunits 1 and 2). Finally, human WAT actively secretes these regulatory cytokines, suggesting that they up-regulate IL-1Ra through a local autocrine/paracrine action, which is hypothesized to play a regulatory role in adipogenesis and metabolism.
Adipocytes↗
Glitazones in lipodystrophy syndrome induced by highly active antiretroviral therapy.
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Adult↗
Leptin activates the promoter of the interleukin-1 receptor antagonist through p42/44 mitogen-activated protein kinase and a composite nuclear factor kappa B/PU.1 binding site.
We have recently shown that leptin strongly induces the expression and secretion of the interleukin-1 receptor antagonist (IL-1Ra) [Gabay, Dreyer, Pellegrinelli, Chicheportiche and Meier (2001) J. Clin. Endocrinol. Metab. 86, 783-791] in monocytes. However, the intracellular signalling mechanisms involved remained unknown. We now demonstrate that the activation of the IL-1Ra promoter by leptin is strictly dependent on the presence of the long form of the leptin receptor (OB-Rb), and that it also requires the activation of the p42/44 mitogen-activated protein kinases (MAPKs) as well as the presence of a nuclear factor kappaB (NF-kappa B)/PU.1 composite site at position -80 of the IL-1Ra promoter. Although leptin is capable of activating a NF-kappa B reporter element in transient transfection experiments, the protein complex binding to the NF-kappa B/PU.1 site of the IL-1Ra promoter is not composed of the p65/p50 subunits of NF-kappa B, as is evident in electrophoretic gel mobility-shift experiments. In contrast, a protein complex which does not contain PU.1 binds to this composite element in a leptin-dependent manner. In summary, we characterize the signalling pathway for leptin and OB-Rb involved in the induction of IL-1Ra, involving p42/44 MAPK, and a yet uncharacterized complex of transcription factor(s) binding to a NF-kappa B/PU.1 composite element of the IL-1Ra promoter.
Binding Sites↗
IP-10, but not RANTES, is upregulated by leptin in monocytic cells.
We and others have previously shown that leptin has direct effects on the function of monocytes and macrophages. Since obesity is associated with an increased cardiovascular risk, as well as with markedly elevated circulating leptin levels, we examined whether leptin has any pro-inflammatory effects on the function of monocytes. Leptin strongly enhanced the expression and secretion of the interferon-gamma-inducible protein (IP-10) in a human monocytic cell line, as well as in peripheral blood mononuclear cells. In contrast, no significant effect on other inflammatory proteins was observed, such as metalloproteinases and other chemokines. In summary, we have demonstrated that leptin selectively induces the expression and secretion of IP-10 in human monocytic cells, potentially contributing to the vascular complications associated with hyperleptinemic obesity in humans.
Cardiovascular System↗
Expression of galectin-3 in normal and malignant thyroid tissue by quantitative PCR and immunohistochemistry.
Galectin-3 has been extensively studied as an immunohistochemical marker of thyroid malignancy, and a high diagnostic accuracy has been reported even for difficult pathological diagnoses, such as minimal invasive follicular carcinoma. We consequently hypothesized that the quantitative analysis of galectin-3 mRNA rather than the more observer-dependent immunohistological determination might enhance the diagnostic workup of ambiguous thyroid lesions. In the present study, we set out to validate this approach by analyzing concomitantly the expression and production of galectin-3 in benign and malignant thyroid tumors by means of quantitative PCR and immunohistochemistry. Twenty-eight benign and 31 malignant thyroid samples were quantified by real-time PCR for the mRNA levels of galectin-3 and thyroglobulin. Galectin-3 protein expression was examined by immunohistochemistry in 13 benign and 14 malignant thyroid samples. There was a significant increase in galectin-3 at both the mRNA (12/20) and protein levels in papillary cancer (8/8), although the mRNA values overlapped partly with benign lesions. Surprisingly, only a focal and discrete galectin-3 immunoreactivity was seen in follicular cancer (1/5); no augmentation of the mRNA was found. The expression of the thyroid-specific gene thyroglobulin was highly variable in benign and malignant thyroid tissue. These results suggest that the quantitative measurement of galactin-3 mRNA is unlikely to be clinically useful and underscore the need for searching for novel markers for thyroid malignancies.
Adenocarcinoma, Follicular↗
Endurance training in humans leads to fiber type-specific increases in levels of peroxisome proliferator-activated receptor-gamma coactivator-1 and peroxisome proliferator-activated receptor-alpha in skeletal muscle.
The peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1 (PGC-1) can induce mitochondria biogenesis and has been implicated in the development of oxidative type I muscle fibers. The PPAR isoforms alpha, beta/delta, and gamma control the transcription of genes involved in fatty acid and glucose metabolism. As endurance training increases skeletal muscle mitochondria and type I fiber content and fatty acid oxidative capacity, our aim was to determine whether these increases could be mediated by possible effects on PGC-1 or PPAR-alpha, -beta/delta, and -gamma. Seven healthy men performed 6 weeks of endurance training and the expression levels of PGC-1 and PPAR-alpha, -beta/delta, and -gamma mRNA as well as the fiber type distribution of the PGC-1 and PPAR-alpha proteins were measured in biopsies from their vastus lateralis muscle. PGC-1 and PPAR-alpha mRNA expression increased by 2.7- and 2.2-fold (P < 0.01), respectively, after endurance training. PGC-1 expression was 2.2- and 6-fold greater in the type IIa than in the type I and IIx fibers, respectively. It increased by 2.8-fold in the type IIa fibers and by 1.5-fold in both the type I and IIx fibers after endurance training (P < 0.015). PPAR-alpha was 1.9-fold greater in type I than in the II fibers and increased by 3.0-fold and 1.5-fold in these respective fibers after endurance training (P < 0.001). The increases in PGC-1 and PPAR-alpha levels reported in this study may play an important role in the changes in muscle mitochondria content, oxidative phenotype, and sensitivity to insulin known to be induced by endurance training.
Adult↗
Adipose tissue is a major source of interleukin-1 receptor antagonist: upregulation in obesity and inflammation.
The secreted form of the interleukin-1 receptor antagonist (IL-1Ra) is an acute-phase protein intervening in the counterregulation of inflammatory processes. We previously showed that this cytokine antagonist is upregulated in the serum of obese patients, correlating with BMI and insulin resistance. In this study, we examined the expression pattern of IL-1Ra and showed that it is highly expressed not only in liver and spleen, but also in white adipose tissue (WAT), where it is upregulated in obesity. In WAT of obese humans, IL-1Ra was also markedly increased. Moreover, human WAT explants secreted IL-1Ra into the medium, a process that could be stimulated fivefold by interferon-beta. Finally, lipopolysaccharide administration induced a long-lasting expression of IL-1Ra in mouse WAT, suggesting that adipose tissue is an important source of IL-1Ra in both obesity and inflammation. In summary, we demonstrated that WAT is one of the most important sources of IL-1Ra quantitatively, suggesting that this tissue could represent a novel target for anti-inflammatory treatment. Moreover, it can be speculated that IL-1Ra, whose production is markedly increased in WAT in obese individuals, contributes further to weight gain because of its endocrine and paracrine effects on the hypothalamus and adipocytes, respectively.
Adipose Tissue↗
Immunomodulatory actions of leptin.
Leptin, the adipocyte-secreted hormone, exerts its main function as regulator of food intake and energy expenditure through central effects at the hypothalamic level. However, it appeared that this cytokine-like peptide has also direct effects on other peripheral tissues and cell types. Remarkable effects have been demonstrated on the immune function in vivo and in vitro. Monocytes are one of the target cells of leptin, and we have demonstrated that secretion of L-1Ra, an IL-1 receptor antagonist, is induced by leptin. In human obesity leptin and IL-1Ra levels are elevated, and these levels are decreased after weight loss. It is discussed that IL-1Ra may contribute to central leptin resistance.
Adjuvants, Immunologic↗
Regulation of the interleukin-1 receptor antagonist in THP-1 cells by ligands of the peroxisome proliferator-activated receptor gamma.
Monocytes/macrophages (Mphi) play a pivotal role in the persistence of chronic inflammation and local tissue destruction in diseases such as rheumatoid arthritis and atherosclerosis. The production by Mphi of cytokines, chemokines, metalloproteinases and their inhibitors is an essential component in this process, which is tightly regulated by multiple factors. The peroxisome proliferator-activated receptors (PPARs) were shown to be involved in modulating inflammation. PPARgamma is activated by a wide variety of ligands such as fatty acids, the anti-diabetic thiazolidinediones (TZDs), and also by certain prostaglandins of which 15-deoxy-Delta(12,14)-PGJ2 (PGJ2). High concentrations of PPARgamma ligands were shown to have anti-inflammatory activities by inhibiting the secretion of interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNFalpha) by stimulated monocytes. The aim of this study was to determine whether PGJ2 and TZDs would also exert an immunomodulatory action through the up-regulation of anti-inflammatory cytokines such as the IL-1 receptor antagonist (IL-1Ra). THP-1 monocytic cells were stimulated with PMA, thereby enhancing the secretion of IL-1, IL-6, TNFalpha, IL-1Ra and metalloproteinases. Addition of PGJ2 had an inhibitory effect on IL-1, IL-6 and TNFalpha secretion, while increasing IL-1Ra production. In contrast, the bona fide PPARgamma ligands (TZDs; rosiglitazone, pioglitazone and troglitazone) barely inhibited proinflammatory cytokines, but strongly enhanced the production of IL-1Ra from PMA-stimulated THP-1 cells. Unstimulated cells did not respond to TZDs in terms of IL-1Ra production, suggesting that in order to be effective, PPAR ligands depend on PMA signalling. Basal levels of PPARgamma are barely detectable in unstimulated THP-1 cells, while stimulation with PMA up-regulates its expression, suggesting that higher levels of PPARgamma expression are necessary for receptor ligand effects to occur. In conclusion, we demonstrate for the first time that TZDs may exert an anti-inflammatory activity by inducing the production of the IL-1Ra.
Antineoplastic Agents↗