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)

A male patient with abnormal postpubertal bone elongation was shown earlier to have a mutation in both alleles of the estrogen receptor, resulting in a nonfunctional gene. Marrow stromal fibroblasts (MSFs) derived from this patient were called HERKOs (human estrogen receptor knock outs), and in order to obtain continuous HERKO cell lines, they were immortalized using a recombinant adenovirus-origin-minus SV40 virus. MSFs are unique cells because they support hematopoesis and contain a mixed population of precursor cells for bone, cartilage, and fat. Three established cell lines (HERKO2, HERKO4, and HERKO7) were characterized and compared with the heterogeneous population of nonimmortalized HERKOs for their osteogenic potential. We performed Northern analysis of matrix genes implicated in bone development and metabolism and an in vivo bone formation assay by transplanting the cells subcutaneously into immunodeficient mice. All three HERKO lines expressed high amounts of collagen 1A1, osteopontin, osteonectin, fibronectin, decorin, biglycan, and alkaline phosphatase. Except for osteopontin, expression of these genes was slightly lower compared with nonimmortalized HERKOs. In the in vivo bone formation assay, the heterogeneous population of nonimmortalized HERKOs formed bone with high efficiency, while the HERKO lines induced a high-density, bone-like matrix. Finally, all HERKO cell types secreted high levels of insulin-like growth factor I and interleukin-6 into the culture medium relative to cells of normal human subjects. In summary, these lines of HERKO cells retain several of the phenotypic traits of MSFs after immortalization, including matrix and cytokine production, and provide a valuable source of a unique human material for future studies involving estrogen action in bone and bone marrow metabolism.
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PMID:Immortalization and characterization of bone marrow stromal fibroblasts from a patient with a loss of function mutation in the estrogen receptor-alpha gene. 955 60

The addition of fibronectin fragments to cultured cartilage causes an initial suppression of proteoglycan synthesis, induction of matrix metalloproteinases, and resultant decrease in proteoglycan content by about 50% during the first few days in culture. Because the proteoglycan loss appears to be limited, we investigated whether the fibronectin fragments induce anabolic responses that might counter the damage. The effects of various lengths of exposure of cultured cartilage to the fibronectin fragment on proteoglycan content, proteoglycan synthesis rates, stromelysin-1 release, and tumor necrosis factor-alpha, interleukin-1alpha, and interleukin-6 release were investigated. The results showed that about 7 days of exposure of cultured cartilage to the fibronectin fragment was required for maximal cytokine release, proteoglycan depletion, and stromelysin-1 release. However, nearly maximal suppression of proteoglycan synthesis occurred within 1 day of the addition of the fibronectin fragment and, after its removal, the rates increased to supernormal levels. Decreasing exposure to 3 days caused only a small decrease in cartilage proteoglycan content, although stromelysin-1 release still occurred. Decreasing exposure to 1 day caused an immediate increase in proteoglycan synthesis and an increase to supernormal proteoglycan contents. The effect of first treating cartilage with the fibronectin fragment for various periods and then allowing a recovery was to make the cartilage more resistant to secondary exposures. This study shows that cartilage damage can be caused by short exposures to the fibronectin fragment and that exposures either optimal or suboptimal for damage additionally amplify anabolic processes to make the cartilage resistant to further damage and, thus, condition it against pending amplification of damage.
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PMID:Exposure of cartilage to a fibronectin fragment amplifies catabolic processes while also enhancing anabolic processes to limit damage. 962 98

The phenotype of cultured fibroblasts from patients affected by Apert's syndrome, a rare connective disorder, differs from that of normal cells in its extracellular matrix macromolecule composition (glycosaminoglycans, collagens and fibronectin) and is further modulated by treatment with interleukins (ILs). As the mechanisms responsible for the changes are unknown, we used our recently described model system for Apert periosteal fibroblasts to ascertain whether the pattern of ILs they secrete into the medium is comparable to that of normal fibroblasts. The results obtained by enzyme-linked immunosorbent assay (ELISA) show that the levels of interleukin-1 (IL-1) and interleukin-6 (IL-6) were lower in Apert than in normal media, whereas levels of IL-1 receptor antagonist (IL-1ra), the natural inhibitor of IL-1, were markedly higher. IL-1 specific bio-activity on thymocyte proliferation was also decreased in Apert supernatants. As we provided also evidence that active transforming growth factor beta (TGFbeta1), an IL-1 antagonist, was not secreted in greater amount in Apert media with respect to normals, the enhancement of IL-1ra appeared critical in down-regulating IL-1. Northern blot analysis of cytokine mRNA revealed no detectable IL-1 or IL-6 gene expression in normal fibroblasts, but high amounts of IL-6 mRNA transcripts in Apert cells. As the increased IL-6 gene expression did not translate into a parallel increase of secreted IL-6, the control of IL-6 secretion may be mainly post-transcriptional. Furthermore, the result that a treatment of the cultures with IL-1ra was able to induce a decrease of IL-6 secretion, suggests that the observed decreased secretion of IL-6 may be due to the autocrine action of overproduction of IL-1ra. The observed imbalance in the production of ILs which we show for the first time suggests ILs may be the natural autocrine regulators of ECM production in Apert fibroblasts. We hypothesize that in vitro differences previously reported in fibroblast phenotypes and several clinical features of Apert's syndrome may correlate with different cytokine patterns.
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PMID:Interleukin pattern of Apert fibroblasts in vitro. 962 25

Cyclosporine A is a powerful immunosuppressive agent which is widely used for the prevention of allograft rejection and for the treatment of autoimmune diseases. Clinical and experimental data show that it may also act on connective tissue. We investigated the influence of cyclosporine A on granulation tissue formation and wound healing. Using an in vitro approach, we followed the time course of rat dermal fibroblasts during wound repair. Granulation fibroblasts were compared to dermal fibroblasts flow cytometrically and by mRNA analysis with respect to the expression of procollagen alpha1(I), integrin beta1, interleukin-6, transforming growth factor beta1, keratinocyte growth factor and activin betaA. The most pronounced effect in cyclosporine-treated rats was the strong down-regulation of activin beta expression. In cryo-sections of granulation tissue from the same rats, the distribution and expression intensity of intercellular adhesion molecule and its receptors were investigated by immunohistology. Clearly, a time course was detectable. Tissue from CsA-treated animals showed a delay of three days compared to untreated animals. Apoptosis was also delayed in CsA-treated rats by around three days. Furthermore, we investigated the effect of CsA on the expression of collagen alpha1(I), fibronectin and matrix metalloprotease 1 genes in dermal fibroblasts from untreated donors. No changes in the mRNA steady state levels of these genes were revealed after direct addition of different doses of CsA to fibroblast cultures. Our data suggest that CsA may interfere with the complicated net of interactions between connective tissue and the immune system by down-regulation of the inflammatory phase by modulation of cytokines and a subsequent delay of tissue repair.
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PMID:Cyclosporine A delays wound healing and apoptosis and suppresses activin beta-A expression in rats. 964 3

Induction of interleukin-6 (IL-6) secretion by whole blood cultures (WBC) was used as an in vitro assay system for pyrogen-induced inflammatory reactions. The assay system was very sensitive to Eschericia coli (E coli) endotoxin (< 10 pg/ml). The potential pyrogenic effects of human serum albumin (HSA), Fibronectin (Fn) and stabilised human serum (SHS) solutions were analyzed using this system. None of the products assayed had an effect on the sensitivity of the WBC assay. Spike recovery studies with isolated endotoxin, gram positive and gram negative bacteria showed that none of the products had an effect on the spike recovery of these pyrogenic substances. Good correlations were found between the WBC assay and the rabbit assay for pyrogens for all the production batches tested. When these samples were analysed by the limulus amoebocyte lysate (LAL) assay, the LAL test gave anomalous results for 1 out of the 22 production batches tested. This batch gave a false negative result on the LAL assay and might be indicative of the inability of the LAL assay to detect pyrogens other than endotoxin.
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PMID:The detection of pyrogens in blood products using an ex vivo whole blood culture assay. 968 26

Gaucher disease is an excellent candidate for gene therapy by transduction of hematopoitic stem cells. In this study, we compared methods which allow an increase in transfer of the glucocerebrosidase gene to human hematopoietic progenitor cells. Several techniques were employed, including the use of cytokines, bone marrow stroma, fibronectin, centrifugal enhancement and in vitro long-term culture. The effect of prestimulation with cytokines interleukin-3 (IL-3), interleukin-6 (IL-6) and stem cell factor (SCF) on transduction of cord blood CD34+ cells was examined. The results suggest that 16-h prestimulation was sufficient for efficient transduction. We examined the effect of bone marrow stroma and fibronectin, both of which increased transduction efficiency up to 36% and 44%, respectively, as measured by PCR for the integrated GC-cDNA in clonogenic cells (9% without any support). Transduction efficiency of 83% was obtained using 2-h centrifugation. Combining centrifugation and in vitro culture in long-term bone marrow culture media containing cytokines (IL-3/IL-6/SCF), CD34+ cells from cord blood and peripheral blood of 3 Gaucher patients were transduced weekly for 21 d. The results of 6 separate experiments consistently demonstrated transduction efficiency of 100% after 7-d in vitro culture. This transduction protocol combining centrifugation and in vitro long-term culture is an attractive method and can be applied to clinical trials.
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PMID:Comparison of methods for retroviral mediated transfer of glucocerebrosidase gene to CD34+ hematopoietic progenitor cells. 968 85

Interleukin-6 (IL-6) belongs to the family of the "four-helix bundle" cytokines. The extracellular parts of their receptors consist of several Ig- and fibronectin type III-like domains. Characteristic of these receptors is a cytokine-binding module consisting of two such fibronectin domains defined by a set of four conserved cysteines and a tryptophan-serine-X-tryptophan-serine (WSXWS) sequence motif. On target cells, IL-6 binds to a specific IL-6 receptor (IL-6R), and the complex of IL-6.IL-6R associates with the signal transducing protein gp130. The IL-6R consists of three extracellular domains. The NH2-terminal Ig-like domain is not needed for ligand binding and signal initiation. Here we have investigated the properties and functional role of the third membrane proximal domain. The protein can be efficiently expressed in bacteria, and the refolded domain is shown to be sufficient for IL-6 binding. When complexed with IL-6, however, it fails to associate with the gp130 protein. Since the second and the third domain together with IL-6 can bind to gp130 and induce signaling, our data demonstrate the ligand binding function of the third domain and point to an important role of the second domain in complex formation with gp130 and signaling.
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PMID:The membrane proximal cytokine receptor domain of the human interleukin-6 receptor is sufficient for ligand binding but not for gp130 association. 969 99

It is well known that ozone (O3) causes acute lung inflammation. What is not known is whether there is progression of the inflammatory response in humans with repeated short-term exposures. Our study was designed to test the hypothesis that repeated exposures to a high-ambient concentration of O3 (0.2 ppm) over several days would cause more inflammation than a single exposure. Fifteen healthy volunteers were exposed in random fashion to 0.2 ppm ozone for 4 h on a single day and to 0.2 ppm O3 for 4 h on 4 consecutive days while exercising moderately for 30 min of each hour. Pulmonary function tests were obtained immediately before and after each 4-h exposure. Bronchoscopy was performed 20 h after the completion of each exposure arm to obtain bronchoalveolar lavage (BAL) for measurement of markers of inflammation. Our results show initial progression followed by attenuation of the acute physiologic response to O3 with repeated daily exposures. We found a significant difference in percent change in FEV1, FVC, and specific airway resistance (SRaw) across the single-day exposure when compared with the change across Day 4 of the 4-d exposure. Bronchial fraction (the first 15 ml of BAL return) and BAL were analyzed for the following end points: total and differential cell counts, total protein, lactate dehydrogenase (LDH), fibronectin, interleukin-6 (IL-6), interleukin-8 (IL-8), and granulocyte-macrophage colony-stimulating factor (GM-CSF). In the bronchial fraction the number of polymorphonuclear cells (PMN)s and fibronectin concentration were significantly decreased after 4-d exposure compared with single-day exposure. In BAL, significant decreases in the number of PMNs, fibronectin, and IL-6 were found after 4-d exposure versus single-day exposure. These results suggest that there is attenuation of the O3-induced inflammatory response in both proximal airways and distal lung with repeated daily exposures.
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PMID:Ozone-induced inflammation is attenuated with multiday exposure. 970 Jan 32

Serotonin (5-hydroxytryptamine (5-MT)) has been shown to be a regulator of gene expression in rat myometrial smooth muscle cells (SMC). Serotonin activates the genes for interstitial collagenase, interleukin-1alpha, -1beta and interleukin-6, among others. On the other hand, serotonin down-regulates the genes for types I and III collagen and fibronectin. Here we show that serotonin is also a negative regulator of the expression of anti-protease alpha2-macroglobulin (alpha2M) in SMC. The serotonin-dependent repression occurs at both the mRNA and protein levels, and is mediated by the 5-HT2A receptor subtype. The inhibitory effect is prevented by cycloheximide, indicating the requirement for the synthesis of one or more proteins. Interleukin-1 (IL-1), which is induced by serotonin in SMC and is required for subsequent interstitial collagenase induction, appears not to be one of these intermediates. On the other hand, progesterone, the major steroid hormone of pregnancy, is capable of reversing the serotonin-mediated inhibition of alpha2M. The phorbol myristate acetate (PMA), which mimics the induction of interstitial collagenase by serotonin, fails to affect the inhibition of alpha2M production. The cell-permeable cyclic AMP analogue 8-bromoadenosine 3':5'-cyclic monophosphate sodium salt (8-bromo-cAMP), is, however, capable of fully reproducing the action of serotonin on alpha2M. These results further speak to the ability of serotonin to regulate gene expression in the myometrial SMC, both positively and negatively. In addition, although all the effects of serotonin so far identified are mediated by the 5-HT2A receptor, different post-receptor pathways appear to mediate the positively and negatively regulated genes.
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PMID:Serotonin regulates the expression of the gene for alpha2-macroglobulin in myometrial smooth muscle cells. 970 76

Genital inflammation may play a major role in the pathogenesis of preterm labor. Screening and early treatment of subclinical genital tract infections (bacterial vaginosis, heavy group B streptococci colonization, primary genital HSV infection and other silent intra-uterine infections) seem to offer promise for the prevention of preterm labor. New factors have been studied in order to appreciate their benefit in the evaluation of the risk of preterm labor. None of these biologic markers (fetal-fibronectin, maternal interleukin-6, vaginal pH measuring) have enough sensitivity to permit efficient screening. Home uterine activity monitoring seems to be interesting for early identification of women with increased risk of preterm delivery, but can't be used on a large scale because of its costs. New tocolytic agents are investigated in order to protect from an adverse outcome. Atosiban exhibits more oxytocin selective and antagonistic activity without side-effects, and nimesulide seems to have a lack of effects on fetal functions.
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PMID:[The threat of premature labor: new aspects for management]. 986 33


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