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)

There is substantial evidence that Kaposi sarcoma-associated herpesvirus (KSHV) plays an important role in the pathogenesis of all forms of Kaposi sarcoma (KS). It has been noted that KS commonly occurs in locations, such as the feet, where tissue may be poorly oxygenated. On the basis of this observation, the potential role of hypoxia in the reactivation of KSHV replication was explored by studying 2 KSHV-infected primary effusion lymphoma B-cell lines (BC-3 and BCBL-1) latently infected with KSHV. Acute and chronic exposure of these cells to hypoxia (1% O(2)) induced KSHV lytic replication, as indicated by an increase in intracellular lytic protein expression and detection of virus in cell supernatants by Western immunoblotting. In addition, hypoxia increased the levels of secreted viral interleukin-6. Moreover, hypoxia enhanced the lytic replication initiated by the viral inducer 12-O-tetradecanoylphorbol-13-acetate. Desferoxamine and cobalt chloride, 2 compounds that increase the intracellular levels of hypoxia-inducible factor 1, were also able to induce KSHV lytic replication. These studies suggest that hypoxia is an inducer of KSHV replication. This process may play an important role in the pathogenesis of KS.
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PMID:Hypoxia induces lytic replication of Kaposi sarcoma-associated herpesvirus. 1134 55

Cytokines and proteases are secreted by fibroblasts in response to particulate wear debris, and these proteins are felt to play an important role in the development of osteolysis and implant loosening. Although metallic and polyethlyene debris have been studied extensively, little is known about the cellular responses to hydroxyapatite, despite the wide clinical use of these materials. Therefore, the effects of hydroxyapatite (HA) and hydroxyapatite/beta-tricalciumphosphate (HA/TCP) on cellular proliferation, cytokine gene expression and protein secretion, protease synthesis, and gelatinolytic activity were investigated in human fibroblasts. HA and HA/TCP particles were synthesized, and their effects were compared to the responses elicited by titanium and cobalt chromium. Sample characterization by scanning electron microscopy and Coulter Counter demonstrated that the materials had a mean particle size of less than 10 microm, and all of the particles were compared using the same concentration ranges. Aliquots of particle suspensions were added to human fibroblasts maintained in tissue culture, and dose-response and time-course experiments were performed. Effects of the particles on fibroblast proliferation were assessed, and alterations in cytokine levels were determined by specific enzyme linked immunosorbent assays (ELISA). Cytokines that were evaluated included interleukin-1 (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha), all of which have been demonstrated to enhance bone resorption and are associated with osteolysis and implant loosening. Gene expression was determined using Northern blot analysis with cytokine-specific probes, while secretion of the proteases collagenase and stromelysin was determined by Western blot analysis. Functional gelatinolytic assay was assessed using zymogram gels. The particles were evaluated in a concentration range from 0.000021 to 0.021 vol%. All of the particles produced increases in cellular proliferation up to 0.0021 vol%, with the largest increases being seen at 0.021 vol% with HA/TCP and titanium. At the highest concentration, both cobalt chromium and HA samples decreased cellular proliferation relative to lower doses, possibly representing cytotoxicity. Hydroxyapatite particles yielded a 30-fold increase in interleukin-6 secretion compared to unstimulated controls, which was also greater than three times the levels produced by cobalt chromium, titanium, or HA/TCP. HA particles also tripled the secretion of IL-1beta at 0.00021 vol%, and doubled TNF-alpha secretion at 0.021 vol%. Addition of conditioned media prepared by incubation of the particles in culture medium in the absence of cells did not alter the secretion of any of the cytokines. Northern blot analysis using IL-6 probes also demonstrated strong increases with HA compared to the other materials, suggesting that the action of the HA particles was at the level of transcription. Secretion of the protease collagenase was increased by all of the samples including HA when compared to unstimulated controls. Stromelysin secretion into the culture medium was decreased by cobalt chromium, but increased by titanium, HA, and HA/TCP. All of the particles including HA increased the gelatinolytic activity of the fibroblasts. These findings demonstrate that HA and HA/TCP particles are capable of stimulating the expression and secretion of cytokines and proteases that enhance bone resorption, and suggest that particulate debris from implants using these coatings may also increase osteolysis and loosening.
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PMID:Effects of hydroxyapatite particulate debris on the production of cytokines and proteases in human fibroblasts. 1151 71

Cobalt is the major component in many orthopedic implants and the introduction of a second generation of metal on metal bearing prosthesis systems actualizes the toxicity and biocompatibility of this compound. We studied the effect of cobalt ions on primary cultures of human osteoblast-like cells. Cobalt ions dissolved in cell culture medium caused a dose-dependent decrease in proliferation of human osteoblasts measured as (3H)thymidine incorporation. We also found that cobalt ion-enriched medium increased the production of interleukin-6 from the osteoblast-like cells. Furthermore, incubation of osteoblasts with cobalt ion-enriched medium reduced collagen type I and osteocalcin production in a dose-dependent manner when 1,25 dihydroxyvitamin-D3 was added to the culture medium. Cobalt concentrations below 10 microg/mL or 0.17 mmollmL in the cell culture medium had no significant effect on human osteoblast proliferation and function.
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PMID:Cobalt ions influence proliferation and function of human osteoblast-like cells. 1214 88

Loss of bone near joint prostheses is thought to be caused by activation of recruited osteoclasts by osteolytic mediators induced by wear particles. It is proposed that particles inhibit osteogenesis during bone remodelling causing a reduction in the levels of peri-implant bone. This study explores whether prosthetic particles modulate bone formation by affecting osteoblastic bone-related mRNAs (alkaline phosphatase, pro-collagen Ialpha1, osteopontin, osteonectin, osteocalcin, bone sialoprotein and thrombospondin) or their translated proteins using titanium alloy, commercially pure titanium, and cobalt-chrome particles. The direct effect of the particles revealed no change to the expression of the bone-related mRNAs in human bone-derived cells (HBDC) at the time points investigated; although non-collagenous translated proteins expressed by these HBDC were significantly effected (p<0.05). Different patterns of expression for bone-related proteins were induced by the different particles both directly and indirectly. Inflammatory mediators (interleukin-1beta, tumor necrosis factor alpha, interleukin-6, and prostaglandin E2) had similar effects on HBDC to the media obtained from monocytes incubated with particles. This study shows that prosthetic wear particles can significantly modify the expression of bone-related proteins by osteogenic cells in vitro. These alterations in osteogenic activity at the interface of the implant and bone may be an important factor in the failure of many orthopaedic implants.
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PMID:Prosthetic particles modify the expression of bone-related proteins by human osteoblastic cells in vitro. 1241 36

Regarding orthopaedic implant loosening it has been hypothesized that particle-activated macrophages release interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha). This in turn stimulates osteoblasts to release interleukin-6 (IL-6) and prostaglandin E(2) (PGE(2)). These mediators recruit and activate osteoclasts and may therefore lead to bone resorption and loss of implant fixation. In this study we compared the ability of different materials to induce the release of IL-6 and PGE(2) from primary isolated, human osteoblasts without preceding activation by macrophages. We tested stainless steel, cobalt-chromium alloy (CoCrMo), commercially pure titanium (cpTi), Ti-6Al-7Nb and Ti-6Al-4V processed in the same manner as corresponding clinical implants. After 12 and 24h the cells had actively secreted IL-6 and PGE(2). There were no clear differences among the implant materials or with the plastic control. The amount of factors the cells released in our study compare well with the findings of other authors who investigated osteoblasts on plastic. In comparison with the literature these amounts are lower than secretion levels of osteoblasts stimulated with implant particles, IL-1 or TNF-alpha. Moreover, other authors found that osteoclasts require higher concentrations of PGE(2) to become activated than the concentrations measured in our experiments. Therefore, the amount of PGE(2) released from the osteoblasts in our study is probably not sufficient to induce osteolytic activity. Because of contradictory statements in the literature it is unclear if the measured IL-6 concentrations promote osteolytic activity. Differences in material composition does not significantly influence the release of these factors if the materials have similar surface roughnesses.
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PMID:IL-6 and PGE2 release by human osteoblasts on implant materials. 1285 49

We have examined the protective effect and mechanisms of heme oxygenase-1 (HO-1) induction in rat liver model of ex vivo cold ischemia preservation using cobalt protoporphyrin (CoPP) as HO-1 inducer and zinc protoporphyrin (ZnPP) as HO-1 inhibitor. There was a decrease in both aspartate transaminase and lactate dehydrogenase activities and in malondialdehyde level in liver of the CoPP-treated group compared with controls (p < 0.05). In the CoPP-treated rats, the histological signs of reperfusion injury were much lower than in control. Up-regulation of HO-1 expression was also associated with reduced levels of tumor necrosis factor alpha and interleukin-6. Markedly fewer apoptotic liver cells (determined by TUNEL assay) could be detected in CoPP-treated group compared with the control group. These protective effects were prevented by administration of ZnPP. In conclusion, induction of HO-1 provides protection against liver injury during cold ischemia preservation and improves the preservation of liver graft. The mechanisms underlying these beneficial effects include reduction of oxidative injury and of inflammatory response and prevention of apoptosis.
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PMID:Induction of heme oxygenase-1 improves cold preservation effect of liver graft. 1757 9

Severe hyperhomocysteinemia (HHC) is associated with atherosclerosis. In hemodialysis (HD) patients, one of the main causes of death is cardiovascular disease. In animals, trace elements such as cobalt, copper, iron, and nickel ameliorated vitamin B(12) deficiency-induced HHC. However, correlations between plasma total homocysteine (tHcy) and trace elements in HD patients have not been investigated. Therefore, tHcy, folate, vitamin B(12), trace elements (cobalt, copper, iron, and nickel), and some laboratory parameters such as serum total protein, albumin, transferrin, ferritin, C-reactive protein (CRP), and interleukin-6 concentrations were determined in 122 hemodialysis patients. When patients were divided into groups according to their tHcy, we found no significant differences in concentrations of cobalt, copper, and total protein, while nickel was higher, and folate, vitamin B(12), and iron were lower in patients with lower than higher tHcy. In univariate regression analysis, tHcy negatively correlated with concentrations of folate (r = -0.302, p < 0.006), vitamin B(12) (r = -0.347, p < 0.0001), nickel (r = -0.289, p < 0.006), and CRP (r = -0.230, p < 0.02) and positively with serum albumin (r = 0.316, p < 0.0004) and hemoglobin (r = 0.329, p < 0.0001) values. No relationship between tHcy and serum concentrations of cobalt, copper, iron, or other laboratory parameters was found in HD patients. The effect of cobalt and nickel on homocysteine production was assessed in human peripheral mononuclear cells (PBMCs). Nickel but not cobalt at concentrations found in HD patients significantly inhibited homocysteine, cysteine, and S-adenosylhomocysteine production in human PBMCs. These results suggest that nickel might also be involved in the regulation of the methionine-folate cycle in humans, as was demonstrated in animal experiments.
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PMID:Relationship between serum nickel and homocysteine concentration in hemodialysis patients. 1846 90

Establishing of alternatives to animal tests is ethically desirable and gains in importance in context of new European Union regulations such as REACH. We have refined our new in vitro assay for prediction of the sensitizing potency of xenobiotics. Monocytes cocultured with primary human keratinocytes develop to a novel class of in vitro generated dendritic cells after treatment with transforming growth factor beta and Interleukin-4 in serum-free medium. These dendritic cell-related cells (DCrc) are the key players in the loose-fit coculture-based sensitization assay (LCSA). Assay duration and cytokine consumption could be cut down without impairing the assay's functionality. DCrc showed a dose-dependent upregulation of CD86 after treatment with the contact allergens 2,4,6-trinitrobenzenesulfonic acid, the prohapten isoeugenol, and alpha-hexyl cinnamic aldehyde. The metal allergens nickel and cobalt could be detected by measuring Interleukin-6 and macrophage inflammatory protein 1-beta (MIP-1beta, CCL-4) in coculture supernatants. The irritant zinc elicited no reaction. Lipopolysaccharide produced upregulation of CD86, IL-6 and MIP-1beta. Determination of tolerable concentrations of an allergen in consumer products requires a widely accepted sharp quantitative assay. Animal-based assays do not meet this requirement. The LCSA provides dose-response information, thereby allowing prediction of the relative ability of a substance to induce sensitization.
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PMID:A new dendritic cell type suitable as sentinel of contact allergens. 1854 6

Wear debris-induced osteolysis is purportedly the limiting problem affecting the long term results of joint arthroplasty. Pathogenic effects of wear debris in peri-implant cells such as macrophages, osteoblasts and osteoclasts have been well studied. In contrast, the effects of wear debris on osteocytes, which make up over 90% of all bone cells, remain unknown. We hypothesized that metal implant debris can induce the pro-inflammatory response in osteocytes. This study demonstrated the effects of cobalt-chromium-molybdenum alloy (Co-Cr-Mo) particles on a well-characterized MLO-Y4 osteocyte cell line. Co-Cr-Mo alloy particle treatment significantly (p<0.05) up-regulated tumor necrosis factor alpha (TNFalpha) gene expression after 3 and 6 h and TNFalpha protein production after 24 h, but down-regulated interleukin-6 (IL-6) gene expression after 6 h. Co-Cr-Mo alloy particle treatment also induced osteocyte apoptosis after 24 h. This apoptotic effect was partially (40%) dependent on TNFalpha. Therefore, our results suggest that osteocytes play a role in particle-induced inflammation and bone resorption following total joint arthroplasty by inducing pro-inflammatory cytokines and inducing osteocyte apoptosis.
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PMID:Co-Cr-Mo alloy particles induce tumor necrosis factor alpha production in MLO-Y4 osteocytes: a role for osteocytes in particle-induced inflammation. 1949 95

Oxidative stresses are believed to play an important role in the induction of both cell adhesion molecules and pro-inflammatory cytokines, a key event in a variety of inflammatory processes. The enzyme heme oxygenase-1 (HO-1) functions as an antioxidant and serves to protect against tissue injury. In this study, we report that HO-1 was induced in cultured human tracheal smooth muscle cells after either treatment with a potent inducer of HO-1 activity, cobalt protoporphyrin IX, or infection with a recombinant adenovirus that carries the human HO-1 gene. Overexpression of HO-1 protected against tumor necrosis factor (TNF)-alpha-mediated airway inflammation via the down-regulation of oxidative stress, adhesion molecules, and interleukin-6 in both cultured human tracheal smooth muscle cells and the airways of mice. In addition, HO-1 overexpression inhibited TNF-alpha-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, adherence of THP-1 cells, generation of interleukin-6, p47(phox) translocation, and nuclear factor-kappaB activation. HO-1 overexpression also attenuated TNF-alpha-induced oxidative stress, which was abrogated in the presence of both the HO-1 inhibitor, zinc protoporphyrin IX, as well as a carbon monoxide scavenger. In addition, HO-1 overexpression reduced the formation of a TNFR1/c-Src/p47(phox) complex. These results suggest that HO-1 functions as a suppressor of TNF-alpha signaling, not only by inhibiting the expression of adhesion molecules and generation of interleukin-6, but also by diminishing intracellular reactive oxygen species production and nuclear factor-kappaB activation in both cultured human tracheal smooth muscle cells and the airways of mice.
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PMID:Overexpression of HO-1 protects against TNF-alpha-mediated airway inflammation by down-regulation of TNFR1-dependent oxidative stress. 1960 69


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