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)

Myofibroblasts have been previously described beneath the bronchial epithelium and were found to increase in number proportional to the accumulation of extracellular matrix in the bronchial lamina reticularis in asthma. The aim of this study was to assess further the contribution of these structural cells to allergic inflammation in the bronchial mucosa through their cytokine expression. Cell cultures were established from the lamina reticularis of human bronchial biopsies from asthmatic and non-asthmatic subjects. Cytokine secretion was measured by ELISA in supernatants of cultures with or without tumour necrosis factor-alpha (TNF-alpha). The mRNA levels for granulocyte-macrophage colony-stimulating factor (GM-CSF) in the cultures were examined by ribonuclease protection assays (RPAs). Bronchial myofibroblasts grown from bronchial biopsies were capable of producing GM-CSF, interleukin-6 (IL-6), interleukin-8 (IL-8), and stem cell factor (SCF) constitutively. The GM-CSF production by myofibroblasts was significantly increased in response to TNF-alpha simulation with a corresponding increase in GM-CSF mRNA expression. The enhancement of GM-CSF production by TNF-alpha in myofibroblasts was blocked by the inhibition of RNA synthesis. Prednisolone abolished the GM-CSF production. This study provides evidence for the role of bronchial myofibroblasts in the regulation of inflammatory cell recruitment and activation by interaction in the cytokine network in the bronchial mucosa.
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PMID:Cytokine production by cell cultures from bronchial subepithelial myofibroblasts. 894 23

Clara cell secretory protein (CCSP) is an abundant component of the extracellular lining fluid of airways. Even though the in vivo function of CCSP is unknown, in vitro studies support a potential role of CCSP in the control of inflammatory responses. CCSP-deficient mice (CCSP -/-) were generated to investigate the in vivo function of this protein (13). In this study, we used hyperoxia exposure as a model to investigate phenotypic consequences of CCSP deficiency following acute lung injury. The pathologic response of the mouse lung to hyperoxia, and recovery of the lung, include inflammatory cell infiltrate and edema. Continuous exposure to > 95% O2 was associated with significantly reduced survival time among CCSP -/- mice as compared with strain-, age-, and sex-matched wild-type control mice. Differences in survival were associated with early onset of lung edema in CCSP -/- mice as compared with wild-type controls. To further investigate these differences in response, mice were exposed to > 95% O2 for either 48 h or 68 h with one group receiving 68 h of hyperoxia followed by room-air recovery. Lung RNA was characterized for changes in the abundance of cytokine messenger RNA (mRNA) using a ribonuclease (RNase) protection assay. After 68 h of hyperoxia, interleukin-6 (IL-6), IL-1beta, and IL-3 mRNAs were 14-, 3-, and 2.5-fold higher, respectively, in CCSP -/- mice than in similarly exposed wild-type control mice. Increased expression of IL-1beta mRNA in hyperoxia-exposed CCSP -/- mice was localized principally within the lung parenchyma, suggesting that the effects of CCSP deficiency were not confined to the airway epithelium. We conclude that CCSP deficiency results in increased sensitivity to hyperoxia-induced lung injury as measured by increased mortality, early onset of lung edema, and induction of proinflammatory cytokine mRNAs.
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PMID:Altered pulmonary response to hyperoxia in Clara cell secretory protein deficient mice. 927 2

Cytokines are hormone-like proteins which mediate and regulate inflammatory and immune responses. The purpose of this study was to investigate the effect of lipopolysaccharide (LPS) and inflammatory cytokines on regulation of interleukin-6 (IL-6) production by human gingival fibroblasts (HGF). The HGF cell lines used in this study, H-CL and F-CL, were established by the explant technique from healthy gingival tissue. Cultured cells were grown to confluency and incubated with various concentrations of LPS from Escherichia coli or Porphyromonas gingivalis or with the recombinant human cytokine tumor necrosis factor alpha (TNF-alpha), IL-1alpha, or IL-1beta. Culture supernatants were collected at various times and assessed for IL-6 production by enzyme-linked immunosorbent assay. Total RNA was isolated from the harvested cells and used to assess levels of IL-6 mRNA by the RNase protection assay. Both LPS preparations induced IL-6 production (1 to 4 ng of IL-6 per ml) by both HGF cell lines. Although TNF-alpha stimulated IL-6 production by HGF, > 10-fold-larger amounts were induced with IL-1alpha and IL-1beta. Furthermore, the addition of both IL-1alpha and TNF-alpha to cultured cells resulted in approximately 600- to 800-fold-higher levels of IL-6 than seen in control cultures, suggesting that these cytokines synergistically induced IL-6 production by HGF. IL-6 message in cultured cells was upregulated 20-fold by TNF-alpha, 1,000-fold by IL-1alpha and IL-1beta, and 1,400-fold by IL-1alpha plus TNF-alpha. IL-1alpha and TNF-alpha alone upregulate IL-6 production in a dose- and time-dependent fashion. The addition of IL-1alpha and TNF-alpha to cultured HGF cells resulted in a synergistic induction of IL-6 after 8 h of incubation and when greater than 10 pg of this combination per ml was used. Our studies show that inflammatory cytokines are hundreds of times more potent than LPS in stimulating IL-6 production by HGF.
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PMID:Effect of lipopolysaccharide and inflammatory cytokines on interleukin-6 production by healthy human gingival fibroblasts. 945 16

To define the potential role of interleukin-6 (IL-6) and its soluble receptor alpha in cartilage metabolism, we analyzed their effects on tissue inhibitor of metalloproteases (TIMP) synthesis by synoviocytes and chondrocytes. TIMP-1 production by isolated human articular synovial fibroblasts and chondrocytes, stimulated by IL-6 and/or its soluble receptor, was first assayed by specific enzyme-linked immunosorbent assay; the slight stimulatory effect of IL-6 on TIMP-1 production by both types of cells was markedly amplified by the addition of soluble receptor, the maximal secretion being observed only at 96 h. TIMP-1 mRNA expression, determined by ribonuclease protection assay, was induced by IL-6 together with its soluble receptor, but TIMP-2 and -3 mRNAs were not affected by these factors. A specific neutralizing antibody abolished the effects of the soluble receptor. Finally, supernatant from synoviocytes stimulated by IL-6 plus its soluble receptor blocked almost completely the collagenolytic activity of supernatant from IL-1-induced synoviocytes. These observations indicate that IL-6 and its soluble receptor have a protective role in the metabolism of cartilage. Given the high levels of soluble receptor in synovial fluid and the marked induction of IL-6 by IL-1 or TNF-alpha, it is likely that IL-6 and its soluble receptor are critical in controlling the catabolic effects of pro-inflammatory cytokines.
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PMID:Interleukin (IL)-6 and its soluble receptor induce TIMP-1 expression in synoviocytes and chondrocytes, and block IL-1-induced collagenolytic activity. 959

The retinoblastoma tumor suppressor gene product (pRb) is involved in controlling cell cycle progression from G1 into S. pRb functions, in part, by regulating the activities of several transcription factors, making pRb involved in the transcriptional control of cellular genes. Transient-transfection assays have implicated pRb in the transcription of several genes, including c-fos, the interleukin-6 gene, c-myc, cdc-2, c-neu, and the transforming growth factor beta2 gene. However, these assays place the promoter in an artificial context and exclude the effects of far 5' upstream regions and chromosomal architecture on gene transcription. In these experiments, we have studied the role of pRb in the control of cell cycle-related genes within a chromosomal context and within the context of the G1 phase of the cell cycle. We have used adenovirus vectors to overexpress pRb in human osteosarcoma cells and breast cells synchronized in early G1. By RNase protection assays, we have assayed the effects of this virus-produced pRb on gene expression in these cells. These results indicate that pRb is involved in the transcriptional downregulation of the E2F-1, E2F-2, dihydrofolate reductase, thymidine kinase, c-myc, proliferating-cell nuclear antigen, p107, and p21/Cip1 genes. However, it has no effect on the transcription of the E2F-3, E2F-4, E2F-5, DP-1, DP-2, or p16/Ink4 genes. The results are consistent with the notion that pRb controls the transcription of genes involved in S-phase promotion. They also suggest that pRb negatively regulates the transcription of two of the transcription factors whose activity it also represses, E2F-1 and E2F-2, and that it plays a role in downregulating the immediate-early gene response to serum stimulation.
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PMID:Regulation of cellular genes in a chromosomal context by the retinoblastoma tumor suppressor protein. 967 66

Borna disease virus (BDV) causes central nervous system (CNS) disease in several vertebrate species, which is frequently accompanied by behavioral abnormalities. In the adult rat, intracerebral (i.c.) BDV infection leads to immunomediated meningoencephalitis. In contrast, i.c. infection of neonates causes a persistent infection in the absence of overt signs of brain inflammation. These rats (designated PTI-NB) display distinct behavioral and neurodevelopmental abnormalities. However, the molecular mechanisms for these virally induced CNS disturbances are unknown. Cytokines play an important role in CNS function, both under normal physiological and pathological conditions. Astrocytes and microglia are the primary resident cells of the central nervous system with the capacity to produce cytokines. Strong reactive astrocytosis is observed in the PTI-NB rat brain. We have used a ribonuclease protection assay to investigate the mRNA expression levels of proinflammatory cytokines in different brain regions of PTI-NB and control rats. We show here evidence of a chronic upregulation of proinflammatory cytokines interleukin-6, tumor necrosis factor alpha, interleukins-1alpha, and -1beta in the hippocampus and cerebellum of the PTI-NB rat brain. These brain regions exhibited only a very mild and transient immune infiltration. In contrast, in addition to reactive astrocytes, a strong and sustained microgliosis was observed in the PTI-NB rat brains. Our data suggest that CNS resident cells, namely astrocytes and microglia, are the major source of cytokine expression in the PTI-NB rat brain. The possible implications of these findings are discussed.
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PMID:Cytokine expression in the rat central nervous system following perinatal Borna disease virus infection. 1022 22

Bone marrow-culture-derived macrophages activated with interferon-gamma and lipopolysaccharide produced less nitric oxide (NO) when cultured with vesicular stomatitis virus (VSV)-infected BALB/c3T3 (3T3-VSV) than macrophages activated in an identical manner and cultured alone, with uninfected BALB/c3T3 (3T3), or with P815. However, all four groups of macrophages produced nearly the same amount of interleukin-6 (IL-6). Addition of VSV to activated macrophages did not change the amount of NO produced. The amount of NO generated by two non-macrophage sources of NO was not affected by the presence of either P815 or 3T3-VSV. Reverse transcriptase-polymerase chain reaction showed a decrease in the amount of inducible nitric oxide synthase (iNOS) but not IL-6 mRNA from macrophages cocultured with 3T3-VSV compared with macrophages cocultured with P815. The reduction in iNOS mRNA was confirmed by ribonuclease protection assay. When RAW 264.7 transfected with an iNOS regulatory construct were activated and incubated with 3T3-VSV there was a decrease in the expression of the reporter luciferase gene and NO production but not IL-6 production compared with cells incubated with either medium alone or with P815.
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PMID:Interaction with vesicular stomatitis virus-infected BALB/c3T3 cells inhibits the synthesis of nitric oxide in activated murine bone marrow culture-derived macrophages. 1033 88

We suggest here that Porphyromonas gingivalis DNA may function as a virulence factor in periodontal disease through expression of inflammatory cytokine. The bacterial DNA markedly stimulated in a dose-dependent manner interleukin-6 (IL-6) production by human gingival fibroblasts. The stimulatory action was eliminated by treatment with DNase but not RNase. The stimulatory effect was not observed in the fibroblasts treated with eucaryotic DNAs. The bacterial DNA also stimulated in dose- and treatment time-dependent manners the expression of the IL-6 gene in the cells. In addition, the stimulatory effect was eliminated when the DNA was methylated with CpG motif methylase. Interestingly, a 30-base synthetic oligonucleotide containing the palindromic motif GACGTC could stimulate expression of the IL-6 gene and production of its protein in the cells. Furthermore, the synthetic oligonucleotide-induced expression of this cytokine gene was blocked by pyrrolidine dithiocarbamate and N-acetyl-L-cystine, potent inhibitors of transcriptional factor NF-kappaB. Gel mobility shift assay showed increased binding of NF-kappaB to its consensus sequence in the synthetic oligonucleotide-treated cells. Also, using specific antibody against p50 and p65, which compose NF-kappaB, we showed the consensus sequence-binding proteins to be NF-kappaB. These results are the first to demonstrate that the internal CpG motifs in P. gingivalis DNA stimulate IL-6 expression in human gingival fibroblasts via stimulation of NF-kappaB.
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PMID:CpG motifs in Porphyromonas gingivalis DNA stimulate interleukin-6 expression in human gingival fibroblasts. 1045 72

Cardiotrophin-1 (CT-1), a novel cytokine that belongs to the interleukin-6 cytokine family, activates gp130 dependent signaling pathway to transduce hypertrophic and cytoprotective signals in cardiac myocytes. To investigate the pathophysiological significance of CT-1 in myocardial disease, the expression of CT-1 was examined after hypoxic stimulation in cardiac myocytes. Highly expressed CT-1 mRNA was observed in embryonic and adult hearts by RNase protection assay. Cardiac myocytes subjected to hypoxic stimulation augmented CT-1 mRNA expression. Although CT-1 mRNA was expressed to a higher extent in non-myocardial cells, the expression was not affected with the stimulation. Conditioned medium from cultured cardiac myocytes presented the ability to tyrosine phosphorylate STAT3 through gp130 and that was further augmented with hypoxic conditioned medium. These results demonstrated for the first time that CT-1 expression is augmented after hypoxic stimulation and hypoxic conditioned medium presented enhanced ability to activate STAT3 in cardiac myocytes. CT-1 might play an important role in the pathogenesis of ischemic heart disease.
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PMID:Hypoxic stress induces cardiotrophin-1 expression in cardiac myocytes. 1052 82

Ozone (O(3)) and nitrogen dioxide (NO(2)) are highly reactive and toxic oxidant pollutants. The objective of this study is to compare chemokine, cytokine, and antioxidant changes elicited by acute exposures of O(3) and NO(2) in a genetically sensitive mouse. Eight-week-old C57Bl/6J mice were exposed to 1 or 2.5 ppm ozone or 15 or 30 ppm NO(2) for 4 or 24 h. Changes in mRNA abundance in lung were assayed by slot blot and ribonuclease protection assay (RPA). Messages encoding metallothionein (Mt), heme oxygenase I (HO-I), and inducible nitric oxide synthase (iNOS) demonstrated increased message abundance after 4 and 24 h of exposure to either O(3) or NO(2). Furthermore, increases in message abundance were of a similar magnitude for O(3) and NO(2). Messages encoding eotaxin, macrophage inflammatory protein (MIP)-1alpha, and MIP-2 were elevated after 4 and 24 h of exposure to 1 ppm ozone. Interleukin-6 was elevated after 4 h of exposure to ozone. After 4 h of 2.5 ppm ozone exposure, increased mRNAs of eotaxin, MIP-1alpha, MIP-2, Mt, HO-I, and iNOS were elevated to a higher magnitude than were detected after 1 ppm ozone. Monocyte chemoattractant protein (MCP-1) was elevated following 15 ppm NO(2) exposure. After 4 h of 30 ppm NO(2) exposure, messages encoding eotaxin, MIP-1alpha, MIP-2, and MCP-1 were elevated to levels similar to those detected after ozone exposure. Our results demonstrate a similar antioxidant and chemokine response during both O(3) and NO(2) exposure. Induction of these messages is associated with the duration and concentration of exposure. These studies suggest that these gases exert toxic action through a similar mechanism.
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PMID:Antioxidant and inflammatory response after acute nitrogen dioxide and ozone exposures in C57Bl/6 mice. 1071 24


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