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 gene expression of five matrix metalloproteinases (MMPs) and two tissue inhibitors of metalloproteinases (TIMPs) was studied in human gliomas in vivo and in vitro to evaluate their roles in glioma invasion. Simultaneous expression of one to four MMP genes and two TIMP genes was found in 17 surgical glioma specimens, and one MMP (gelatinase A) gene and two TIMP genes were simultaneously expressed in tissue of three brains. The concomitant overexpression of gelatinase A, gelatinase B, and occasional matrilysin genes was associated with the malignancy of gliomas and accompanied by overexpression of the TIMP-1 gene. In five human glioma cell lines, gelatinase A, TIMP-1, and TIMP-2 genes were constitutively expressed in alll cell lines: the matrilysin gene in three cell lines; the stromelysin gene in two cell lines; and the interstitial collagenase gene in one cell line. There was a clear difference in the expression of gelatinase B and stromelysin genes between surgical glioma specimens and glioma cell lines: the gelatinase B gene was not expressed constitutively in vitro but was overexpressed in vivo, whereas the stromelysin gene was not expressed in vivo but was expressed in some cell lines. To find the cause of that difference in vivo and in vitro, the transcriptional regulations of MMP and TIMP genes by tumor promoter, growth factors, or cytokines were studied in vitro. Interstitial collagenase, gelatinase B, stromelysin, and TIMP-1 genes were upregulated in many cell lines by phorbol-12-myristate-13-acetate (PMA) and in some cell lines by epidermal growth factor, tumor necrosis factor-alpha, or interleukin-1 beta. Transforming growth factor-beta 1 (TGF beta 1) upregulated gelatinase A and matrilysin genes in some cell lines, and there were no clear responses from any MMP and TIMP genes to interleukin-6. Thus, the transcriptional modulation of MMP genes by these growth factors and cytokines seemed insufficient to explain the difference in gelatinase B and stromelysin gene expressions in vivo and in vitro and was suggestive of the genetic alteration of glioma cells in vitro, the heterogeneous cell population in glioma tissues, or both. Furthermore, the in vitro invasion of glioma cells through Matrigel in response to PMA, TGF beta 1, or TIMP-1 was assessed by chemoinvasion assay. In most cell lines, invasion was significantly stimulated by PMA or TGF beta 1 but suppressed by TIMP-1.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Matrix metalloproteinases and tissue inhibitors of metalloproteinases in human gliomas. 761 76

Multiple myeloma is a very devastating cancer with a high capacity to destroy bone matrix. Matrix metalloproteinases (MMPs) play a critical role in bone remodeling and tumor invasion. In this study, we have investigated the involvement of interstitial collagenase (MMP-1) and gelatinases (MMP-2 and MMP-9) in the biology of multiple myeloma. We show (1) that myeloma cells express MMP-9 and (2) that this expression is not subjected to regulation either by interleukin-6 (IL-6), the major myeloma cell growth factor, or by other cytokines involved in the multiple myeloma cytokine network. In the tumoral environment, we show that bone marrow stromal cells express MMP-1 and MMP-2. Whereas MMP-1 is positively regulated by IL-1beta, tumor necrosis factor-alpha, and Oncostatin M, MMP-2 is not modulated by any of these cytokines. To evaluate whether myeloma cells can modify the bone marrow stromal environment, we have examined these MMP activities in coculture. Interestingly, we have observed an upregulation of MMP-1 and a partial conversion of the proMMP-2 into its activated form. We conclude that the increase of MMP activity produced or induced by myeloma cells in these cocultures could favor bone resorption and tumor invasion. Inhibition of such activities could represent a new therapeutical approach in multiple myeloma.
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PMID:Metalloproteinases in multiple myeloma: production of matrix metalloproteinase-9 (MMP-9), activation of proMMP-2, and induction of MMP-1 by myeloma cells. 926 85

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

We recently reported on the successful generation of immortalized (CEPI-17-CL4) cells from primary human corneal epithelial (P-CEPI) cells which exhibited phenotypic, immunohistochemical and metabolic characteristics akin to the P-CEPI cells. The aims of the present studies were to investigate the ligand binding and functional coupling of the histamine receptors to various biochemical and physiological systems in the P-CEPI and CEPI-17-CL4 cells and to relate these findings to the normal and/or pathophysiological role of histamine on the human ocular surface. Specific [3H]-pyrilamine binding to CEPI-17-CL4 cell homogenates comprised >93% of the total binding and represented interaction with an apparent single population of high affinity (Kd=3.76+/-0.78 nM; n=4) and saturable (Bmax = 1582+/-161 fmol g(-1) tissue) number of histamine-1 (H1) receptor binding sites on CEPI-17-CL4 cell homogenates. The H1-receptor selective antagonists, pyrilamine (Ki=3.6+/-0.84 nM, n=4) and triprolidine (Ki = 7.7+/-2.6 nM, n=3), potently displaced [3H]-pyrilamine binding, while the H2- and H3-receptor selective antagonists, ranitidine and clobenpropit, were weak inhibitors (K(i)s>13 microM). Histamine induced phosphoinositide (PI) hydrolysis 2.7-4.4 fold above basal levels and with a potency of 14.9+/-4.9 microM (n=9) and 4.7+/-0.2 microM (n=9) in P-CEPI and CEPI-17-CL4 cells, respectively. Histamine-induced PI turnover was antagonized by H1-receptor selective antagonist, triprolidine, with a potency (Ki) of 3.2+/-0.66 nM (n=10) and 3.03+/-0.8 nM (n=4) in P-CEPI and CEPI-17-CL4 cells, respectively, but weakly effected by 10 microM cimetidine and clobenpropit, H2- and H3-receptor antagonists. The PI turnover response was attenuated by pre-treatment of the cells with the selective phospholipase C inhibitor, U73122 (1-(6-((17beta-3-methoxyestra- 1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione) (IC50=4.8+/-2.4 microM, n = 3). Histamine stimulated intracellular Ca2+ ([Ca2+]i) mobilization in CEPI-17-CL4 cells with a potency of 6.3+/-1.5 microM (n=4). The histamine-induced [Ca2+]i mobilization was reduced by about 28% following pre-incubation of the cells with 4 mM EGTA. While triprolidine completely inhibited histamine-induced [Ca2+]i mobilization, it did not influence the bradykinin-induced [Ca2+]i mobilization response. Histamine (EC50s = 1.28-2.77 microM, n=3-4) concentration-dependently stimulated the release of interleukin-6 (IL-6), IL-8 and granulocyte macrophage colony-stimulating factor, but it did not significantly alter release of tumour necrosis factor-alpha, PGE2 or collagenase-1 (matrix metalloproteinase-1; MMP-1) from CEPI cells. However, IL-1 (10 ng ml(-1)), foetal bovine serum (10%) and phorbol-12-myristate-13-acetate (3 microg ml(-1)) were effective positive control secretagogues of all the cytokines, PGE2 and MMP-1, respectively, from these cells. It is concluded that the CEPI cells express H1-histamine receptors which are positively coupled to PI turnover and [Ca2+]i mobilization which may be directly or indirectly responsible for the release of various cytokines from these cells at physiologically and/or pathologically relevant concentrations.
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PMID:Pharmacology of [3H]-pyrilamine binding and of the histamine-induced inositol phosphates generation, intracellular Ca2+ -mobilization and cytokine release from human corneal epithelial cells. 986 65

Ultraviolet-B irradiation of human dermal fibroblasts has earlier been shown to induce matrix-degrading metalloproteinases, thus driving connective tissue degradation in photoaging and photocarcinogenesis. Herein, we report that Ultraviolet-B irradiation led to a dramatic increase in specific mRNA and protein levels of interstitial collagenase, stromelysin and interleukin-6. By contrast, the major tissue inhibitor of matrix-degrading metalloproteinases, TIMP-1, was unaffected. Monospecific neutralizing antibodies directed against human interleukin-6 significantly reduced the interstitial collagenase and stromelysin-1 protein levels. Taken together, our data provide the first evidence that Ultraviolet-B induction of interstitial collagenase and stromelysin-1 occurs via the synthesis and release of interleukin-6. Hence, this newly identified autocrine mechanism may contribute to dermal photodamage.
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PMID:Ultraviolet-B induction of interstitial collagenase and stromelyin-1 occurs in human dermal fibroblasts via an autocrine interleukin-6-dependent loop. 1022 23

Airway remodeling is a well-recognized feature in patients with chronic asthma. The accumulation in the submucosa of fibrous proteins that are substrates of matrix metalloproteinases (MMP), and the demonstration of increased levels of MMP-9 in bronchoalveolar lavage fluid, prompted us to determine whether there was an imbalance between MMPs and tissue inhibitors of metalloproteinase (TIMP) in such patients. We investigated the presence of TIMPs and other MMPs. TIMP levels were compared with those of all MMPs and inflammatory cytokines. Adults with stable asthma, either untreated or treated with glucocorticoids (GCs), were enrolled. Healthy nonsmokers served as a control population. MMPs and TIMPs were identified through zymography or immunoblotting. TIMPs, MMPs, and cytokines were measured with enzyme immunoassays. TIMP-1 levels were significantly higher in untreated asthmatic subjects than in GC-treated subjects or controls (p < 0.0001), and were far greater than those of MMP-1, MMP-2, MMP-3, and MMP-9 combined. TIMP-2 was undetectable. TIMP-1 levels were correlated with levels of interleukin-6 (p < 0.012) and the number of alveolar macrophages recovered (p < 0.005). This observation has important implications, since an excess of TIMP-1 could lead to airway fibrosis, a hallmark of airway remodelling in patients with chronic asthma.
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PMID:Tissue inhibitor of metalloproteinase-1 levels in bronchoalveolar lavage fluid from asthmatic subjects. 1039 Apr 19

Sex steroids are important regulators of bone cell function and osteoblast-derived matrix metalloproteinases (MMPs) are key mediators of bone resorption during the initial stage of osteoid removal prior to osteoclast attachment. To investigate the mechanism of bone loss following estrogen deficiency, we examined the effects of estrogen on osteoblast synthesis of MMPs and tissue inhibitor of metalloproteinases (TIMPs). Immunolocalization in mouse bone samples ex vivo and primary mouse osteoblast (MOB) cultures was used to document the synthesis of mouse interstitial collagenase (MMP-13), stromelysin-1 (MMP-3), gelatinase-A (MMP-2), and gelatinase-B (MMP-9). Endosteal bone lining cells from distal femoral head and lumbar vertebral body showed an increase in the pattern of synthesis of stromelysin-1 following ovariectomy, compared with sham-operated controls; the synthesis of other MMPs was unaffected. The expression of all classes of MMPs and TIMP-1 and TIMP-2 by MOB in culture was demonstrated by reverse transcriptase-polymerase chain reaction. Following the withdrawal of 17beta-estradiol, MOB cultures showed a significant increase in the number of cells synthesizing stromelysin-1; this effect was enhanced by stimulation with either interleukin-1 or interleukin-6. Northern blot analysis showed only a slight increase in stromelysin-1 mRNA message following the withdrawal of 17beta-estradiol. Our data show an unexpected up-regulation of stromelysin-1 synthesis by osteoblasts both in vivo and in vitro following estrogen withdrawal. Although this effect was not reflected in a significant change in stromelysin-1 mRNA expression in vitro, there is evidence to suggest a role for this enzyme in the early stages of bone loss during the pathogenesis of osteoporosis.
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PMID:Stromelysin (MMP-3) synthesis is up-regulated in estrogen-deficient mouse osteoblasts in vivo and in vitro. 1057 88

Bisphosphonates have recently been introduced in the therapeutic armamentarium for the long-term treatment of patients with multiple myeloma (MM). These pyrophosphate analogs not only reduce the occurrence of skeletal-related events but also provide patients with a clinical benefit and improve the survival of some of them. We investigated the effects of two bisphosphonates, pamidronate and zoledronate, on both myeloma cells and bone marrow stromal cells (BMSCs). We show here that both bisphosphonates induce both myeloma cell and BMSC apoptosis. Furthermore, at lower concentrations, they induce a significant inhibition (40% and 60%, respectively) of the constitutive production of interleukin-6 (IL-6) by BMSCs. We have recently shown that BMSCs produce MMP-1, the major metalloproteinase involved in the initiation of bone resorption, production up-regulated by IL-1beta. Here, we demonstrate that zoledronate significantly inhibits MMP-1 production by BMSCs stimulated with IL-1beta more efficiently than pamidronate. However, zoledronate and to a lesser extent pamidronate are responsible for an up-regulation of MMP-2 secretion by BMSCs. MMP-2 is involved both in bone resorption and in the metastatic process. In conclusion, the apoptosis of myeloma cells and BMSCs and the inhibition of both IL-6 and MMP-1 production induced by bisphosphonates, mainly zoledronate, could have antitumoral effects in patients with MM. However, the up-regulation of MMP-2 secretion observed in vitro suggests a putative risk of tumor cell dissemination in vivo when using these new potent bisphosphonates. This potentially deleterious effect could be abolished by combining bisphosphonates with metalloproteinase inhibitors.
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PMID:Zoledronate is a potent inhibitor of myeloma cell growth and secretion of IL-6 and MMP-1 by the tumoral environment. 1062 64

BMS-275291 is an p.o. bioavailable, sulfhydryl-based matrix metalloproteinase (MMP) inhibitor currently in clinical development for the treatment of cancer. This inhibitor was designed to potently inhibit MMP activities while minimally affecting those of other metalloproteases (e.g., sheddases) involved in the release of cell-associated molecules such as tumor necrosis factor-alpha, tumor necrosis factor-alpha receptor, interleukin-6 receptor, or L-selectin. In vitro, BMS-275291 is a potent inhibitor (nM) of the activities of MMP-1, MMP-2, MMP-7, MMP-9, and MMP-14. BMS-275291 inhibits tumor growth in a B16BL6 model of experimental metastasis, and in this model, BMS-275291 treatment results in a dose-dependent reduction in the number of lung metastases compared with vehicle controls. BMS-275291 also inhibits angiogenesis in a murine angiogenesis model, where once daily treatment with BMS-275291 results in a dose-dependent inhibition of endothelial cell migration into s.c. implanted Matrigel plugs. Pharmacokinetic studies demonstrated that the plasma concentrations of parent BMS-275291 in mice exceeds the in vitro IC(50) values for MMP-1, MMP-2, MMP-7, MMP-9, and MMP-14 for at least 4 h after the administration of a therapeutic dose of BMS-275291. Taken together, these data demonstrate that BMS-275291 inhibits MMP activities that contribute to tumor metastasis and angiogenesis.
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PMID:Inhibition of angiogenesis and metastasis in two murine models by the matrix metalloproteinase inhibitor, BMS-275291. 1173 31

The aim of this study was to investigate the metabolic properties of human articular chondrocytes derived from young, aged and osteoarthritic subjects and their genetic adaptation to a catabolic challenge (i.e. the inflammatory cytokines interleukin-1alpha and tumor necrosis factor-alpha), in the absence or presence of diacerein, a drug potentially useful in osteoarthritis. Chondrocytes in primary culture were analyzed for newly secreted proteins, metalloproteinase synthesis and activity, and production of nitric oxide by-products. Results show that chondrocytes from normal but aged subjects present biochemical properties closer to osteoarthritic-derived cartilage than to normal young cartilage, as indicated by cell morphology, cell proliferation rate and pattern of protein secretion (in particular stromelysin-1 and interstitial collagenase). According to patient age and cartilage physiopathology, chondrocytes secrete increasing amounts of a protein identified by micro-sequencing as chitinase-like protein. Upon exposure to the inflammatory cytokines, chondrocytes, regardless the age or the status of the donor, significantly enhance their production of stromelysin-1, interstitial collagenase, interleukin-6 and interleukin-8. By contrast, the chitinase-like protein is not modulated by the cytokines. The pattern of protein secretion and metalloproteinase activity in chondrocytes from aged subjects appeared to be different from that of young patients, but was highly expressed in osteoarthritic chondrocytes. Diacerein, at therapeutically useful concentrations, consistently counteracts the stimulatory effect of cytokines on newly secreted proteins, metalloproteinase activity and nitric oxide production, whereas a selective nitric oxide blocker alone is ineffective. These data demonstrate that a specific gene program is turned on in cytokine-stimulated chondrocytes, which involves production of proteins engaged in remodeling and destruction of cartilage matrix. Part of these mechanisms appears to be operative also in unstimulated aged chondrocytes. Diacerein largely prevents the metabolic alterations caused by cytokine exposure in human chondrocytes, possibly through its ability to block early intracellular mediators after cytokine stimulation, such as oxygen radicals.
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PMID:Response of young, aged and osteoarthritic human articular chondrocytes to inflammatory cytokines: molecular and cellular aspects. 1222 10

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