Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A proinflammatory cytokine cascade, including IL-1 alpha, IL-1 beta, TNF-alpha, IL-6, and IL-8, is activated in response to infection or immunologic insult. Besides their immunologic effects, several of these mediators stimulate bone resorption and inhibit bone formation. Osteocalcin, the most abundant noncollagenous protein present in bone, is an osteoblast-specific product whose production closely correlates with bone formation, and which has also been implicated in control of bone resorption. IL-1 and TNF have previously been shown to down-regulate osteocalcin production in vitro and in vivo, although the mechanism of this inhibition is unknown. In the present studies, IL-1 beta and TNF-alpha both inhibited 1,25-dihydroxyvitamin D3-stimulated production of osteocalcin protein and mRNA by ROS 17/2.8 osteosarcoma cells, whereas IL-6 had no effect on protein and only weakly inhibited mRNA. To determine if down-regulation was exerted at the transcriptional level, an osteocalcin promoter-chloramphenicol acetyltransferase (CAT) fusion gene was constructed (PHOC-CAT). After transient transfection of PHOC-CAT into ROS 17/2.8 osteosarcoma cells, reporter CAT activity was up-regulated by vitamin D at concentrations above 10(-12) M. In screening studies, TNF-alpha (-57%) and IL-6 (-37%) inhibited vitamin D-stimulated osteocalcin transcription, whereas IL-1 alpha, IL-1 beta, and IL-8 had no effect. Other immune cytokines and growth factors, including IL-2, IL-3, IL-7, and M-CSF, also failed to regulate osteocalcin transcription. Despite their lack of promoter regulation, IL-1 alpha and IL-1 beta also stimulated PGE2 production by ROS 17/2.8, further confirming the ability of the host cell to respond to these mediators. In dose-response experiments, down-regulation by TNF-alpha was significant at concentrations as low as 0.14 pM (0.1 U/ml), whereas approximately 10(4)-fold higher concentration of IL-6 was required to exert a similar effect. TNF-alpha-mediated down-regulation was unaffected by indomethacin. These data demonstrate that of these cytokines, TNF-alpha alone potently down-regulates osteocalcin promoter function, whereas IL-1 acts post-transcriptionally, possibly by reducing mRNA stability. Heterogeneity therefore exists among the proinflammatory cytokines with respect to the level at which control of osteocalcin expression is exerted.
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PMID:Proinflammatory cytokines tumor necrosis factor-alpha and IL-6, but not IL-1, down-regulate the osteocalcin gene promoter. 130 41

There is little information concerning the incidence of alveolar bone loss in estrogen-deficient women. Ovariectomized sheep are valid models for study of the effects of estrogen deficiency on bone metabolism. The objective of this study was to compare alveolar bone loss in control (C) and ovariectomized sheep (OVX) at 3 and 12 months following surgery. OVX animals had decreased serum levels of 17-beta-estradiol and increased serum levels of osteocalcin, IL-6, and urinary levels of deoxypyridinoline which, taken together, suggest development of osteoporosis. The mean probing depths and percentage of sites with pocket depths 4 to 6 mm and > 6 mm were significantly greater in OVX than C at each time period and in OVX were significantly greater at 12 months that at 3 months. Gingival tissue interleukin-6 (IL-6) levels (but not the number of IL-6(+) cells) were elevated adjacent to deep periodontal pockets; however, there was no significant elevation of levels of the proinflammatory cytokines IL-1 beta and IL-8 within gingiva. Taken together, the data suggest a systemic contribution for progression of periodontal disease associated with estrogen deficiency. This may involve upregulation of systemic IL-6 synthesis and transfer to gingiva in serum, resulting in enhanced IL-6 accumulation within the gingival tissues or reduced bone density allowing for a greater amount of alveolar bone loss.
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PMID:Alveolar bone loss one year following ovariectomy in sheep. 937 31

During orthodontic tooth movement, mechanical forces acting on periodontal ligament (PDL) cells induce the synthesis of mediators which alter the growth, differentiation, and secretory functions of cells of the PDL. Since the cells of the PDL represent a heterogeneous population, we examined mechanically stress-induced cytokine profiles in three separate clones of human osteoblast-like PDL cells. Of the four pro-inflammatory cytokines investigated, only IL-6 and TGF-beta1 were up-regulated in response to mechanical stress. However, the expression of other pro-inflammatory cytokines such as IL-1 beta, TNF-alpha, or IL-8 was not observed. To understand the consequences of the increase in TGF-beta1 expression following mechanical stress, we examined the effect of TGF-beta1 on PDL cell phenotype and functions. TGF-beta1 was mitogenic to PDL cells at concentrations between 0.4 and 10 ng/mL. Furthermore, TGF-beta1 down-regulated the osteoblast-like phenotype of PDL cells, i.e., alkaline phosphatase activity, calcium phosphate nodule formation, expression of osteocalcin, and TGF-beta1, in a dose-dependent manner. Although initially TGF-beta1 induced expression of type I collagen mRNA, prolonged exposure to TGF-beta1 down-regulated the ability of PDL cells to express type I collagen mRNA. Our results further show that, within 4 hrs, exogenously applied TGF-beta1 down-regulated IL-6 expression in a dose-dependent manner, and this inhibition was sustained over a six-day period. In summary, the data suggest that mechanically stress-induced TGF-beta1 expression may be a physiological mechanism to induce mitogenesis in PDL cells while down-regulating its osteoblast-like features and simultaneously reducing the IL-6-induced bone resorption.
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PMID:Autoregulation of periodontal ligament cell phenotype and functions by transforming growth factor-beta1. 978 34

Chronic crystal-associated arthropathies such as gout and pseudogout can lead to local bone destruction. Because osteoblasts, which orchestrate bone remodeling via soluble factors and cell-to-cell interactions, have been described in contact with microcrystals, particularly in uratic foci of gout, we hypothesized that microcrystals of monosodium urate monohydrate (MSUM) and of calcium pyrophosphate dihydrate (CPPD) could alter osteoblastic functions. MSUM and CPPD adhered to human osteoblastic cells (hOB) in vitro and were partly phagocytized as shown by scanning electron microscopy. MSUM and CPPD dose-dependently stimulated the production of PGE(2) in hOB as assessed by enzyme immunoassay, a response that was synergistically enhanced in the presence of IL-1. The mechanism of this synergism was, at least in part, at the level of the expression of cyclooxygenase-2 as evaluated by immunoblot analysis. MSUM and CPPD also stimulated the expression of IL-6 and IL-8 and reduced the 1,25-dihydroxyvitamin D(3)-induced activity of alkaline phosphatase and osteocalcin in hOB (with no synergism with IL-1). MSUM- or CPPD-stimulated expression of IL-6 in hOB pretreated with the selective cyclooxygenase-2 inhibitor NS-398 was increased, unlike that induced by IL-1 alone which was partially reduced. MSUM-, CPPD- or IL-1-induced expression of IL-8 was unchanged by pretreating hOB with NS-398. These results suggest that inflammatory microcrystals alter the normal phenotype of hOB, redirecting them toward reduced bone formation and amplified osteoblast-mediated bone resorption, abnormalities that could play a role in the bone destruction associated with chronic crystal-induced arthritis.
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PMID:Inflammatory microcrystals alter the functional phenotype of human osteoblast-like cells in vitro: synergism with IL-1 to overexpress cyclooxygenase-2. 1199 89

The present study was designed to test if the serum cytokines (interleukin, or IL-1beta, -2, -2r, -6, -6r, -8, and -10, and tumor necrosis factor alpha, or TNF-alpha) and osteocalcin levels were different between 50 osteoporotic and 30 postmenopausal nonosteoporotic women and to evaluate the efficacy of calcitonin therapy during 6 months on serum cytokines and osteocalcin levels in postmenopausal osteoporotic women. In our study, serum levels of osteocalcin, TNF-alpha, IL-2, and IL-8 were significantly higher in the patient group (P < 0.05), whereas serum levels of IL-10 and IL-6r were significantly lower in the patient group (P < 0.05). When analysed separately according to bone turnover, serum levels of IL-10 and IL-6r were significantly lower in the normal-turnover group (P < 0.05), and IL-2, IL-8, and TNF-alpha were significantly higher in the high-turnover group than in the control group (P < 0.05). Statistically significant improvement seemed to happen in the patients receiving calcitonin plus calcium therapy (P < 0.05) concerning levels of serum IL-6r at the 1st month (P < 0.05), IL-10, IL-2r, IL-6r, and osteocalcin at the 3rd month, and IL-6r and osteocalcin at the end of the 6th month. Our findings demonstrate that calcitonin plus calcium therapy appears to be particularly more effective for patients with high turnover. In addition, our study suggests that IL-10 and IL-6r may have an important role in normal-turnover osteoporosis, while IL-2, IL-8, and TNF-alpha may play an important role in high-turnover postmenopausal osteoporosis.
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PMID:Possible pathogenetic role of new cytokines in postmenopausal osteoporosis and changes during calcitonin plus calcium therapy. 1221 65

We analyzed bone turnover markers (osteocalcin, bone ALP, beta-crosslaps-CTX) and cytokines (IL-1, IL-8 and IL-10) in hip joint fluid in 10 patients before revision surgery and in 39 with idiopathic coxarthrosis. Patients with loose implants had lower concentrations of resorption marker than those with arthrosis (0.8 vs 1.3 ng/mL), but bone formation marker osteocalcin was reduced (4.2 vs 22.6 ng/mL). IL-8 and IL-10 levels were elevated in patients with implant failure (870 vs 340 pg/mL; 14.3 vs 4.0 pg/mL). We found a negative correlation between the bone resorption marker (CTX) and IL-10 in cases with prosthesis loosening and a positive correlation between IL-10 and time-to-revision. We conclude that enhanced local production of inflammatory cytokines leading to suppressed bone formation is a part of the loosening process. The expression of anti-inflammatory mediators is not sufficient to counteract the imbalance in bone turnover.
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PMID:Bone turnover markers and cytokines in joint fluid: analyses in 10 patients with loose hip prosthesis and 39 with coxarthrosis. 1244 Apr 94

Members of the mammalian p160 family, such as GRIP1, are known as glucocorticoid receptor (GR) coactivators; at certain glucocorticoid response elements (GREs), however, GRIP1 acts as a GR corepressor. We characterized functional interactions of GR and GRIP1 in a repression complex where GR tethers to DNA-bound activator protein-1 (AP-1), as at the human collagenase-3 gene, and tested whether the identified interactions were similar or different at other response elements. At the AP-1 tethering GRE, we mapped the GRIP1 corepressor activity to a domain distinct from the two known GRIP1 activation domains; it exhibited intrinsic GR-independent repression potential when recruited to DNA via Gal4 DNA-binding domain. Interestingly, neither the domain nor the activity was detected in the other two p160 family members, SRC1 and RAC3. The same GRIP1 corepression domain was required for GR-mediated repression at the nuclear factor-kappaB (NF-kappaB) tethering GRE of the human IL-8 gene. In contrast, at the osteocalcin gene GRE, where GR represses transcription by binding to a DNA site overlapping the TATA box, both GRIP1 and SRC1 corepressed, and the GRIP1-specific repression domain was dispensable. Thus, in a single cell type, GR and GRIP1 conferred one mode of activation and two modes of repression by selectively engaging distinct surfaces of GRIP1 in a response element-specific manner.
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PMID:Alternate surfaces of transcriptional coregulator GRIP1 function in different glucocorticoid receptor activation and repression contexts. 1248 Oct 24

Patients undergoing trauma sustain an initial injury followed by further physiological challenges during surgery. Plasma osteocalcin (OC), a marker of osteoblastic activity, declines after major surgery. Increased cortisol secretion, and other components of the perioperative stress response, may play a role in mediating this response. We have examined the osteocalcin, hormonal and cytokine responses in twenty patients undergoing post-traumatic pelvic reconstruction surgery. We measured plasma osteocalcin, serum cortisol, bone specific alkaline phosphatase (BSAP), IL-6, IL-8, IL-10, plasma epinephrine and norepinephrine concentrations for up to 3 days after surgery. We recorded an increase in IL-6, IL-10 and epinephrine concentrations perioperatively and a fall in OC and BSAP concentrations. There were no significant changes in cortisol or IL-8 concentrations. Patients undergoing pelvic reconstruction surgery following trauma have a preserved inflammatory and catecholamine response but the cortisol response may be obtunded. Osteocalcin concentrations are affected by factors other than glucocorticoids.
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PMID:The hormonal and inflammatory responses to pelvic reconstructive surgery following major trauma. 1566 95

When human blood monocytes were cocultured with stromal cells derived from human giant cell tumor of bone (GCTSC) and a Millipore filter (0.4 microm) was interposed between monocytes and GCTSC, multinucleated giant cell formation of monocytes was induced. The multinucleated giant cells have characters as osteoclast-like cells, indicating that a soluble osteoclast-inducing factor(s) is secreted from GCTSC expressing RANK, RANKL/ODF/OPGL and TACE mRNA. Furthermore, OCIF/OPG inhibited GCTSC-induced osteoclastogenesis, showing that the RANK-RANKL system is involved in GCTSC-induced osteoclastogenesis and that soluble form of ODF/RANKL induces osteoclasts from monocytes. GCTSC expressed the cytokine mRNAs such as M-CSF, GM-CSF, IL-3, IL-4, IL-6, and IFN-gamma mRNAs. None of IL-1ralpha, IL-1alpha, IL-1beta, IL-2, IL-4, IL-10, IL-18, TNF-alpha, G-CSF and IFN-gamma could be detected in all culture media. A significant amount of IL-6 could be detected in the culture media of all GCTSC. IL-8 was found in the culture media of two GCTSC and two osteosarcoma-derived cells. M-CSF was detected in all culture media. GCTSC express CaSR, and stimulation of GCTSC with either extracellular Ca(2+) or neomycin, agonist of CaSR, augmented the expression of RANKL. Some lines of GCTSC expressed alkaline phosphatase, osteocalcin and Cbfa1, suggesting that GCTSC are intimately related to osteoblastic lineage.
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PMID:Cytological properties of stromal cells derived from giant cell tumor of bone (GCTSC) which can induce osteoclast formation of human blood monocytes without cell to cell contact. 1602 7

Bone deposition, for any implant system, is the deciding factor for the success. The biochemical signals at the cellular level will help elucidate the direction of host response. In this report, intercellular messenger, cytokines, that are regulatory for osteoblast and osteoclast function, were measured. Production of osteocalcin, a marker for osteoblast maturation was also estimated. Human osteoblast-like cells from osteosarcoma cell line MG 63 were grown in wells in the presence of titanium (Ti), titanium alloy (Ti6A14V) and stainless steel implant materials incubated at 37 degrees C. Interleukin-1alpha (IL-1alpha), IL-6, IL-8, IL-11 and osteocalcin were quantitated using standard enzyme linked immunosorbant assay (ELISA) kits from the growth media extracted at specific intervals over the critical ten day period. In all dishes, cells were seen adhering to the base after 24 hours and to confluence at 96 hours. Both IL-1alpha and IL-11 were not produced in sufficient quantities to be measured in the assay (< pg/ml). Interleukin-6 production was significantly higher for stainless steel than for titanium and the alloy. There was a progressive rise in osteocalcin production for titanium contrasted to a basal rate for stainless steel and alloy. Interleukin-8 levels for all metals and controls increased markedly after two days implicating inherent cellular characteristics. A relatively high constant range for macrophage colony stimulating factor from the first day was seen for all metals, including the controls. In conclusion, it appears that titanium implants activate osteocalcin production while stainless steel activates IL-6.
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PMID:An in vitro comparison of implant materials cell attachment, cytokine and osteocalcin production. 1631 93


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