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)

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

Interleukin-6 (IL-6) levels are markedly increased in the synovial fluid of patients with rheumatoid arthritis or osteoarthritis. However, the effects of IL-6 on proliferation and proteoglycan metabolism in articular cartilage are not known. We demonstrated here the effects of human recombinant (hr) IL-6 on proliferation and proteoglycan metabolism in rabbit articular chondrocyte cultures. In vitro, these cells proliferated and produced abundant extracellular matrices. We found that 1-10 ng/ml of hrIL-6 inhibited proliferation to approximately 65% of control levels and suppressed colony formation induced by bFGF in soft agarose. The same concentration of hrIL-6 depressed proteoglycan synthesis to approximately 60% of control levels. Moreover, hrIL-6 significantly enhanced proteoglycan degradation induced by hrIL-1beta, although hrIL-6 alone did not affect proteoglycan degradation. These findings suggest that IL-6 is a negative regulator for chondrocyte proliferation and articular cartilage metabolism.
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PMID:Effects of interleukin-6 on proliferation and proteoglycan metabolism in articular chondrocyte cultures. 1045 31

Serum samples drawn at diagnosis from 174 myeloma patients were analyzed for the presence of the heparan [corrected] sulfate proteoglycan, syndecan-1. Syndecan-1 was elevated in 79% of patients (median, 643 units/mL) compared with 40 healthy controls (median, 128 units/mL), P <.0001. Serum syndecan-1 correlated with the following: serum creatinine, secretion of urine M-component over the course of 24 hours, soluble interleukin-6 (IL-6) receptor, C-terminal telopeptide of type I collagen, beta(2)-microglobulin, percentage of plasma cells in the bone marrow, disease stage, and serum M-component concentration. In order to evaluate syndecan-1 as a prognostic marker in multiple myeloma, it was entered into a multivariate Cox regression model. Data from 138 patients were available for this analysis. As a continuous variable, syndecan-1 was an independent prognostic parameter in addition to serum beta(2)-microglobulin and World Health Organization performance status. When syndecan-1 was dichotomized by the best cutoff (66th percentile, 1170 units/mL), the survival difference between the groups was highly significant: "high" syndecan-1 group had a median survival of 20 months, and the "low" syndecan-1 group had a median of 44 months (P <.0001). We conclude that syndecan-1 is a new independent prognostic parameter in multiple myeloma, and its role in prognostic classification systems should be further investigated. (Blood. 2000;95:388-392)
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PMID:Serum syndecan-1: a new independent prognostic marker in multiple myeloma. 1062 39

Elevated concentrations of interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) in the synovial fluids and serum of patients with arthritis have been implicated in the joint tissue destruction associated with these conditions, however studies conducted to date on the role and effects of IL-6 in the process of cartilage proteoglycan (aggrecan) catabolism are disparate. In the present study, bovine articular cartilage explants were maintained in a model organ culture system in the presence or absence of IL-1alpha or TNF-alpha, and under co-stimulation with or without IL-6 and/or sIL-6R. After measuring proteoglycan loss from the explants, the proteolytic activity and expression profiles of aggrecanase(s) was assessed for each culture condition. Stimulation of cartilage explants with IL-6 and/or sIL-6R potentiated aggrecan catabolism and release above that seen in the presence of IL-1alpha or TNF-alpha alone. This catabolism was associated with aggrecanase (but not MMP) activity, with correlative mRNA expression for aggrecanase-2.
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PMID:IL-6 and its soluble receptor augment aggrecanase-mediated proteoglycan catabolism in articular cartilage. 1106 9

Immunization of BALB/c mice with a select group of cartilage proteoglycans induces progressive polyarthritis. The pathological mechanisms of proteoglycan-induced arthritis are based on autoimmune reactions developed against the mouse self-proteoglycan. This autoimmune inflammatory animal model, which shows many similarities to human rheumatoid arthritis, has close to 100% incidence in susceptible BALB/c mice and is an excellent in vivo model for testing disease-modifying agents. The aim of this work was to study the regulatory mechanisms which control the autoimmune reactions in proteoglycan-induced arthritis, in association with the release of most important cytokines/mediators (interleukin 1 (IL-1), interleukin-2 [IL-2], interleukin-6 [IL-6], tumor necrosis factor-alpha [TNF-alpha], and prostaglandin E(2)) which are believed to play key roles in inflammatory events and cartilage degredation. We have found relatively high levels of IL-1 sera and synovial-cell culture supernatants of arthritic animals, whereas IL-1 was not detected in nonarthritic control animals. Serum autoantibody and IL-1 levels seemed to be sensitive indicators of the oncoming inflammatory events in the joints, whereas autoreactive T-cell responses to mouse proteoglycan became evident only after the onset of arthritis. As proteoglycan-specific T-cell responses were mainly restricted to the joint-draining lymph nodes during the arthritic process, it is likely that the autoantigen-driven mechanism of joint inflammation became local and self-sustaining during cartilage degradation. Thus, autoimmune mechanisms seem to be essential in the "organ specificity" of inflammatory reactions, as "arthritogenic" lymphocytes migrate to and accumulate in both the lymphoid organs and the synovium. IL-1 and IL-2 are among the most important mediators in proteoglycan-induced arthritis and are able to influence autoimmune reactions and the migration of lymphocytes to the synovium.
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PMID:Immunoregulation of Proteoglycan-Induced Arthritis in Balb/c Mice. 1185 96

It has been demonstrated previously that interleukin-1 (IL-1) induces articular cartilage explants and chondrocytes in culture to produce elevated levels of inflammatory mediators such as interleukin-6 (IL-6) and prostaglandins. Previous studies have also demonstrated a relationship between IL-6 secretion and the ability of IL-1 to modulate proteoglycan synthesis by chondrocytes. In this study we have utilized an alginate culture system in an effort to investigate a role for eicosanoids in IL-1 induction of IL-6 expression in human articular chondrocytes. IL-1 treatment of chondrocytes cultured in alginate resulted in increased synthesis of IL-6 and prostaglandins, but not leukotrienes. Cyclo-oxygenase inhibitor, indomethacin (5 &mgr;g ml(minus sign1)), was able to inhibit prostaglandin synthesis to below basal levels with no significant effect on the levels of IL-6 released by chondrocytes in response to IL-1. When chondrocytes were treated with 5 &mgr;g ml(minus sign1) indomethacin and 10 &mgr;M of the general lipoxygenase inhibitor, nordihydroguiaretic acid (NDGA), an approximate 50% decrease in IL-1-induced IL-6 expression was observed. Alone, levels of NDGA specific for lipoxygenase inhibition (10 &mgr;M) did not affect IL-1-induced IL-6 expression, but higher levels of NDGA (50 &mgr;M) which inhibited both prostaglandin and leukotriene biosynthesis reduced IL-1-induced IL-6 expression to the same extent as that observed with 5 &mgr;g ml(minus sign1) indomethacin and 10 &mgr;M NDGA. This inhibition of IL-6 expression by NDGA and indomethacin was dose responsive and also reversible with the addition of exogenous prostaglandin E(2) (PGE(2)) or leukotriene B(4) (LTB(4)). Although IL-1-induced IL-6 expression was only affected when both prostaglandin and leukotriene biosynthesis were inhibited, elevated levels of PGE(2) but not leukotriene B(4), C(4), D(4), or E(4) were observed in the culture medium of IL-1-treated chondrocytes. These findings may indicate that cyclo-oxygenase products such as PGE(2) normally contribute to IL-1 induction of IL-6 expression in chondrocytes, and under conditions when cyclo-oxygenase is inhibited, lipoxygenase products alternatively contribute to this response.
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PMID:Evidence of an Eicosanoid Contribution to IL-1 Induction of IL-6 in Human Articular Chondrocytes. 1185 79

Genistein, a soybean isoflavone, has estrogen-like activity in mammals, including the prevention of bone loss. However, whether its mechanism of action on bone turnover is distinct from that of estrogen or raloxifene is unknown. Although genistein has been reported to bind both estrogen receptor (ER) isoforms (alpha and beta), little is known concerning differential activation of gene expression via these ER isoforms. To examine this question, comparison of the responses of normal fetal osteoblast (hFOB) cells stably expressing either ERalpha (hFOB/ERalpha9) or ERbeta (hFOB/ERbeta6), to treatment with genistein, 17beta-estradiol (E(2)) or raloxifene were conducted. In hFOB/ERalpha9 cells, both genistein and E(2) increased the endogenous gene expression of the progesterone receptor (PR), the proteoglycan versican, and alkaline phosphatase (AP), but inhibited osteopontin (OP) gene expression and interleukin-6 (IL-6) protein levels. Raloxifene had no effect on these bone markers. Genistein, but not raloxifene, also mimicked E(2) action in the hFOB/ERbeta6 cells increasing PR gene expression and inhibiting IL-6 production. To determine whether the gene regulatory actions of genistein in human osteoblast cells occur at the level of transcription, its action on the transcriptional activity of a PR-A promoter-reporter construct was assessed. Both genistein and E(2) were found to stimulate the PR promoter in the hFOB cell line when transiently co-transfected with either ERalpha or ERbeta. Whereas hFOB cell proliferation was unaffected by E(2), raloxifene or genistein at low concentrations, higher concentrations of genistein, displayed significant inhibition. Together, these findings demonstrate that genistein behaves as a weak E(2) agonist in osteoblasts and can utilize both ERalpha and ERbeta.
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PMID:Phytoestrogen genistein acts as an estrogen agonist on human osteoblastic cells through estrogen receptors alpha and beta. 1276 96

The underlying mechanisms responsible for both cartilage loss and subchondral bone changes in osteoarthritis (OA) remain unknown. It is becoming recognized that the extracellular matrix influences the metabolism of cells both in vivo and in vitro and can modify their responses to external stimuli. Indeed, the glycosaminoglycan/proteoglycan matrix is of major importance for the proliferation and/or differentiation of a number of cells. Here, we determined the potential role of hyaluronic acid (HA) of increasing molecular weight (MW) to alter the expression of metabolic markers and cytokine production by human osteoarthritic (OA) subchondral osteoblasts (Ob). Both 1,25(OH)(2)D(3)-induced alkaline phosphatase activity (ALPase) and osteocalcin release were increased in OA Ob when compared to normal. HA reduced osteocalcin release in OA Ob at MW of 300 and above, whereas HA failed to significantly modify ALPase. Parathyroid hormone (PTH) stimulated cyclic AMP (cAMP) formation by OA Ob. HA had a biphasic effect on this PTH-dependent activity, totally inhibiting cAMP formation at MW of 300 and 800. HA of increasing MW progressively reduced the levels of Prostaglandin E(2) (PGE(2)) and interleukin-6 (IL-6) produced by OA Ob. Interestingly, urokinase plasminogen activator (uPA) and and PA inhibitor-1 (PAI-1) levels were not significantly affected by HA of increasing MW; however, the PAI-1 to uPA ratio showed a slight, yet nonsignificant increase. Surprisingly, uPA activity was increased in OA Ob under the same conditions. Last, HA had no effect on the production of insulin-like growth factor-1 by these cells. Our data suggest that high MW HA can modify cellular parameters in OA Ob that are increased when compared to normal. The effect of HA on inflammatory mediators, such as PGE(2) and IL-6, and on uPA activity is more striking at higher MW as well. Taken together, these results could suggest that HA of increasing MW has positive effects on OA Ob by modifying their biological synthetic capacities.
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PMID:Hyaluronic acid reverses the abnormal synthetic activity of human osteoarthritic subchondral bone osteoblasts. 1455 76

We previously found that some myeloma cell lines express the heparin-binding epidermal growth factor-like growth factor (HB-EGF) gene. As the proteoglycan syndecan-1 is an HB-EGF coreceptor as well as a hallmark of plasma cell differentiation and a marker of myeloma cells, we studied the role of HB-EGF on myeloma cell growth. The HB-EGF gene was expressed by bone marrow mononuclear cells in 8 of 8 patients with myeloma, particularly by monocytes and stromal cells, but not by purified primary myeloma cells. Six of 9 myeloma cell lines and 9 of 9 purified primary myeloma cells expressed ErbB1 or ErbB4 genes coding for HB-EGF receptor. In the presence of a low interleukin-6 (IL-6) concentration, HB-EGF stimulated the proliferation of the 6 ErbB1+ or ErbB4+ cell lines, through the phosphatidylinositol 3-kinase/AKT (PI-3K/AKT) pathway. A pan-ErbB inhibitor blocked the myeloma cell growth factor activity and the signaling induced by HB-EGF. This inhibitor induced apoptosis of patients'myeloma cells cultured with their tumor environment. It also increased patients' myeloma cell apoptosis induced by an anti-IL-6 antibody or dexamethasone. The ErbB inhibitor had no effect on the interaction between multiple myeloma cells and stromal cells. It was not toxic for nonmyeloma cells present in patients' bone marrow cultures or for the growth of hematopoietic progenitors. Altogether, these data identify ErbB receptors as putative therapeutic targets in multiple myeloma.
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PMID:An inhibitor of the EGF receptor family blocks myeloma cell growth factor activity of HB-EGF and potentiates dexamethasone or anti-IL-6 antibody-induced apoptosis. 1457 62

Embryonic stem (ES) cells derived from the inner cell mass of blastocyst-stage embryos are a potential large scale source of oligodendrocytes and of their progenitors for transplantation into the central nervous system for the repair of demyelinating lesions. We found previously that interleukin-6 (IL-6) fused to its soluble receptor (IL-6R), a potent activator of the gp130 receptor, induces myelin gene expression in Schwann cells of embryonic dorsal root ganglia. Like leukemia inhibitory factor, IL-6R/IL-6 inhibits the differentiation of murine ES cells into embryoid bodies. In the present study, we show that this recombinant cytokine may be efficiently used to stimulate the differentiation of oligodendrocytes if added to ES cell-derived neural precursors. IL-6R/IL-6 leads to an increase in early chondroitin sulfate proteoglycan positive and late O4 positive progenitors and to a stimulation of maturation into O1 and myelin basic protein expressing oligodendrocytes. Expression of the genes for transcription factor genes Olig-1 and Sox10, which appear early in the oligodendrocyte lineage, was stimulated by IL-6R/IL-6 addition. We conclude that this cytokine can significantly enhance the derivation of oligodendrocytes from ES cells.
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PMID:Enhancement of oligodendrocyte differentiation from murine embryonic stem cells by an activator of gp130 signaling. 1515 11

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