UNIPROT:P05231 - FACTA Search

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Query: UNIPROT:P05231 (interleukin-6)
23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A panel of cytokines was tested for inhibitors of interleukin-6 (IL-6)-dependent cell proliferation. Murine type I and II interferons (mIFNs) strongly inhibited proliferation of IL-6-dependent B9 and 7TD1 cells in a dose-dependent manner. Human tumor necrosis factor-alpha (hTNF-alpha) and human transforming growth factor-beta (hTGF-beta) potently inhibited B9 and to a lesser extent 7TD1 cells, while hIL-11, human oncostatin M (hOSM), and human leukemia inhibitory factor (hLIF) had no inhibitory effects on IL-6-dependent growth. Conversely, IL-11 and OSM but not LIF stimulated B9 and 7TD1 cell growth. However, compared with IL-6, up to 1000-fold higher IL-11 and OSM concentrations were required to induce maximal cell proliferation. Increasing concentrations of IL-6 (up to 100 ng/ml) could not overcome the antiproliferative effects of mIFNs, hTNF-alpha and hTGF-beta. Supernatants from mIFN-gamma and lipopolysaccharide (LPS)-treated mouse macrophages (ANA-1 cell line) were tested in B9 cell assays to identify cytokines among stimulatory and inhibitory biological activities that can inhibit IL-6-dependent proliferation. Undiluted or relatively concentrated supernatants from ANA-1 macrophages treated with mIFN-gamma and/or LPS did not contain detectable IL-6 bioactivity. However, diluted samples contained considerable amounts of detectable IL-6 bioactivity (nanogram levels). Testing the same samples for IL-6 immunoreactivity using enzyme-linked immunoabsorbent assay revealed comparable levels of mIL-6. We conclude that IFNs, TNF-alpha, and TGF-beta and possibly other factors are potent, dominant inhibitors of IL-6-dependent plasmacytoma/hybridoma growth in vitro.
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PMID:Multiple cytokines inhibit interleukin-6-dependent murine hybridoma/plasmacytoma proliferation. 859 34

Bone marrow stem cells reside in close proximity to endosteal osteoblasts. To explore the potential role of osteoblasts in hematopoietic differentiation, we measured the mRNA accumulation, protein production, and secretion of hematopoietic growth factors by the nonmineralizing MG-63 and the mineralizing SaOS-2 human osteosarcoma cell lines. mRNA for the osteoblast-specific protein osteocalcin was well as granulocyte colony-stimulating factor (G-CSF), transforming growth factor-beta 1 (TGF-beta 1), and tumor necrosis factor-alpha (TNF-alpha) was produced by the MG-63 and SaOS-2 cells, like primary human cells, in the presence and absence of L-ascorbate and beta-glycerol phosphate. In contrast, both cell lines expressed c-kit ligand mRNA only in the absence of L-ascorbate and beta-glycerol phosphate induction. Granulocyte-macrophage (GM)-CSF and interleukin-6 (IL-6) mRNA appeared to develop with increasing culture age. G-CSF protein was identified in several cell-associated forms including the 28- and 32-kD species, In addition, GM-CSF was found in cell-associated form. These results suggest that osteoblasts might play a central role in the hematopoietic microenvironment as basal producers of G-CSF and GM-CSF and suggest the possibility that osteoblasts may locally present these proteins in an membrane-associated fashion
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PMID:Human osteosarcoma cell lines MG-63 and SaOS-2 produce G-CSF and GM-CSF: identification and partial characterization of cell-associated isoforms. 860

We examined the massive early cell death that occurs in the ventral horn of the cervical spinal cord of the chick embryo between embryonic days 4 and 5 (E4 and E5). Studies with immunohistochemical, in situ hybridization, and retrograde-tracing methods revealed that many dying cells express Islet proteins and Lim-3 mRNA (motoneuron markers) and send their axons to the somatic region of the embryo before cell death. Together, these data strongly suggest that the dying cells are somatic motoneurons. Cervical motoneurons die by apoptosis and can be rescued by treatment with cycloheximide and actinomycin D. Counts by motoneuron numbers between E3.5 and E10 revealed that, in addition to cell death between E4 and E5, motoneuron death also occur between E6 and E10 in the cervical cord. Studies with [3H]thymidine autoradiography and morphological techniques revealed that in the early cell-death phase (E4-E5), genesis of motoneurons, axonal elongation, and innervation of muscles is still ongoing. However, studies with [3H]thymidine autoradiography also revealed that the cells dying between E4 and E5 become postmitotic before E3.5. Increased size of peripheral targets, treatment with neuromuscular blockade, and treatment with partially purified muscle or brain extracts and defined neurotropic agents, such as NGF, BDNF, neurotrophin-3, CNTF, bFGF, PDGF, S100-beta, activin, cholinergic differentiation factor/leukemia inhibitory factor, bone morphogenetic protein-2, IGF-I, interleukin-6, and TGF-beta 1, were all ineffective in rescuing motoneurons dying between E4 and E5. By contrast, motoneurons that undergo programmed cell death at later stages (E6-E10) in the cervical cord are target-dependent and respond to activity blockade and trophic factors. Experimental approaches revealed that early cell death also occurs in a notochord-induced ectopic supernumerary motoneuron column in the cervical cord. Transplantation of the cervical neural tube to other segmental regions failed to alter the early death of motoneurons, whereas transplantation of other segments to the cervical region failed to induce early motoneuron death. These results suggest that the mechanisms that regulate motoneuron death in the cervical spinal cord between E4 and E5 are independent of interactions with targets. Rather, this novel type of cell death seems to be determined by signals that either are cell-autonomous or are derived from other cells within the cervical neural tube.
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PMID:A novel type of programmed neuronal death in the cervical spinal cord of the chick embryo. 864 12

Directed migration of lymphocytes from blood into lymph nodes and organ-associated lymphatic tissue, also referred to as homing, is initiated by T-cell adhesion to specialized high endothelial cells of postcapillary vessels. Here, we demonstrate that selective signal transduction pathways specifically modulate the expression of the cutaneous lymphocyte antigen (CLA), the putative skin-homing receptor, during naive to memory transition of CD4+ T cells in vitro. The results show that the expression of CLA is strongly induced by activation via CD2 [T11.1 + T11.2 monoclonal antibodies (mAb)]. Addition of transforming growth factor-beta 1 (TGF-beta 1), interleukin-6 (IL-6), and, to a lesser extent, IL-2 further enhanced the generation of CLA+ T cells, whereas the induction of this antigen was markedly inhibited by IL-4. Periodic restimulation via CD2 and long-term culture of activated cells in the presence of IL-2 and TGF-beta 1 resulted in stable expression of CLA during a culture period of more than 100 days. In contrast, activation of naive CD4+ T cells via CD3, CD28 or by mitogens induced a rapid naive to memory phenotype transition but a much lower percentage of CLA+ T cells showing only weak expression of the antigen. Furthermore, activation of purified CD4+ memory T cells by CD2 strongly induced expression of activation-related antigens CD25 and HLA-DR, but failed to up-regulate CLA expression. Our results show that primary stimulation conditions highly modulate the development of skin-associated T cells and indicate a new functional role for costimulatory adhesion pathways in regulating the expression of molecules associated with T-cell homing.
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PMID:CD2-mediated stimulation of the naive CD4+ T-cell subset promotes the development of skin-associated cutaneous lymphocyte antigen-positive memory cells. 869 Apr 52

Many osteoblastic cell lines are currently in use, but these have limitations either in terms of their relevance to adult human biology and disease or in terms of their suitability for biochemical and molecular analyses. Consequently, we undertook the development of conditionally transformed adult human osteoblastic cell lines. Osteoblasts were obtained from a normal explant cancellous bone chip culture. These cells were infected with adenovirus-ori-SV40 tsA 209, which encodes a temperature-sensitive large T-antigen mutant. Cells immortalized with this virus express a transformed phenotype at the permissive temperature of 34 degrees C but revert to a normal phenotype at the nonpermissive temperature of 40 degrees C. Using this approach, we have isolated several cell clones and describe the characterization of one that was designated HOB-02-C1. Immunocytochemistry revealed that > 95% of the cells express the large T-antigen at both temperatures. These cells exponentially proliferate at 34 degrees C with a doubling time of approximately 2 days but irreversibly stop dividing at 40 degrees C. However, cell volume increases > 2-fold when the cells are maintained for 6 days at the higher temperature. This clone expresses alpha 1 type (I) procollagen mRNA and secretes type I procollagen C-peptide at both temperatures, although the levels were slightly elevated at 40 degrees C. The cell line expresses alkaline phosphatase activity at 34 degrees C, and the basal level of this enzyme increases 2- to 6-fold at 40 degrees C. Alkaline phosphatase activity is induced 4- to 8-fold by 1 alpha,25-dihydroxyvitamin D3 (vitamin D3) at both temperatures, but transforming growth factor-beta 1 (TGF-beta 1) suppresses enzyme expression > 90% at 40 degrees C. Vitamin D3 also induces a 10-fold increase in osteocalcin secretion when the clone is maintained at 34 degrees C, and this induction is enhanced > 8-fold at 40 degrees C. Parathyroid hormone and forskolin stimulate a 4- to 6-fold increase in the production of intracellular cyclic AMP (cAMP) by the cells at 34 degrees C, and this stimulation is enhanced 2- to 4-fold at 40 degrees C. In contrast, prostaglandin E2 stimulates a 7- to 8-fold increase in cAMP only when the cells are maintained at 34 degrees C. This cell line secretes TGF-beta 1 and interleukin-6 (IL-6) at 34 degrees C, but only the basal secretion of IL-6 increases 70% at 40 degrees C. Finally, alizarin red-S histochemical staining demonstrates that these cells produce mineralized nodules at both temperatures. In summary, the results of this study indicate that the HOB-02-C1 cells have a mature osteoblastic phenotype. Consequently, this new cell line and others obtained in a similar fashion should be valuable in vitro tools for cellular, biochemical, and molecular studies of adult human osteoblast biology.
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PMID:Development and characterization of a conditionally transformed adult human osteoblastic cell line. 872 78

The expression of insulin-like growth factor-I (IGF-I), interleukin-6 (IL-6), and transforming growth factor-beta 1 (TGF-beta 1) mRNA in rat femurs was examined following marrow ablation. Northern blot analysis showed multiple transcripts of IGF-I, a major transcript of 1.3 kb and a minor one of 2.4 kb for IL-6 and a single band of 2.5 kb for TGF-beta 1, respectively. Examination of the temporal activation pattern showed IGF-I expression peaked at day 3 (150% over the basal level) after injury and preceded the maximal expression of procollagen alpha 1(I), osteopontin, alkaline phosphatase, and osteocalcin mRNAs. This suggests that IGF-I is involved mainly in osteoblast development and bone formation. In contrast, IL-6 expression was elevated between days 3 and 9 (45-60% over the basal level). The sustained elevation of IL-6 expression at day 9 is consistent with the role for this cytokine in the development of osteoclasts and bone resorption. The expression of TGF-beta 1 was not altered up to day 9 after marrow ablation. While the temporal expression patterns of IGF-I and IL-6 mRNA did not differ between adult and old rats, the maximal level of IGF-I mRNA at day 3 was 72% higher in adult as compared to old bones. In contrast, the peak level of IL-6 mRNA at days 6-9 was 45% higher in old as compared to adult bones. Although the level of TGF-beta 1 mRNA did not change following marrow ablation, levels of TGF-beta 1 were consistently higher in old rats. Our results suggest that the impaired bone formation and elevated bone resorption in aged animals may be due in part to the reduced expression of IGF-I and an overexpression of IL-6 in old bone.
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PMID:Effect of age on the expression of insulin-like growth factor-I, interleukin-6, and transforming growth factor-beta mRNAs in rat femurs following marrow ablation. 873 6

A variety of cytokines are found in the intestinal mucosa of individuals with inflammatory diseases. The potential role of cytokines in mediating lipoprotein assembly and secretion in the human intestinal cell line, Caco-2, was investigated. Interleukin-1 beta, interleukin-6 (IL-6), and tumor necrosis factor-alpha all decreased the basolateral secretion of apolipoprotein B (apo B), with IL-6 being the most potent. IL-6 was also found to inhibit triacylglycerol secretion. In contrast, transforming growth factor-beta 1 (TGF-beta 1) increased the secretion of apo B and triacylglycerol. In pulse-chase experiments, IL-6 decreased the rate of synthesis and secretion of apo B-100 and apo B-48 without altering the rate of apo B degradation, whereas TGF-beta 1 increased the rate of synthesis and secretion of apo B-100 and apo B-48. Degradation of apo B was also not affected by TGF-beta 1. The abundance of apo B mRNA in cells incubated with IL-6 was decreased, whereas cells incubated with TGF-beta 1 had higher levels of apo B mRNA. In conditions of small intestinal inflammation, cytokines could contribute to the observed malabsorption of fat and other nutrients by the small intestine.
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PMID:Cytokines regulate apolipoprotein B secretion by Caco-2 cells: differential effects of IL-6 and TGF-beta 1. 877 6

Chronic lung disease of prematurity (CLD) is a common respiratory disorder of preterm infants. At autopsy, fibroblast proliferation, and components of the extracellular matrix, including collagen and fibronectin, are markedly increased in the lungs of infants who die from CLD. Examination of broncho-alveolar fluid suggests that the persistence of neutrophils is associated with the development of CLD. In our studies, the pro-inflammatory cytokines, interleukin-1 beta (IL-1 beta) and interleukin-6, (IL-6) and mediators which reflect neutrophil recruitment and activation, including soluble intercellular adhesion molecule, interleukin-8 (IL-8) and neutrophil elastase, were increased in lavage fluid obtained from infants who developed CLD when compared to infants who did not. Furthermore, semiquantitative reverse transcriptase-polymerase chain reaction of mRNA extracted from lavage cells suggested that luminal cells may be the source of IL-6 detected in lavage fluid but non-luminal cells may be the sources of IL-1 beta and IL-8. Fibrosis is thought to be mediated by the pro-fibrotic cytokines including transforming growth factor-beta1 (TGF-beta 1). Both active and total TGF-beta 1 were increased in lavage fluid from infants who developed CLD. Furthermore, both type I procollagen and TGF-beta were increased qualitatively in lung tissue obtained at autopsy from infants who died from respiratory failure. The increase in inflammatory mediators was maximal at 10 days of age. By contrast, the increase in TGF-beta 1 was maximal at 4 days of age. This suggests that the interaction between inflammation and fibrosis in CLD is complex, and that prenatal factors may be important in the pathogenesis of CLD.
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PMID:Cytokines in chronic lung disease of prematurity. 883 40

The introduction of molecular therapy through the delivery of nucleic acids either as oligonucleotides or genetic constructs holds enormous promise for the treatment of renal disease. Significant barriers remain, however, before successful organ-specific molecular therapy can be applied to the kidney. These include the development of methods to target the kidney selectively, the definition of vectors that transduce renal tissue, the identification of appropriate molecular targets, the development of constructs that are regulated and expressed for long periods of time, the demonstration of efficacy in vivo, and the demonstration of safety in humans. As the genetic and pathophysiologic basis of renal disease is clarified, obvious targets for therapy will be defined, for example, polycystin in polycystic kidney disease, human immunodeficiency virus (HIV) type 1 in HIV-associated nephropathy, alpha-galactosidase A in Fabry's disease, insulin in diabetic nephropathy, and the "minor" collagen IV chains in Alport's syndrome. In addition, several potential mediators of progressive renal disease may be amenable to molecular therapeutic strategies, such as interleukin-6, basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and transforming growth factor-beta(TGF-beta). To test the in vivo efficacy of molecular therapy, appropriate animal models for these disease states must be developed, an area that has received too little attention. For the successful delivery of genetic constructs to the kidney, both viral and nonviral vector systems will be required. The kidney has a major advantage over other solid organs since it is accessible by many routes, including intrarenal artery infusion, retrograde delivery through the uroexcretory pathways, and ex vivo during transplantation. To further restrict expression to the kidney, tropic vectors and tissue-specific promoters also must be developed. For the purpose of inhibition of endogenous or exogenous genes, current therapeutic modalities include the delivery of antisense oligodeoxynucleotides or ribozymes. For these approaches to succeed, we must gain a much better understanding of the nature of their transport into the kidney, requirements for specificity, and in vivo mechanisms of action. The danger of a rush to clinical application is that superficial approaches to these issues will likely fail and enthusiasm will be lost for an area that should be one of the most exciting developments in therapeutics in the next decade.
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PMID:Molecular therapy for renal diseases. 884 Sep 36

Human keratinocyte growth factor (KGF) is a recently identified mitogen for epithelial cells produced by normal stromal fibroblasts. KGF has been shown to stimulate keratinocyte migration and promote re-epithelialization of skin suggesting a critical role for KGF in wound healing. To understand how KGF might be regulated during wound healing, we examined the ability of the pro-inflammatory cytokines interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta) interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) transforming growth factor-beta 1 (TGF-beta 1) and interferon-gamma (IFN-gamma) to modulate KGF gene expression in cultured human fibroblasts, using northern blot analysis. Exposure to IL-1 alpha (20 units/ml) or IL-1 beta (100 units/ml) for 24 h increased KGF mRNA expression by 352% and 504%, respectively, with early induction seen at 2 h and maximal induction seen at 8 h. TNF-alpha (30 ng/ml) increased KGF mRNA expression by 535% at 24 h, with induction first seen at 8 h. The maximal induction of KGF mRNA was observed when IL-1 alpha, IL-1 beta and TNF-alpha were used at 100 units/ml, and 3 ng/ml, respectively, although concentrations 100-500-fold lower (IL-1 alpha, 0.02 units/ml; IL-beta, 0.02 units/ml; and TNF-alpha, 0.03 ng/ml) were nearly as stimulatory, increasing KGF mRNA expression by 175%, 254% and 322%, respectively. IL-6 (200 units/ml), TGF-beta 1 (5 ng/ml) and IFN-gamma (200 units/ml) did not change the level of KGF mRNA at 24 h in human fibroblasts under the same conditions. The protein synthesis inhibitor cycloheximide abrogated the effects of IL-1 alpha, IL-1 beta and TNF-alpha on KGF gene induction, indicating that new protein synthesis is required in the process. Dexamethasone (10(-7) M), known to inhibit inflammatory reactions and retard wound healing, also inhibited the induction of KGF mRNA expression by IL-1 alpha, IL-1 beta and TNF-alpha. Individual variation in KGF mRNA expression was see when fibroblasts from different aged donors were analysed, but no consistent age-associated change was observed. These results suggest that IL-1 alpha, IL-1 beta and TNF-alpha up-regulate KGF gene expression in fibroblasts and might be responsible for its induction following skin wounding or other injury.
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PMID:Regulation of keratinocyte growth factor gene expression in human skin fibroblasts. 886 66

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