Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ciliary neurotrophic factor (CNTF), interleukin-6 (IL-6), leukemia inhibitory factor (LIF), and oncostatin M (OSM) share functional properties, a predicted common helical framework, and partially identical receptor components. CNTF is a survival promoting factor for various types of neurons in vitro and in vivo. In the present study, structural features essential for the biological function of human CNTF were investigated. Several recombinant CNTF variants were constructed by PCR and expressed in E. coli. Their survival promoting activities were determined using cultures of embryonic chick and newborn rat dorsal root ganglion cells. Deletion of 14 N-terminal and 18 C-terminal amino acids significantly increased bioactivity compared to wild-type (wt) CNTF. Further truncation of the CNTF molecule at the N- or C-terminus resulted in a significant reduction or complete loss of activity. Substitution of two amino acids (Lys154Glu and Trp157Pro) abolished the survival promoting effect. Recently described analogous substitutions in IL-6 had resulted in a partial IL-6 receptor antagonist. However, the double substitution variant had no significant inhibitory effect on wtCNTF activity in assays with both wt and mutant factor. The CNTF variants constructed had almost identical effects on both chick and rat neurons indicating a close similarity of the avian and the mammalian CNTF receptor complex. The present results also demonstrate that a core segment of the CNTF molecule is indispensable for biological function. Analogous segments important for activity have already been identified in the related molecules IL-6, LIF, and OSM. Thus, our data confirm the close structural relationship of CNTF to these "neuropoietic" cytokines. In addition, they demonstrate that site-directed mutagenesis of recombinant human CNTF can yield molecules which show increased survival promoting activity on mammalian neurons.
 ...
PMID:Site-directed mutagenesis of human CNTF: functional analysis of recombinant variants. 762 95

Although RA is an inflammatory disease primarily affecting the synovial joints it also has marked systemic consequences. Pro-inflammatory systemically active cytokines are produced within the joint, found in the serum and are capable of inducing the hepatic synthesis of acute-phase proteins. Initially it was believed that the acute-phase response was elicited by the cytokine, interleukin-1 alone. However, it is now clear that there is a complex interaction between the cytokines with interleukin-6 predominant, but also involving interleukin-1, tumour necrosis factor and a group of recently described cytokines including interleukin-11, leukaemia inhibitory factor and oncostatin M all of which influence the levels of acute-phase proteins. In clinical practice CRP is frequently used as a marker of the acute-phase response. It has a short half-life and consequently is a sensitive measure of cytokine-induced protein synthesis. The rate of appearance of bony erosions early in disease correlates with the mean serum concentration of CRP in some studies. It has been suggested that a weak correlation probably reflects the fact that joints in which erosions most frequently occur, namely the small joints of the hand, produce smaller amounts of cytokine than the large joints such as the knee. A recent study examining the rate of spinal trabecular bone loss in the first year of rheumatoid disease found a strong correlation between bone loss and serum CRP concentrations. It appears that CRP concentrations reflect the level of 'systemic osteoclast-activating factor' and are, therefore, a good measure of the general catabolic state of the patient.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:The validity of surrogate markers in rheumatic disease. 768 27

During the host response to inflammation/tissue injury there are many changes in intermediary metabolism including a dramatic change in the concentrations of many "acute phase" plasma proteins. Although many of these acute phase proteins are predominantly derived from the liver and the response can be elicited from liver cells incubated in tissue culture with cytokines such as interleukin-6 (IL-6), interleukin-1 (IL-1), tumor necrosis factor-alpha, interferon-gamma, leukemia inhibitory factor, interleukin-11 (IL-11), and oncostatin M, there is now evidence that the response can also be elicited in extrahepatic tissues and cell types. In this study, we show that many of the acute phase plasma proteins are expressed in human intestinal epithelial cell lines Caco2 and T84 and that their expression is induced or regulated by cytokines IL-6, IL-1, interferon, and tumor necrosis factor in a manner characteristic of the acute phase response. In fact, effects of IL-1 and IL-6 which are additive, synergistic, and antagonistic in liver cell lines are also observed in these intestinal epithelial cell lines. Responses to IL-6 and IL-1 are seen at all stages of differentiation of Caco2 cells from crypt-like enterocytes to villus-like enterocytes. Caco2 cells express binding sites for IL-6 at both poles, for IL-1 at the basolateral pole and, to a lesser extent, at the apical pole. T84 cells have IL-1 and IL-6 receptor binding sites only at the basolateral pole. IL-6 and IL-1 also regulate the expression of enterocyte-specific integral membrane proteins as exemplified by down-regulation of sucrase-isomaltase gene expression in response to IL-6. These data raise the possibility that enterocytes are involved in a local response to injury/inflammation at the epithelial surface and establish a model system for examining coordination of the acute phase response in a bipolar cell.
 ...
PMID:Evidence for an acute phase response in human intestinal epithelial cells. 768 49

Human gp130 (IL6ST) is one of the most widely used chains of the cytokine receptor family. Indeed, it is involved in signal transduction of interleukin-6, interleukin-11, leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor. In a previous report, IL6ST was assigned to chromosomes 5 and 17. Here we specify the chromosomal sublocalization of IL6ST and show that the sequence detected on 17p11 corresponds, in fact, to a nontranscribed pseudogene, whereas the active gene is located at chromosome band 5q11.
 ...
PMID:Human gp130 transducer chain gene (IL6ST) is localized to chromosome band 5q11 and possesses a pseudogene on chromosome band 17p11. 773 92

Ciliary neurotrophic factor (CNTF) has recently been found to share receptor components with, and to be structurally related to, a family of broadly acting cytokines, including interleukin-6, leukemia inhibitory factor, and oncostatin M. However, the CNTF receptor complex also includes a CNTF-specific component known as CNTF receptor alpha (CNTFR alpha). Here we describe the molecular cloning of the human and mouse genes encoding CNTFR. We report that the human and mouse genes have an identical intron-exon structure that correlates well with the domain structure of CNTFR alpha. That is, the signal peptide and the immunoglobulin-like domain are each encoded by single exons, the cytokine receptor-like domain is distributed among 4 exons, and the C-terminal glycosyl phosphatidylinositol recognition domain is encoded by the final coding exon. The position of the introns within the cytokine receptor-like domain corresponds to those found in other members of the cytokine receptor superfamily. Confirming a recent study using radiation hybrids, we have also mapped the human CNTFR gene to chromosome band 9p13 and the mouse gene to a syntenic region of chromosome 4.
 ...
PMID:Genomic organization and chromosomal localization of the human and mouse genes encoding the alpha receptor component for ciliary neurotrophic factor. 777 13

In this report we document the derivation of pluripotential embryonic stem (ES) cells in the absence of a feeder layer by supplementation of culture media with either ciliary neurotrophic factor or oncostatin M, or with a combination of interleukin-6 (IL-6) plus soluble interleukin-6 receptor (sIL-6R). These factors all activate gp130-associated signaling processes, as does the previously characterized ES cell maintenance factor Differentiation Inhibiting Activity (Leukemia Inhibitory Factor). In particular, the IL-6/sIL-6R complex is thought to act exclusively through gp130. All ES cell lines derived using IL-6/sIL-6R contributed extensively to chimeras and were transmitted through the germline at high frequency. These findings point to a pivotal role for gp130 in ES cell propagation and may be relevant to attempts to derive ES cells from species other than mouse.
 ...
PMID:Derivation of germline competent embryonic stem cells with a combination of interleukin-6 and soluble interleukin-6 receptor. 795 76

The development of clinically frank malignant melanomas in humans is thought to evolve over decades in a stepwise process of progression. By analogy with certain other adult cancers, eg, colorectal carcinomas, alterations in expression or function of a number of different suppressor genes might be expected to be involved in this process. This could lead to loss of expression of a number of different negative growth controls. Evidence is reviewed implicating the presence of putative suppressor genes for the melanocytic lineage located on chromosomes 9p21, 6q, and 1p. In addition, there is evidence suggesting a contribution for the p53 and NF1 tumor-suppressor genes, and the nm23 metastasis-suppressor gene, in melanoma development or progression. Additional possible suppressor genes include those encoding manganese superoxide dismutase, and possibly c-kit. An accumulation of such alterations may be responsible for the progressive loss of responsiveness to several independent growth inhibitors for melanocytes or early stage melanomas, including interleukin-6, transforming growth factor-beta, and oncostatin M. They may also be responsible for some aspects of the production of direct acting autocrine growth factors or production of angiogenesis stimulating factors, or both, by melanoma cells. The acquisition of resistance to several growth inhibitors and the multiplicity of putative suppressor gene alterations (combined with the production of multiple autocrine and paracrine growth factors) may be necessary for the evolution of nondividing single melanocytes resident in the epidermis into highly proliferative and metastatic melanomas capable of growing multicellularly in ectopic organ sites.
 ...
PMID:Cytokines, growth factors and the loss of negative growth controls in the progression of human cutaneous malignant melanoma. 801 99

Human interleukin-11 (IL-11) is a cytokine with a broad spectrum of activity, similar to interleukin-6 (IL-6). However, its role in human disease is poorly understood, partly because of a lack of sensitive bioassays. A subclone (B9-11) obtained from the B9 hybridoma (which responds poorly to human IL-11) enabled us to develop a highly sensitive bioassay for human IL-11. B9-11 cells responded only to human IL-11 and IL-6 and not to other human cytokines using the same gp130 transducer chain (ciliary neurotrophic factor, leukemia inhibitory factor and oncostatin M) or to other human interleukins (interleukin-1 to interleukin-13), human hematopoietic cytokines (granulocyte colony stimulating factor, granulocyte-macrophage colony stimulating factor, colony stimulating factor-1) and various other human cytokines (interferon-alpha, tumor necrosis factor-alpha, tumor necrosis factor-beta, fibroblast growth factor and nerve growth factor). In addition, these cytokines did not interfere with the IL-11 response of B9-11 cells. IL-11-induced proliferation of B9-11 cells was unaffected by anti-murine IL-6 receptor mAb but inhibited by anti-gp130 mAb. Half-maximal proliferation of B9-11 cells was obtained with 30 pg/ml of recombinant IL-11, a concentration 300-fold lower than IL-11 concentrations known to be active on human cells. Finally, culturing of B9-11 cells with an anti-IL-6 mAb enabled us to measure the natural IL-11 produced by various cell lines. Thus, B9-11 cells should be useful for studies of IL-11 involvement in various human diseases as well as for a better understanding of the mechanisms of action of this cytokine.
 ...
PMID:A highly sensitive quantitative bioassay for human interleukin-11. 803 82

Leukemia inhibitory factor (LIF) is structurally related to interleukin-6 (IL-6), oncostatin M (OSM), and ciliary neurotrophic factor (CNTF). Since LIF-deficient mice do not exhibit overt phenotypic effects in cell types known to be targets for LIF action in vitro, we examined the ability of IL-6, OSM, and CNTF to reproduce the effects of LIF in five different bioassays. OSM, CNTF, and LIF are able to promote embryonic stem cell growth and to maintain them in an undifferentiated state as marked by a high alkaline phosphatase activity (ED50 are, respectively, 0.5, 3 and 1 ng/ml). Whereas LIF and OSM maintain close to 100% of ES cells in an undifferentiated state, CNTF, at optimal concentrations, prevents differentiation of only 60% of the ES population. Murine 7TD1 hybridoma cell growth is induced only in the presence of IL-6 (ED50 = 0.1 ng/ml). Both LIF and OSM stimulate DA1a cell proliferation (ED50 are, respectively, 1 and 12 ng/ml). OSM appears, therefore, to act as a weak agonist of LIF-dependent processes on murine cells, however, with a 10-fold lower specific activity than that of LIF, which is in agreement with human OSM cross-reacting with the murine LIF-R. Though IL-6, LIF, and OSM all stimulate haptoglobin and fibrinogen production by human HepG2 hepatoma cells, the dose-response curves of these three factors exhibit very different characteristics. CNTF stimulates acute-phase protein production by HepG2 cells only at high concentrations (greater than 1 microgram/ml). A549 epithelial cells are subjected to growth inhibition only in the presence of OSM (ED50 = 6 ng/ml), even though they expressed LIF-R and gp130 transcripts. These data suggest that OSM and LIF act on human cells through different receptors. Altogether, these results indicate that none of the factors examined in this study are precisely interchangeable in terms of their biological actions.
 ...
PMID:Are LIF and related cytokines functionally equivalent? 805 Apr 91

Interleukin-6 (IL-6) was found to be a pleiotropic cytokine which plays important roles not only in immune response but also in inflammation and hematopoiesis since the cDNA for IL-6 was originally cloned as a B cell differentiation factor (BCDF). IL-11, leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor have similar effects with IL-6. This functional redundancy was well explained by the common signal transducer gp 130. Furthermore, recent studies have revealed the mechanisms to regulate the gene expression of IL-6 and to transduce the signal through IL-6 receptor system. On the basis of these results, elucidation of pathogenic significances of IL-6 and new therapeutic approaches in various diseases are now expected.
 ...
PMID:[Interleukin-6]. 806 Jan 52


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>