Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Janus kinase 1 (Jak1) is a cytoplasmic tyrosine kinase that noncovalently associates with a variety of cytokine receptors. Here we show that the in vitro translated N-terminal domains of Jak1 are sufficient for binding to a biotinylated peptide comprising the membrane-proximal 73 amino acids of gp130, the signal-transducing receptor chain of interleukin-6-type cytokines. By the fold recognition approach amino acid residues 36-112 of Jak1 were predicted to adopt a beta-grasp fold, and a structural model was built using ubiquitin as a template. Substitution of Tyr(107) to alanine, a residue conserved among Jaks and involved in hydrophobic core interactions of the proposed beta-grasp domain, abrogated binding of full-length Jak1 to gp130 in COS-7 transfectants. By further mutagenesis we identified the loop 4 region of the Jak1 beta-grasp domain as essential for gp130 association and gp130-mediated signal transduction. In Jak1-deficient U4C cells reconstituted with the loop 4 Jak1 mutants L80A/Y81A and Delta(Tyr(81)-Ser(84)), the interferon-gamma, interferon-alpha, and interleukin-6 responses were similarly impaired. Thus, loop 4 of the beta-grasp domain plays a role in the association of Jak1 with both class I and II cytokine receptors. Taken together the structural model and the mutagenesis data provide further insight into the interaction of Janus kinases with cytokine receptors.
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PMID:Mapping of a region within the N terminus of Jak1 involved in cytokine receptor interaction. 1146 94

Nuclear factor-interleukin-6 (NF-IL6), a human transcription factor of the CCAAT-box/enhancer binding protein (C/EBP) family, is widely implicated as a "master regulator" of hepatic acute-phrase response and inflammatory cytokine gene expression. NF-IL6 contains, at its N-terminus, an alanine- and proline-rich transactivation domain, followed at the C-terminus by a basic domain-leucine zipper (bZIP) DNA-binding motif. Understanding how the NF-IL6 transcription factor interacts with DNA is fundamental to its role as a transactivator because sequence-specific DNA-binding is prerequisite to promoter activation. We review our findings on the identification of the minimal "core" DNA-binding domain and the discovery of a novel bZIP element that influences DNA-binding kinetics. Manipulation of this domain allows for design of molecules that can be used as competitive antagonists or targeted delivery of molecules to selected regions of the eukaryotic genome.
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PMID:The Basic Amino Acid-Rich DNA-Binding Element of the NF-IL6 Transcription Factor Contains Two Functionally Distinct Subdomains. 1185 44

The glycoprotein 130 (gp130) is the common signal transducing receptor chain of the interleukin-6 family of cytokines. Here we investigated the requirements for transfer of the information given by ligand binding to the cytoplasmic domain of gp130. It is demonstrated that the box 1/2 region has to be located membrane-proximally in order to bind and activate Janus kinases. To test the possible requirement of an alpha-helical orientation, we inserted 1-4 alanine residues into this juxtamembrane intracellular region. The insertion of one alanine results in a strongly reduced activation of STAT1 and STAT3, whereas insertion of three alanine residues leads to a stronger STAT activation. These results suggest that gp130-mediated activation of STATs is sensitive to rotational changes around the receptor axis perpendicular to the membrane. Surprisingly, insertion of 1, 2, 3, or 4 alanine residues into this juxtamembrane region leads to successive impairment but not abolishment of Janus kinase and receptor phosphorylation, supporting the finding of sensitivity of Janus kinases toward changes in distance of box 1/2 from the plasma membrane. We suggest a new model concerning the gp130 activation mode in which the relative orientation of the cytoplasmic regions seems to be critical for further signal transduction.
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PMID:Orientational constraints of the gp130 intracellular juxtamembrane domain for signaling. 1201 Oct 64

Muropeptides contribute to the recognition of bacteria by modulating immune responses: the structural requirements for adjuvant activity were described in the seventies. During the last years, our knowledge of bacterial pattern recognition has increased dramatically and the importance of the absence of contaminations in both muropeptide preparations and other bacterial stimuli has become clear. We investigated a panel of 15 synthetic Limulus-negative muropeptides, four of them synthesized for the first time, as to their potency to synergize with lipopolysaccharide (LPS) in cytokine induction in human whole blood. No muropeptide was capable of stimulating cytokine release from human blood. However, as little as 20 nM of the muropeptides N-acetyl-muramyl-l-alanyl-d-isoglutamine (muramyl dipeptide, M(AdiQ)), N-acetyl-glucosamine-muramyl dipeptide GM(AdiQ), or C(18)M(AdiQ), which carries a non-natural additional fatty acid, sufficed to induce an up to 3 log-order shift in tumor necrosis factor alpha-release in response to 100 pg/ml LPS. The release of interleukin-1beta, interleukin-6, and interleukin-10 was also significantly enhanced although to a lesser extent. The synergistic effect was stereoselective with M(AdiQ) being the minimal active principle. Synergy was also observed on the transcriptional level by means of real-time PCR. Smaller molecules like N-acetylmuramic acid (M), aM, carrying a naturally occurring 1,6-anhydro-bound in M or M(A), containing only the amino acid l-alanine neither synergized with LPS nor influenced the synergy of other muropeptides with LPS. In conclusion, these data show that nanomolar quantities of muropeptides dramatically potentiate LPS-induced monocyte activation. This has implications for pyrogenicity testing and endotoxemia in patients.
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PMID:Structural requirements of synthetic muropeptides to synergize with lipopolysaccharide in cytokine induction. 1466 50

The effects of cystatin C and other cysteine proteinase inhibitors on osteoclast formation and differentiation have been investigated. Cystatin C decreased osteoclast formation stimulated by parathyroid hormone (PTH), 1,25(OH)2-vitamin D3 or interleukin-6 (IL-6) (in the presence of its soluble receptor) as assessed by the number of tartrate-resistant acid phosphatase (TRAP+) multinucleated cells in mouse bone marrow cultures. The inhibitory effect was associated with decreased mRNA expression for the calcitonin receptor as well as decreased number of specific binding sites for 125I-calcitonin, and without any effect on the mRNA expression of receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL). Similarly, the cysteine proteinase inhibitors leupeptin, E-64 and benzyloxycarbonyl-Phe-Ala-diazomethane (Z-FA-CHN2) decreased PTH-stimulated formation of TRAP+ multinucleated cells and binding of 125I-calcitonin. A peptidyl derivative synthesized to mimic part of the proteinase-binding site of cystatin C (benzyloxycarbonyl-Arg-Leu-Val-Gly-diazomethane, or Z-RLVG-CHN2) also decreased PTH-stimulated osteoclast formation. In a 9-day culture, addition of cystatin C during the last 5 days was sufficient to cause substantial inhibition of osteoclast formation. Cystatin C-induced decrease of osteoclast formation was associated with enhanced number of F4/80-positive macrophages and increased mRNA expression of the macrophage receptor c-fms in the bone marrow culture. Osteoclast formation in mouse bone marrow cultures as well as in mouse spleen cell cultures, stimulated by macrophage colony-stimulating factor (M-CSF) and RANKL was also decreased by different cysteine proteinase inhibitors. In addition, cystatin C inhibited M-CSF/RANKL induction of calcitonin receptor mRNA in spleen cell cultures. The inhibitory effect by cystatin C in spleen cells was associated with decreased mRNA expression of RANK and the transcription factor NFAT2. It is concluded that cysteine proteinase inhibitors decrease formation of osteoclasts by interfering at a late stage of pre-osteoclast differentiation.
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PMID:Osteoclastogenesis is decreased by cysteine proteinase inhibitors. 1500 89

Increased circulating levels of liver enzymes emerging during treatment with psychotropic drugs are frequently encountered and, in general, attributed to drug metabolism or toxic effects. Because obesity was shown to be associated with elevated liver enzyme levels in different non-psychiatric study samples, we hypothesized that drug-induced weight gain might be an additional causative factor. We tested this hypothesis in 67 inpatients who received psychopharmacological treatment across five weeks. Stepwise linear regression was used to predict changes in the serum levels of aspartate-amino transferase (ASAT) and alanine-amino transferase (ALAT) by changes in the body mass index (BMI), by changes in other biological parameters related to body weight (tumor necrosis factor-alpha [TNF-alpha], soluble TNF receptors [sTNF-R], interleukin-6 [IL-6], leptin plasma levels) and by the respective liver enzyme baseline level. BMI changes from baseline to endpoint were significantly associated with the changes in ALAT and ASAT levels across five weeks of treatment and with ALAT and ASAT levels at the end point of the study. The baseline levels of ALAT and ASAT also had a significant impact on these liver enzyme level changes, whereas all other variables had not. These results suggest that weight gain-associated metabolic changes occurring during treatment with psychotropic drugs have consistent and clinically relevant effects on the liver.
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PMID:Elevation of liver enzyme levels during psychopharmacological treatment is associated with weight gain. 1550 22

Interleukin-6 (IL-6) is a pleiotropic cytokine involved in the pathophysiology of various human diseases such as type 2 diabetes and obesity. IL-6 signals via a heterodimeric receptor complex consisting of a soluble IL-6 alpha-subunit (IL-6 receptor [IL6R]) and a signal transducing subunit (gp130). The IL6R gene maps to an important candidate locus for type 2 diabetes on chromosome 1q21. An Asp358Ala polymorphism of the IL6R has been reported to associate with obesity in Pima Indians. We investigated the Asp358Ala polymorphism in relation to type 2 diabetes, obesity, and other pre-diabetic quantitative traits among Danish whites. By applying a recessive genetic model in a case-control study of 1,349 type 2 diabetic patients and 4,596 glucose-tolerant control subjects, we found a significant difference in genotype distribution (P = 0.008) and in allele frequency (Ala-allele 38.3% [95% CI 36.5-40.1] in diabetic subjects vs. 41.2% [40.2-42.2] in control subjects; P = 0.007). The odds ratio for the Asp/Asp carriers versus Ala/Ala carriers was 1.38 (1.09-1.71). Among 4,251 middle-aged glucose-tolerant subjects, the Asp358Ala polymorphism was not associated with estimates of obesity, post-oral glucose tolerance test serum insulin release, or the homeostasis model assessment of insulin resistance index. In conclusion, the Asp358Ala polymorphism of the IL6R associates with type 2 diabetes in Danish whites.
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PMID:Variation in the interleukin-6 receptor gene associates with type 2 diabetes in Danish whites. 1556 70

Interaction of leptin with its receptors resembles that of interleukin-6 and granulocyte colony-stimulating factor, which interact with their receptors through binding sites I-III. Site III plays a pivotal role in receptors' dimerization or tetramerization and subsequent activation. Leptin's site III also mediates the formation of an active multimeric complex through its interaction with the IGD (immunoglobulin-like domain) of LEPRs (leptin receptors). Using a sensitive hydrophobic cluster analysis of leptin's and LEPR's sequences, we identified hydrophobic stretches in leptin's A-B loop (amino acids 39-42) and in the N-terminal end of LEPR's IGD (amino acids 325-328) that are predicted to participate in site III and to interact with each other in a beta-sheet-like configuration. To verify this hypothesis, we prepared and purified to homogeneity (as verified by SDS/PAGE, gel filtration and reverse-phase chromatography) several alanine muteins of amino acids 39-42 in human and ovine leptins. CD analyses revealed that those mutations hardly affect the secondary structure. All muteins acted as true antagonists, i.e. they bound LEPR with an affinity similar to the wild-type hormone, had no agonistic activity and specifically inhibited leptin action in several leptin-responsive in vitro bioassays. Alanine mutagenesis of LEPR's IGD (amino acids 325-328) drastically reduced its biological but not binding activity, indicating the importance of this region for interaction with leptin's site III. FRET (fluorescence resonance energy transfer) microscopy experiments have documented that the transient FRET signalling occurring upon exposure to leptin results not from binding of the ligand, but from ligand-induced oligomerization of LEPRs mediated by leptin's site III.
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PMID:Identification of the hydrophobic strand in the A-B loop of leptin as major binding site III: implications for large-scale preparation of potent recombinant human and ovine leptin antagonists. 1595 38

The combined effect of Peroxisome proliferator-activated receptor gamma (PPARG) Pro/Ala and interleukin-6 G174C gene variants, was evaluated in 429 Caucasian subjects in order to determine whether subjects carrying both variants were at different risk for obesity. In particular, the combined contribution of these two variants (both independent and interaction effects) to the total variation of obesity-related factors was estimated. All subjects were genotyped for codon 12 Pro/Ala locus variability and for the interleukin-6-174 C/G promoter polymorphism. Subjects with the Ala variant had significantly lower BMI, insulin resistance, triglyceride levels than those without. Furthermore, subjects with Ala variant had significantly lower IL-6 levels (0.88 +/- 0.9 vs 1.61 +/- 2.25 pg/ml; p = 0.041). In contrast, the IL6-C variant was significantly associated with lower plasma IL-6 and with lower total cholesterol levels but was not significantly associated with any other obesity risk factors. Indeed, subjects carrying both PPARG and IL-6 gene variants, had a clearly more favourable profile of obesity related risk factors than subjects with one variant, having Ala+/C+ carriers lower BMI (22.8 +/- 2.3 vs 24.14 +/- 1.9; f = 5.31; p < 0.005), insulin resistance (1.49 +/- 0.70 vs 2.13 +/- 0.92; f = 4.342; p = 0.038) and triglyceride levels (79.15 +/- 32.9 vs 98 +/- 6.73 mg/dl; f = 3.120; p < 0.005). These findings suggest that the effect of the two genetic variants on 'obesity related' factors is additive.
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PMID:Role of interaction between variants in the PPARG and interleukin-6 genes on obesity related metabolic risk factors. 1602 43

The aim of this study was to investigate the influence of N-acetylcysteine (NAC) on acute necrotizing pancreatitis (ANP) induced by glycodeoxycholic acid in rats. The induction of ANP resulted in significant increase in mortality rate, pancreatic necrosis and serum activity of amylase, alanine aspartate transferase (ALT), interleukin-6 (IL-6), lactate dehydrogenase (LDH) in bronchoalveolar lavage (BAL) fluid, serum concentration of urea, tissue activity of myeloperoxidase (MPO) and malondialdehyde (MDA) in the pancreas and lung, and significant decrease of concentrations of calcium, blood pressure, urine output and pO(2). The use of NAC inhibited the changes in urine output, pO(2), tissue activity of MPO and MDA in pancreas and lungs, and the serum activity of IL-6, ALT, and serum concentrations of urea and calcium. NAC reduced the mortality and pancreatic damage. The use of NAC has a beneficial effect on the course of ANP in rats. It may be used in the treatment of acute pancreatitis.
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PMID:Effects of N-acetylcysteine on acute necrotizing pancreatitis in rats. 1608 83


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