Clinical, immune and metabolic effects of trace element supplements in burns: a double-blind placebo-controlled trial.
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Journal Article↗
Biomedical subjects
C Schindler
Publications and source records attributed to C Schindler.
Regulation of IFN-alpha/beta genes: evidence for a dual function of the transcription factor complex ISGF3 in the production and action of IFN-alpha/beta.
BACKGROUND: Efficient production of interferons (IFNs) in virally infected cells is an essential aspect of the host defence. The transcription factor complex ISGF3 (IFN-stimulated gene factor 3) was originally identified as a critical mediator of the IFN signal; it is formed upon IFN receptor (IFNR) stimulation and binds to ISREs (IFN-stimulated response elements) to activate IFN-inducible genes. It has recently been shown that the DNA binding component of ISGF3, p48 (ISGF3gamma) also binds to virus-inducible elements in the IFN-alpha/beta genes, suggesting a potential new role of p48 in IFN production. RESULTS: Primary cells from mice with a targeted disruption of the p48 gene show severe defects in virus-induced IFN-alpha/beta gene expression. A similar defect was also observed in cells lacking type I IFNR or Stat1, further demonstrating the role of IFN signalling in the induction of these IFN genes. ISGF3 in fact binds to the virus-inducible elements within the IFN-alpha/beta promoters. We also provide evidence showing that these elements are additionally controlled by an unidentified factor(s) which presumably triggers the primary phase of IFN gene induction. CONCLUSIONS: Our results demonstrate that the IFN signal transducing complex ISGF3 plays a crucial role in IFN production and suggest that ISGF3 may participate directly in the activation of IFN-alpha/beta promoters. This dual function of ISGF3 may insure the efficient operation of this cytokine system in the host defence.
Animals↗
Lung function in healthy never smoking adults: reference values and lower limits of normal of a Swiss population.
BACKGROUND: Reference values and definitions of "normal" are prerequisites for population screening and classification of lung diseases. The aim of this study was to calculate reference values for never smoking Caucasian adults. METHODS: In the SAPALDIA cross sectional study respiratory health was assessed in a random sample of 9651 subjects, aged 18-60 years, from eight areas of Switzerland. Lung function was measured according to ATS criteria including quality control. In 3157 healthy never smoking adults without respiratory symptoms the mean values and fifth percentiles of lung function variables were calculated. For each sex, logarithms of lung function were regressed against age, age squared, and the logarithm of height. Residuals were used to estimate fifth percentiles across the age range using a technique not requiring normality or homoscedasticity of residuals. RESULTS: Most lung function variables were non-linear with age and showed an increase in early adulthood and an accelerated decline thereafter. The reference values for forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were higher than those of the European Community for Coal and Steel and those from North America. The prediction equations for lower fifth percentile values defined a stable proportion of subjects outside this limit whereas alternative methods for estimating the fifth percentile showed a loss of sensitivity with age. CONCLUSIONS: The reference equations for mean values of spirometric indices and their lower fifth percentiles gave an improved and unbiased lower limit of normal. The higher mean values may in part be due to the strictly selected population, quality control procedures, cohort effects, and altitude, and are not explained by the statistical model used.
Adolescent↗
IgE levels, atopy markers and hay fever in relation to age, sex and smoking status in a normal adult Swiss population. SAPALDIA (Swiss Study on Air Pollution and Lung Diseases in Adults) Team.
Within the framework of the SAPALDIA survey (Swiss study on Air Pollution and Lung Diseases in Adults), we studied the influence of sex, age and smoking habits on total serum IgE and allergen-specific IgE antibody concentrations (assessed by means of the Phadiatop test) and on the prevalence of hay fever. A total of 8,344 subjects aged 18-60 years, comprising 2,776 current smokers, 1,888 former smokers and 3,680 nonsmokers, were included in the study. Smokers had both a statistically significant (p<0.001) higher mean serum IgE concentration (geometric mean 39.7 kU/l), and a higher percentage (27.5%) of persons with elevated serum IgE (> 100 kU/l) than nonsmokers (27.2 kU/l; respectively 20.5%). The IgE level was significantly lower in women than men (p<0.001) in all smoking categories. The percentage of persons with positive atopic markers (positive Phadiatop test, positive skin prick tests to common inhalant allergens) and self-reported hay fever was significantly higher in nonsmokers than in smokers or former smokers. In Phadiatop positive (atopic) subjects, the IgE levels were highest, with a mean of 104.3 kU/l (99.0-109.8), and lowest in Phadiatop-negative nonsmokers at 27.2 kU/L (25.9-28.6). These findings correlate well with the current interpretation of total serum IgE values in screening for atopic diseases in adults (IgE < 20 kU/l: atopy improbable; IgE > 100 kU/l: atopy probable). In multivariate logistic regression models, the prevalence of positive Phadiatop tests, positive skin tests, and atopy decreased significantly with age. The odds of having a positive Phadiatop and skin test, or being atopic were found to decrease on average by 23.0, 21.1 and 21.0%, respectively, with every 10-year increase in age. With respect to smoking status, the odds ratios for the three atopic markers were significantly lower in current and former smokers than in nonsmokers. The prevalence of (self-reported) hay fever was highest in nonsmokers, intermediate in former smokers (odds ratio = 0.81, p<0.05) and lowest in current smokers (odds ratio = 0.76 in comparison to former smokers, p<0.01). The odds ratio of self-reported current hay fever decreased with age at an estimated average of 23% every 10 years. The decrease in former smokers might be slightly faster than in the other two categories. In conclusion, the present results demonstrated that tobacco smoking is associated with increased IgE levels and negatively related to atopy and hay fever. In addition, it is shown that atopy prevalence decreases with age.
Adolescent↗
Functional STAT 1 and 3 signaling by the leptin receptor (OB-R); reduced expression of the rat fatty leptin receptor in transfected cells.
The leptin receptor (OB-R) bears homology to members of the class I cytokine receptor family. We demonstrate that leptin binding to OB-R stimulates formation of STAT-1 and STAT-3 complexes, thereby defining transcriptional motifs for genes that are under leptin control. Transfected fa OB-R bound leptin with equal affinity to that of wild type OB-R. fa OB-R abundance was about 7 fold reduced compared to control cells. Surprisingly, the low level of fa OB-R is fully capable of activating the STAT signal transduction pathway. We discuss plausible explanations for the obese phenotype in Zucker fatty rats.
Animals↗
Activation of the JAK-STAT signal transduction pathway by oncostatin-M cultured human and mouse osteoblastic cells.
Oncastatin M (OSM) is one member of the leukemia inhibitory factor/interleukin-6 family of cytokines that has been shown to be a growth regulatory molecule. In osteoblastic cultures, OSM causes marked phenotypic changes and the enhanced secretion of interleukin-6. In this study, we have shown that stimulation of murine and human osteoblastic cultures and a human osteosarcoma cell line with OSM resulted in the tyrosine phosphorylation of a number of cellular proteins including members of both the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) family of signaling proteins. The JAKs, a family of intracellular kinases, and the STATs, a family of transcription factors, have both previously been shown to be tyrosine phosphorylated and activated in response to various cytokines, interferons, and growth factors in cells of non-skeletal origin. Using three different sources of cells of the osteoblast lineage, we demonstrate that OSM induces a rapid but transient tyrosine phosphorylation of the three JAK family members tested, JAK1, JAK2 and Tyk2. In addition, two members of the STAT family, Stat1alpha and Stat3, are tyrosine phosphorylated in osteoblastic cells in culture in response to OSM. OSM activation of this pathway in cells of the osteoblast lineage will result in the transcription of specific genes that ultimately may be associated with osteoblast function.
Animals↗
Cerebral manifestation of an actinomycosis infection. A case report.
Affection of the CNS by actinomycosis is a rare but treatable manifestation of an infection with actinomyces israeli. Neurological involvement includes a meningeal, granulomatous and also pseudotumoral form. We report the case of a patient suffering from an intracerebral actinomycosis abscess. The source of infection was the upper jaw. After a right frontal craniotomy the intracerebral abscess was removed. Postoperatively the patient received initially a combined antiedemateous and antibiotic therapy with 12 mg dexamethasone and 6 g cefotaxime and 3 g amoxicilline. After 4 weeks of treatment with improving neurological deficits dexamthasone therapy was reduced followed by an exclusive antibiotic therapy for another 4 weeks. During this time the patient recovered completely.
Actinomycosis↗
Transcriptional induction of the PML growth suppressor gene by interferons is mediated through an ISRE and a GAS element.
PML is a nuclear matrix protein with growth suppressing properties, whose expression is deregulated during oncogenesis. Moreover, in the t(15;17) translocation of acute promyelocytic leukaemia (APL), PML fusion to the retinoic acid receptor alpha (RAR alpha) is the likely molecular basis of leukaemogenesis. Here we show that interferons (IFNs) alpha, beta, and gamma upregulate PML mRNA expression. Analysis of 5' genomic sequences of the PML gene revealed an IFN-alpha/-beta stimulated response element (ISRE) and an IFN-gamma activation site (GAS) in the untranslated first exon. Binding of IFN signal transducers and activators of transcription (STATs) was demonstrated to be weak for the PML GAS, but strong for the PML ISRE which also seemed to contribute substantially to the IFN-gamma response. Thus, PML is a primary target gene of IFNs and would appear as a suitable candidate for mediating some of their antiproliferative effects. Abnormalities of PML structure, localisation or expression in human malignancy, constitute examples of how an IFN target gene may be altered in oncogenesis.
Amino Acid Sequence↗
Stat5 as a target for regulation by extracellular matrix.
Transcription of tissue-specific genes in mammary gland requires signals from both prolactin and basement membrane. Here we address the mechanism by which this specialized extracellular matrix regulates transcription. Using mammary cell cultures derived from transgenic mice harboring the ovine beta-lactoglobulin gene, we show that either a basement membrane extract, or purified laminin-1, induced high levels of beta-lactoglobulin synthesis. It is known that prolactin signals through Stat5 (signal transducer and activator of transcription). This transcription factor interacts with gamma-interferon activation site-related motifs within the beta-lactoglobulin promoter, which we show are required for matrix dependence of beta-lactoglobulin expression. The DNA binding activity of Stat5 was present only in extracts of mammary cells cultured on basement membrane, indicating that the activation state of Stat5 is regulated by the type of substratum the cell encounters. Thus, basement membrane controls transcription of milk protein genes through the Stat5-mediated prolactin signaling pathway, providing a molecular explanation for previous studies implicating extracellular matrix in the control of mammary differentiation.
Animals↗
Activation of STAT factors by prolactin, interferon-gamma, growth hormones, and a tyrosine phosphatase inhibitor in rabbit primary mammary epithelial cells.
In numerous studies on mammary epithelial cell lines multiple factors, added to the medium or contained in the serum, were required for casein gene expression. It has been shown in these systems that the mammary gland factor (MGF) is implicated in the activation of the beta-casein gene promoter. In the present study, we determined the relationship between known agents that affect casein gene expression and MGF activity using the properties of rabbit primary mammary epithelial cells to respond to PRL alone, when cultured in chemically defined medium. We demonstrate that MGF is rapidly activated by PRL alone or by human growth hormone, a natural ligand of many PRL receptors (PRL-Rs), in the cytoplasm and accumulated in the nucleus. The MGF activation by PRL occurred in the absence of endogenous extracellular matrix, a condition where casein synthesis is known to be markedly reduced. Different inhibitors of protein-tyrosine kinases, which have been shown to reduce casein mRNA synthesis, but not of protein kinase C, decrease the MGF activity. A tyrosine phosphatase inhibitor, sodium pervanadate, induced two GAS-binding complexes related to MGF and STAT1. Our data show that MGF is a latent cytoplasmic factor rapidly activated in mammary epithelial cells, by a mechanism involving a tyrosine kinase and a tyrosine phosphatase.
Animals↗
Distribution of the mammalian Stat gene family in mouse chromosomes.
Studies of transcriptional activation by interferons and a variety of cytokines have led to the identification of a family of proteins that serve as signal transducers and activators of transcription, Stats. Here, we report that the seven mouse Stat loci map in three clusters, with each cluster located on a different mouse autosome. The data suggest that the family has arisen via a tandem duplication of the ancestral locus, followed by dispersion of the linked loci to different mouse chromosomes.
Animals↗
Lack of interferon gamma receptor beta chain and the prevention of interferon gamma signaling in TH1 cells.
The ability of interferon gamma (IFN-gamma) to inhibit the proliferation of type 2 T helper cells (TH2), but not that of type 1 (TH1) cells, suggests that helper cell subsets might differ in their activation of the IFN-gamma signaling pathway. The IFN-gamma-inducible signal transducing factor (STF-IFN gamma) was activated in murine TH2 but not in TH1 cell clones, because in the latter the second chain of the IFN-gamma receptor (accessory factor 1 or IFN-gamma R beta) was absent. Thus, TH1 cells use receptor modification to prevent the activation of STF-IFN gamma and achieve an IFN-gamma-resistant state.
Animals↗
Gamma chain-associated cytokine receptors signal through distinct transducing factors.
The IL-2, IL-4, and IL-7 signaling pathways have been shown to utilize shared components. The receptors for these cytokines are composed of ligand-specific binding chains that associate with a shared signaling subunit, the common gamma (gamma c) chain. In addition, IL-2, IL-4, and IL-7 induce activation of a common set of nonreceptor tyrosine kinases, Jak-1 and Jak-3. We have further investigated the signaling events induced by these cytokines and find that the gamma c-associated receptors activate distinct signal transducing factors (STFs). In addition, we show that a 94-kDa STAT-related protein (p94) is activated in response to IL-2 and IL-7, but not IL-4. These data indicate that IL-2, IL-4, and IL-7 activate distinct signaling molecules which might be differentially recruited to the receptor complex by the ligand-specific units of the IL-2, IL-4, and IL-7 receptors.
Amino Acid Sequence↗
Interleukin-3 signals through multiple isoforms of Stat5.
The interleukin (IL)-3 family of cytokines mediates its numerous effects on myeloid growth and maturation by binding a family of related receptors. It has been shown recently that IL-3 induces the activation of two distinct cytoplasmic signal transducing factors (STFs) that are likely to mediate the induction of immediate early genes. In immature myeloid cells, IL-3 activates STF-IL-3a, which comprises two tyrosine-phosphorylated DNA binding proteins of 77 and 80 kDa. In mature myeloid cells, IL-3 and granulocyte-macrophage colony-stimulating factor activate STF-IL-3b, which consists of a 94 and 96 kDa tyrosine-phosphorylated DNA binding protein. Peptide sequence data obtained from the purified 77 and 80 kDa proteins (p77 and p80) indicate that they are closely related but are encoded by distinct genes. Both peptide and nucleotide sequence data demonstrate that these two proteins are the murine homologs of ovine mammary gland factor (MGF)/Stat5. The peptide data also indicate that p77 and p80 are phosphorylated on tyrosine 699, a position analogous to the tyrosine that is phosphorylated in Stat1 and Stat2 in response to interferon. Additionally, antiserum raised against bacterially expressed p77/p80 recognizes the 94 and 96 kDa protein components of STF-IL-3b, suggesting that these may be additional isoforms of Stat5. These studies indicate that the IL-3 family of ligands is able to activate multiple isoforms of the signal transducing protein Stat5.
Amino Acid Sequence↗
Requirement of serine phosphorylation for formation of STAT-promoter complexes.
Members of the interleukin-6 family of cytokines bind to and activate receptors that contain a common subunit, gp130. This leads to the activation of Stat3 and Stat1, two cytoplasmic signal transducers and activators of transcription (STATs), by tyrosine phosphorylation. Serine phosphorylation of Stat3 was constitutive and was enhanced by signaling through gp130. In cells of lymphoid and neuronal origins, inhibition of serine phosphorylation prevented the formation of complexes of DNA with Stat3-Stat3 but not with Stat3-Stat1 or Stat1-Stat1 dimers. In vitro serine dephosphorylation of Stat3 also inhibited DNA binding of Stat3-Stat3. The requirement of serine phosphorylation for Stat3-Stat3.DNA complex formation was inversely correlated with the affinity of Stat3-Stat3 for the binding site. Thus, serine phosphorylation appears to enhance or to be required for the formation of stable Stat3-Stat3.DNA complexes.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Interleukin-6-induced serine phosphorylation of transcription factor APRF: evidence for a role in interleukin-6 target gene induction.
The cytokine interleukin-6 (IL-6) rapidly activates a latent cytoplasmic transcription factor, acute-phase response factor (APRF), by tyrosine phosphorylation. Activation and DNA binding of APRF are inhibited by inhibitors of protein tyrosine kinases but not serine/threonine kinases. However, immediate-early gene induction by IL-6 and, as we show here, stimulation of the promoters of the genes for alpha 2-macroglobulin, Jun-B, and intercellular adhesion molecule-1 (ICAM-1) are blocked by the serine/threonine kinase inhibitor H7. We now show that IL-6 triggers a delayed phosphorylation of APRF at serine resudues which can be reversed in vitro by protein phosphatase 2A and is also inhibited by H7. Therefore, APRF serine phosphorylation is likely to represent a crucial event in IL-6 signal transduction leading to target gene induction.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Differentiation-regulated serine phosphorylation of STAT1 promotes GAF activation in macrophages.
Gamma interferon (IFN-gamma), a macrophage-activating cytokine, modulates gene expression through the activity of a transcription factor designated IFN-gamma activation factor (GAF). GAF is formed after phosphorylation on tyrosine and dimerization of the 91-kDa protein STAT1. We have recently reported that differentiation of the promonocytic cell line U937 into monocytes increases the amount of cellular GAF after IFN-gamma treatment and at the same time increases the phosphorylation of STAT1. Here we show that activation of the JAK family kinases, which are instrumental in mediating STAT1 phosphorylation on tyrosine, did not increase upon monocytic U937 differentiation. Consistent with this finding, levels of STAT1 tyrosine phosphorylation were virtually identical in promonocytic and monocytic U937 cells. Analysis of STAT1 phosphoamino acids and mapping of phosphopeptides showed an IFN-gamma-dependent increase in Ser phosphorylation in differentiated cells. Analyses of STAT1 isoforms by two-dimensional gel electrophoresis demonstrated a differentiation-induced shift toward more acidic isoforms. All isoforms were equally sensitive to subsequent tyrosine phosphorylation, as indicated by a sodium dodecyl sulfate-polyacrylamide gel electrophoresis mobility shift typical for tyrosine-phosphorylated STAT1. Consistent with the importance of Ser phosphorylation for high-affinity binding to the IFN-gamma activation site sequence, phosphatase 2A treatment strongly reduced the formation of IFN-gamma activation site-GAF complexes in an electrophoretic mobility shift assay. Our data indicate that the activity of GAF is modulated by STAT1 serine kinases/phosphatases and suggest that this mechanism is employed in the developmental control of macrophage responsiveness to IFN-gamma.
Amino Acids↗
Transcriptional responses to polypeptide ligands: the JAK-STAT pathway.
Cytokines and growth factors regulate multiple aspects of cell growth through their interactions with specific receptors. These receptors initiate signals directed at both the cytoplasmic and the nuclear compartments. Many of the nuclear signals culminate in the induction of new genes. Characterization of the ability of IFN-alpha to rapidly induce new genes has led to the identification of a new signaling paradigm, the JAK-STAT (Signal Transducers and Activators of Transcription) pathway. In the IFN-alpha pathway, two receptor associated tyrosine kinases from the JAK family, Jak1 and Tyk2, mediate the activation of two latent cytoplasmic transcription factors, Stat1 and Stat2. More recent studies have not only determined that this pathway is used extensively, but have led to the identification of additional components (e.g., Jak2, Jak3, Stat3, Stat4, Stat5, and Stat6). This review will examine how these components mediate the transduction of signal directly from receptor to nucleus.
Amino Acid Sequence↗