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)

The secretion of alpha 1-microglobulin by primary cultures of rat hepatocytes was found to increase upon the addition of interleukin-6 or leukemia inhibitory factor, two mediators of acute phase response. This stimulatory effect was further enhanced by dexamethasone. alpha 1-Microglobulin is synthesized as a precursor also containing bikunin, and the precursor protein is cleaved shortly before secretion. Our results therefore suggest that both alpha 1-microglobulin and bikunin are acute phase reactants in rat hepatocytes. Furthermore, we found that retinoic acid, previously shown to be involved in the regulation of cell differentiation and development, also stimulated alpha 1-microglobulin synthesis. Only free, uncomplexed alpha 1-microglobulin (28,000 Da) was detected in the hepatocyte media, suggesting that the complex between alpha 1-microglobulin and alpha 1-inhibitor 3, found in rat serum, is formed outside the hepatocyte.
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PMID:Synthesis of alpha 1-microglobulin in cultured rat hepatocytes is stimulated by interleukin-6, leukemia inhibitory factor, dexamethasone and retinoic acid. 137 72

The coding region of the human interleukin-6 (hIL6) gene was fused to the prepro secretion signal of the alpha-mating factor gene in several yeast host strains. It was found that the KEX-2 protease was unable to cleave the prepro-Lys-Arg-Pro-IL6 sequence, but that unspecific cleavage of the precursor protein had occurred. The prepro-Lys-Arg-Ala-Pro-IL6 sequence, however, was correctly recognized and cleaved by the KEX-2 protease, and IL6 was efficiently secreted into the culture medium. The N-terminal Ala-Pro peptide was removed during processing by wild-type yeast strains, but was retained in a ste13 mutant. IL6 as well as the aberrant proteins were not glycosylated. The transformed cells could secrete up to 30 micrograms/ml IL6. The protein was purified from the medium to homogeneity by ion-exchange chromatography and gel filtration, and had a specific activity of about 2 x 10(8) IU/mg in a proliferation assay.
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PMID:Production and purification of recombinant human interleukin-6 secreted by the yeast Saccharomyces cerevisiae. 204 Feb 82

A variety of injuries, such as bacterial infection or ischemic tissue necrosis, induce systemic acute phase reaction expressed as fever, leukocytosis, release of several hormones, activation of clotting, complement and kinin forming pathways, and drastic increase of synthesis of certain plasma proteins. The reaction is triggered by 'alarm molecules', including free radicals, which activate several stress-sensitive protein kinases (ERK, p38, JNK) in macrophages and other responsive cells. These kinases phosphorylate, usually in a multi-step cascade, transcription factors belonging primarily to C/EBP, NF-kappa B and AP-1 families. Active transcription factors after translocation to nucleus interact with responsive elements in the gene promoters of acute-phase cytokines: tumor necrosis factor-alpha, interleukin-1 and interleukin-6. Enhanced transcription of these genes is usually followed by rapid translation and precursor protein processing leading to the release of biologically active cytokines. Fine tuning of the acute phase response appears to be regulated at all stages: primary signals, kinase cascades, transcription factors, mRNA stability and translation, cytokine precursor processing, secretion and bioavailability. This makes possible designing of specific inhibitors of cytokine synthesis as potential therapeutic drugs.
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PMID:Initiation of acute phase response and synthesis of cytokines. 895 Jan 92

To analyze the interactions among immunoneuroendocrinological systems in a miniature Shiba goat, we attempted to clone and express caprine cDNA-encoding interleukin-6 (IL-6) which is well-known to exert a variety of effects on neuroendocrinological functions in small experimental animals. The cDNA-encoding caprine IL-6 was molecularly cloned from a lipopolysaccharide-stimulated adherent splenocyte library by the reverse transcription-polymerase chain reaction. The sequence analysis shows that the cloned caprine IL-6 cDNA encodes a precursor protein of 208 amino acids that is processed to mature protein of 180 amino acids with a predicted molecular weight of 20,524. The amino acid sequence of caprine IL-6 displays 97.8 and 51.1% degree of homology with ovine and human equivalents, respectively. A recombinant baculovirus containing the caprine IL-6 cDNA was shown to induce insect cells to efficiently secrete caprine IL-6 into culture supernatant up to 10(5) U/ml, as confirmed by Western blot analysis and bioassay with an IL-6-dependent cell line.
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PMID:Molecular cloning of caprine IL-6 cDNA and its expression in insect cells. 925 May 86

Amyloid precursor protein (AbetaPP), a precursor of amyloid beta (Abeta) peptide, is one of the molecules involved in the pathogenesis of Alzheimer's disease (AD). Specific mutations in AbetaPP have been found in patients inheriting familial AD (FAD). These mutant AbetaPP proteins cause cell death in neuronal cell lines in vitro, but the molecular mechanism of cytotoxicity has not yet been clarified completely. We analyzed the cytotoxic mechanisms of the London-type AbetaPP mutant, V642I-AbetaPP, in primary cortical neurons utilizing an adenovirus-mediated gene transfer system. Expression of V642I-AbetaPP protein induced degeneration of the primary neurons. This cytotoxicity was blocked by pertussis toxin, a specific inhibitor for heterotrimeric G proteins, Go/i, and was suppressed by an inhibitor of caspase-3/7 and an antioxidant, glutathione ethyl ester. A specific inhibitor for NADPH oxidase, apocynin, but not a xanthine oxidase inhibitor or a nitric oxide inhibitor, blocked V642I-AbetaPP-induced cytotoxicity. Among mitogen-activated protein kinase (MAPK) family proteins, c-Jun N-terminal kinase (JNK) and p38MAPK, but not extracellular regulated kinase (ERK), were involved in this cytotoxic pathway. The V642I-AbetaPP-induced cytotoxicity was not suppressed by two secretase inhibitors, suggesting that Abeta does not play a major role in this cytotoxicity. Two neuroprotective factors, insulin-like growth factor I (IGF-I) and Humanin, protected these primary neurons from V642I-AbetaPP-induced cytotoxicity. Furthermore, interleukin-6 and -11 also attenuated this cytotoxicity. This study demonstrated that the signaling pathway activated by mutated AbetaPP in the primary neurons is the same as that by the other artificial insults such as antibody binding to AbetaPP and the artificial dimerization of cytoplasmic domain of AbetaPP. The potential of neurotrophic factors and cytokines in AD therapy is also indicated.
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PMID:Characterization of V642I-AbetaPP-induced cytotoxicity in primary neurons. 1519 38

Background and Aims: The urinary trypsin inhibitor (UTI), a wide range protein inhibitor synthesized by hepatocytes, is considered to play an important role not only in the protection of organ injury during severe inflammation but also in the inhibition of tumor invasion and metastasis. However, the precise mechanisms underlying control of its synthesis, secretion, and processing remain unclarified. The aim of this study is to determine whether human hepatoma HepG2 cells secrete UTI in free form and whether its synthesis and secretion are regulated by proinflammatory cytokines. Methods: Cultured HepG2 cells were stimulated using different concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). The concentration of free UTI in the medium was measured by ELISA and the intracellular UTI precursor was identified by western blotting. UTI mRNA expression was studied by reverse transcription polymerase chain reaction (RT-PCR). Results: HepG2 cells constantly secreted free UTI and this secretion was significantly up-regulated by IL-6, IL-1beta, and TNF-alpha. IL-6, IL-1beta, and TNF-alpha enhanced the synthesis of the intracellular UTI precursor protein, and IL-1beta up-regulated UTI mRNA expression. Conclusions: HepG2 cells constantly secrete free UTI. The proinflammatory cytokines, IL-1beta, IL-6, and TNF-alpha, up-regulate UTI synthesis and secretion by up-regulating UTI mRNA expression.
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PMID:Proinflammatory cytokines up-regulate synthesis and secretion of urinary trypsin inhibitor in human hepatoma HepG2 cells. 1528 18

A plastid-resident basic helix-loop-helix protein, previously identified in Nicotiana tabacum and designated as NtWIN4 (N. tabacum wound-induced clone 4), has been converted from a nuclear transcription repressor into a plastid-resident regulatory factor through replacement of the DNA-binding domain with a plastid transit sequence during evolution. N. tabacum is a natural amphidiploid plant derived from Nicotiana tomentosiformis and Nicotiana sylvestris and immunoblot staining using anti-NtWIN4 antibodies identified two protein species, a 26 kDa form and a 17 kDa form, in N. sylvestris, whereas only the 17 kDa form was found in N. tabacum. The 26 kDa protein is produced when translation starts from the first AUG codon of the mRNA and is predominantly localized in the cytoplasm and nucleus, whereas the 17 kDa protein is derived from a 24 kDa precursor protein, synthesized from the second AUG codon, and localizes only to plastids. Subsequent analyses revealed that the lengths of the mRNAs vary in the two plant species. One major form lacks the first AUG, while minor populations possess variable 5'-untranslated regions prior to the first AUG codon. Translation of the two types produces the 24 kDa and 26 kDa proteins respectively. In vitro translation assays indicated that initiation frequency from the first AUG codon is higher in mRNAs from N. sylvestris than from N. tabacum. In contrast, initiation from the second AUG codon was found to be equally efficient in mRNAs from both species. These results suggest that both mRNA populations and translation efficiency changed during the amphidiploidization responsible for generation of N. tabacum. This scheme could reflect a molecular mechanism of protein evolution in plants.
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PMID:Functional diversification of a basic helix-loop-helix protein due to alternative transcription during generation of amphidiploidy in tobacco plants. 1741 82

Cerebral microvascular amyloid beta protein (Abeta) deposition and associated neuroinflammation is increasingly recognized as an important component leading to cognitive impairment in Alzheimer's disease and related cerebral amyloid angiopathy disorders. Transgenic mice expressing the vasculotropic Dutch/Iowa (E693Q/D694N) mutant human Abeta precursor protein in brain (Tg-SwDI) accumulate abundant cerebral microvascular fibrillar amyloid deposits and exhibit robust neuroinflammation. In the present study, we investigated the effect of the anti-inflammatory drug minocycline on Abeta accumulation, neuroinflammation, and behavioral deficits in Tg-SwDI mice. Twelve-month-old mice were treated with saline or minocycline by intraperitoneal injection every other day for a total of 4 weeks. During the final week of treatment, the mice were tested for impaired learning and memory. Brains were then harvested for biochemical and immunohistochemical analysis. Minocycline treatment did not alter the cerebral deposition of Abeta or the restriction of fibrillar amyloid to the cerebral microvasculature. Similarly, minocycline-treated Tg-SwDI mice exhibited no change in the levels of total Abeta, the ratios of Abeta40 and Abeta42, or the amounts of soluble, insoluble, or oligomeric Abeta compared with the saline-treated control Tg-SwDI mice. In contrast, the numbers of activated microglia and levels of interleukin-6 were significantly reduced in minocycline-treated Tg-SwDI mice compared with saline-treated Tg-SwDI mice. In addition, there was a significant improvement in behavioral performance of the minocycline-treated Tg-SwDI mice. These finding suggest that anti-inflammatory treatment targeted for cerebral microvascular amyloid-induced microglial activation can improve cognitive deficits without altering the accumulation and distribution of Abeta.
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PMID:Minocycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloid. 1737 66

Interleukin-6 (IL-6) is a pleiotropic cytokine synthesized by many different cells after appropriate stimulation. IL-6 binds first to the interleukin-6 receptor alpha (IL6-Ralpha) and then this complex binds to the signal-transducing gp130 receptor, forming a functional hexameric receptor complex. We observed by Western blot analysis with anti-IL6-Ralpha two bands of approximately 80 kDa and approximately 110 kDa in the rat sciatic nerve, cerebral cortex, spleen, pancreas and liver, corresponding to the mature glycosylated form and possibly to the dimer of the non-glycosylated precursor protein. By immunohistochemistry, high levels of IL6-Ralpha expression are observed in non-myelinating Schwann cells. In myelinating Schwann cells IL6-Ralpha is present as discrete dots in the perinuclear region, in distinct membrane domains of the Schwann cell sheath and at the nodes of Ranvier, suggesting that IL6-Ralpha is clustered both on the axonal side of the node and within the Schwann cells. After sciatic nerve crush injury IL6-Ralpha is upregulated in denervated Schwann cells between the myelin ovoids during the period of Schwann cell proliferation. The expression of IL6-Ralpha continues during the period of remyelination, suggesting that IL6-Ralpha might be involved in both Schwann cell proliferation and remyelination of the rat sciatic nerve.
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PMID:Expression of interleukin-6 receptor alpha in normal and injured rat sciatic nerve. 1831 28

Proinflammatory stimuli, after amyloid beta (Abeta) deposition, have been hypothesized to create a self-reinforcing positive feedback loop that increases amyloidogenic processing of the Abeta precursor protein (APP), promoting further Abeta accumulation and neuroinflammation in Alzheimer's disease (AD). Interleukin-6 (IL-6), a proinflammatory cytokine, has been shown to be increased in AD patients implying a pathological interaction. To assess the effects of IL-6 on Abeta deposition and APP processing in vivo, we overexpressed murine IL-6 (mIL-6) in the brains of APP transgenic TgCRND8 and TG2576 mice. mIL-6 expression resulted in extensive gliosis and concurrently attenuated Abeta deposition in TgCRND8 mouse brains. This was accompanied by up-regulation of glial phagocytic markers in vivo and resulted in enhanced microglia-mediated phagocytosis of Abeta aggregates in vitro. Further, mIL-6-induced neuroinflammation had no effect on APP processing in TgCRND8 and had no effect on APP processing or steady-state levels of Abeta in young Tg2576 mice. These results indicate that mIL-6-mediated reactive gliosis may be beneficial early in the disease process by potentially enhancing Abeta plaque clearance rather than mediating a neurotoxic feedback loop that exacerbates amyloid pathology. This is the first study that methodically dissects the contribution of mIL-6 with regard to its potential role in modulating Abeta deposition in vivo.
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PMID:Massive gliosis induced by interleukin-6 suppresses Abeta deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. 1982 75


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