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)

Previous work has shown that fibroblast-derived collagenase/matrix-metalloproteinase-1 (MMP-1), responsible for the breakdown of dermal interstitial collagen, was dose-dependently induced in vitro and in vivo by UVA irradiation and this induction was at least partly mediated by interleukin-6 (IL-6). We here provide evidence that UVA-induced IL-1 alpha and IL-1 beta play a central role in the induction of the synthesis both of IL-6 and collagenase/MMP-1. In contrast to the late increase of IL-1 alpha and IL-1 beta mRNA levels at 6 h postirradiation, bioactivity of IL-1 is already detectable at 1 h postirradiation. This early peak of IL-1 bioactivity appears to be responsible for the induction of IL-6 synthesis and together with IL-6 lead to an increase of the steady-state mRNA level of collagenase/MMP-1 as deduced from studies using IL-1 alpha and IL-1 beta antisense oligonucleotides or neutralizing antibodies against IL-1 alpha and IL-1 beta. Besides the early posttranslationally controlled release of intracellular IL-1, a latter pretranslationally controlled synthesis and release of IL-1 perpetuates the UV response. From these data we suggest a UV-induced cytokine network consisting of IL-1 alpha, IL-1 beta and IL-6, which via interrelated autocrine loops induce collagenase/MMP-1 and thus may contribute to the loss of interstitial collagen in cutaneous photoaging.
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PMID:UVA-induced autocrine stimulation of fibroblast-derived collagenase/MMP-1 by interrelated loops of interleukin-1 and interleukin-6. 804 11

The importance of a collagen-binding adhesin in the pathogenesis of septic arthritis has been examined by comparing the virulence of two sets of Staphylococcus aureus mutants in an animal model. Collagen adhesin-negative mutant PH100 was constructed by replacing the chromosomal collagen adhesin gene (cna) in a clinical strain, Phillips, with an inactivated copy of the gene. Collagen adhesin-positive mutant S. aureus CYL574 was generated by introducing the cna gene into CYL316, a strain that normally lacks the cna gene. Biochemical, immunological, and functional analyses of the generated mutants and their respective parent strains showed that binding of 125I-labeled collagen, expression of an immunoreactive collagen adhesin, and bacterial adherence to cartilage were directly correlated with the presence of a functional cna gene. Greater than 70% of the mice injected with the Cna+ strains developed clinical signs of arthritis, whereas less than 27% of the animals injected with Cna- strains showed symptoms of disease. Furthermore, mice injected with the Cna+ strain Phillips had remarkably elevated levels of immunoglobulin G1 and interleukin-6 compared with mice injected with the Cna- mutant PH100. Taken together, these results demonstrate that collagen adhesin plays an important role in the pathogenesis of septic arthritis induced by S. aureus.
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PMID:The Staphylococcus aureus collagen adhesin is a virulence determinant in experimental septic arthritis. 826 22

The effect of a 24-kDa fibroblast-activating factor (FAF) isolated from outer membrane vesicles of Porphyromonas gingivalis W50 on the modulation of [3H]thymidine uptake and cell proliferation was examined in selected fibroblast and transformed cell lines. FAF enhanced the proliferation of human gingival fibroblasts, human skin fibroblasts, and human umbilical vein endothelial cells in subconfluent and confluent cells, suggesting that FAF might be functioning as a competence factor. The transformed cell lines, U-937 and HEp-2, were not responsive. FAF and several human-derived growth factors showed a synergistic effect on proliferation. [3H]proline and [3H]leucine were rapidly incorporated into fibroblasts in the presence of FAF; however, there was no selective induction of collagen synthesis. FAF was not active in the induction of interleukin-1 and interleukin-6. It is hypothesized that FAF from P. gingivalis functions as a growth factor for human fibroblasts but is without activity for transformed cells.
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PMID:Modulation of growth and function of human gingival fibroblasts by fibroblast-activating factor derived from Porphyromonas gingivalis W50. 838 Jul 96

The legal procedure for evaluating the toxicity of cosmetic, household, chemical and pharmaceutical products is still the irritancy Draize test on rabbits. Various irritation tests are currently being developed as alternatives to in vivo animal testing. Our in vitro model system is composed of 24 equivalent dermis (ED) comprising a chitosan-cross-linked collagen-glycosaminoglycan matrix populated by foreskin fibroblasts. In evaluating this system for irritancy testing, three different measures of toxicity were used: MTT (dimethylthiazol diphenyltetrazolium bromide) reduction, and lactate dehydrogenase and interleukin-6 release. The experiments described herein represent a preliminary evaluation to determine the usefulness and predictive value of our 24 ED kit as an alternative method for the prediction of human dermal reaction, versus three chemical products: cadmium chloride, lauryl sulfate, and benzalkonium chloride. Preliminary results suggest that the ED may be a useful in vitro model for the prediction of cutaneous and ocular toxicity and allow the development of a 24-skin-equivalent kit realized by seeding human normal keratinocytes onto the equivalent dermis.
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PMID:Pharmacotoxicological applications of an equivalent dermis: three measurements of cytotoxicity. 856 46

A mesothelioma cell line, termed T-85, was established from a patient with malignant peritoneal mesothelioma and remarkable thrombocytosis (1.4 x 10(6)/mm3). Electron microscopically, two types of mesothelioma cells have been characterized; the major type of cells with dense-cored granules in the cytoplasm and the minor one with evenly dense granules. Immunologically, the cells showed staining for interleukin-6 (IL-6), cytokeratin, collagen type IV, vimentin, laminin, fibronectin and Factor VIII-related antigen. Quantitation by ELISA revealed a high concentration of IL-6 in T-85 cell culture supernatants. RT-polymerase chain reaction of T-85 cells showed two positive bands of cDNA at 628 and 251 base pairs indicating the constitutive expression of IL-6 and IL-6 receptor mRNA. Moreover, prominent pro-platelet process formation activity in T-85 cell culture supernatants indicated the presence of a thrombopoietic activity due mainly to IL-6 but not the c-Mpl ligand or erythropoietin. However, the fact that 15% of PPF activity remained in the supernatants treated with anti-IL-6 antibody indicated the presence of another thrombopoietic substance. T-85 is so far the first mesothelioma cell line derived from a case with remarkable thrombocytosis.
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PMID:Establishment and characterization of a new human mesothelioma cell line (T-85) from malignant peritoneal mesothelioma with remarkable thrombocytosis. 887 1

Sclerosing pseudotumorous immune reactions of the retroperitoneum have been shown to consist of HLA-DR-positive spindle-shaped fibroblasts and macrophages that resemble fibroblasts, and in some instances they contain clonal populations of T lymphocytes not found in granulation tissue, keloids, nodular fasciitis, or fibromatoses. In patients who are iatrogenically immunosuppressed, circulating monocytes may be induced in vitro to transform into spindle-shaped macrophages, and secrete collagen after stimulation by conditioning medium from activated T lymphocytes. The authors investigated a series of five inflammatory pseudotumors (IPT) of lymph node origin for identification of spindle-shaped macrophages, T-cell receptor gene rearrangements, and lymphocyte-derived cytokine mRNA production. All cases of IPT demonstrated spindle-shaped macrophages resembling fibroblasts or myofibroblasts characterized by vimentin, CD45 (LCA), CD68 (KP1) or HAM-56, and HLA-DR(LN3) immunoreactivity and demonstrated production of procollagen-alpha1 (I) mRNA by in situ hybridization. Clonal T-cell receptor chain gene rearrangements were undetectable by polymerase chain reaction. Strong specific lymphocyte-derived interleukin-1beta and interleukin-6 mRNA cytokine transcripts were identified. Although all patients with IPT were managed with steroids and nonsteroidal anti-inflammatory medication, some had treatment-refractory disease. Because all-trans retinoic acid has been demonstrated to inhibit the in vitro transformation of monocytes into collagen-producing spindle-shaped macrophages ("neofibroblasts"), it may be of benefit for patients with IPT.
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PMID:Inflammatory pseudotumors of lymph node origin show macrophage- derived spindle cells and lymphocyte-derived cytokine transcripts without evidence of T-cell receptor gene rearrangements. Implications for pathogenesis and classification as an idiopathic retroperitoneal fibrosis-like sclerosing immune reaction. 860 85

Like many other cytokines and growth factors, interleukin-6 (IL-6) activates p21ras. However, the precise biochemical mechanisms inducing this activation are unknown. Therefore, we investigated the effects of IL-6 on some recently identified signaling intermediates, Shc (Src homology and collagen) and Grb2 (growth factor receptor bound protein 2), known to activate p21ras. In the multiple myeloma cell line LP-1, IL-6 stimulated the tyrosine phosphorylation of Shc in a time- and concentration-dependent manner. This led to the complex formulation of Shc with Grb2, an adaptor protein known to relocate a p21ras-GDP exchange factor. Sos1 (Son-of-sevenless), to the cell membrane. Taken together, these findings suggest that IL-6 might activate the Ras signaling pathway via tyrosine phosphorylation of Shc and subsequent recruitment of Grb2. Further studies will elucidate which of the IL-6 receptor associated non-receptor tyrosine kinases of the Src kinase or Janus kinase family, mediate these effects.
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PMID:Interleukin-6 induces tyrosine phosphorylation of the Ras activating protein Shc, and its complex formation with Grb2 in the human multiple myeloma cell line LP-1. 861 7

Osteoblasts and their precursors respond to specific cytokines, growth factors, and hormones. One facet of this response includes the secretion of additional cytokines, some of which are part of the circuitry involved in the regulation of osteoblast and osteoclast function. Therefore, understanding which cytokines are able to activate osteoblastic cells and the consequences of that activation are central to understanding normal and pathologic bone remodeling. Oncostatin M (OSM) is a glycoprotein belonging to a new subfamily of cytokines related by sequence and structural homology and the use of the signal transducing receptor component gp130. Osteoblastic cells secrete and respond to leukemia-inhibiting factor (LIF) both in vitro and in vivo, suggesting that LIF is an autocrine regulatory factor. OSM is closely related to LIF, and therefore we hypothesized that OSM should regulate the function of cells in the osteoblastic lineage. Primary neonatal murine or fetal rat calvarial osteoblastic cultures were treated with OSM or LIF and a series of biochemical and biological parameters were determined. In these cultures, OSM induced proliferation, collagen synthesis, and interleukin-6 secretion, whereas it inhibited alkaline phosphatase activity. Bone resorption was also inhibited by OSM. These data represent the first report of OSM's effects on bone cell function and indicate that, like some other members of the LIF/interleukin-6 subfamily, OSM has potent bone regulatory activity.
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PMID:Oncostatin-M: a new bone active cytokine that activates osteoblasts and inhibits bone resorption. 862 82

Recombinant thrombopoietin has been reported to stimulate megakaryocytopoiesis and thrombopoiesis and it may be quite useful to treat patients with low platelet counts after chemotherapy. As little is known regarding the possible activation of platelets by thrombopoietin, we examined the effects of thrombopoietin on platelet aggregation induced by shear stress and various agonists in native plasma. Using hirudin as an anticoagulant, thrombopoietin (1 to 100 ng/mL) enhanced platelet aggregation induced by 2 micromol/L adenosine-diphosphate (ADP) in a dose dependent fashion. The enhancement was not affected by treatment of platelets with 1 mmol/L aspirin plus SQ-29548 (a thromboxane antagonist, 1 micromol/L) but was inhibited by a soluble form of the thrombopoietin receptor, suggesting that the enhancement was mediated by the specific receptors and does not require thromboxane production. Epinephrine (1 micromol/L), which does not induce platelet aggregation in hirudin platelet rich plasma (PRP), did so in the presence of thrombopoietin (10 ng/mL). Thrombopoietin (10 ng/mL) also enhanced or primed platelet aggregation induced by collagen (0.5 micron.mL),. thrombin, serotonin, and vasopressin. Thrombopoietin does not induce any rise in cytosolic ionized calcium concentration nor activation of protein kinase C, as estimated by phosphorylation of preckstrin, indicating that the priming effects of thrombopoietin does not require those processes. The ADP- or thrombin-induced rise in cytosolic ionized calcium concentration was not enhanced by thrombopoietin (100 ng/mL). Further, shear (ca. 90 dyn/cm2)-induced platelet aggregation was also potentiated by thrombopoietin. The priming effect on epinephrine-induced platelet aggregation in hirudin PRP was unique to thrombopoietin, with no effects seen using interleukin-6 (IL-6), IL-11, IL-3, erythropoietin, granulocyte-colony stimulating factor, granulocyte macrophage-colony stimulating factor, or c-kit ligand. These data indicate that monitoring of platelet functions may be necessary in the clinical trials of thrombopoietin.
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PMID:Thrombopoietin primes human platelet aggregation induced by shear stress and by multiple agonists. 863 35

Interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) are major proinflammatory cytokines inducing the synthesis and release of many inflammatory mediators. They are involved in immune regulation, autoimmune diseases, and inflammation. Acanthoic acid, (-)-pimara-9(11),15-dien-19-oic acid, is a pimaradiene diterpene isolated from the Korean medicinal plant, Acanthopanax koreanum. When human monocytes/macrophages stimulated with silica were treated with 0.1-10 microg/ml acanthoic acid, the production of IL-1 and TNF-alpha was inhibited up to 90%, but the production of interleukin-6 (IL-6) was not inhibited at all. At these concentrations, it had no cytotoxic effect on human monocytes/macrophages. It also suppressed the production of TNF-alpha by alveolar macrophages and lymphocytes stimulated with silica. In addition, acanthoic acid inhibited the release of superoxide anion and hydrogen peroxide from human monocytes/macrophages and neutrophils. To know the antifibrotic effects of acanthoic acid, its effects on fibroblast proliferation and collagen synthesis were tested. The proliferation of NIH3T3 cells was inhibited almost completely by the addition of the culture supernatants of human monocytes/macrophages treated with acanthoic acid, but not by the addition of acanthoic acid only. In vitro and in vivo treatment with acanthoic acid reduced collagen production by rat lung fibroblasts and lung tissue. Furthermore, acanthoic acid suppressed granuloma formation and fibrosis in the experimental silicosis. Acanthoic acid reduced serum GOT and GPT in the rats with cirrhosis induced by CCl4, and it was effective in reducing hepatic fibrosis and nodular formation. Taken together, these data indicate that acanthoic acid has a potent anti-inflammatory and antifibrosis effect by reducing IL-1 and TNF-alpha production.
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PMID:Suppression of interleukin-1 and tumor necrosis factor-alpha production by acanthoic acid, (-)-pimara-9(11),15-dien-19-oic acid, and it antifibrotic effects in vivo. 866 Aug 20


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