Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin 1 alpha (IL-1 alpha), interleukin 1 beta (IL-1 beta), and interleukin 6 (IL-6) are cytokines with potent bone-resorbing effects; some of these biologic effects are opposed by interleukin-1 receptor antagonist (IL-1ra). In vitro and animal model studies suggest that these cytokines are paracrine mediators of the increased bone resorption associated with estrogen deficiency, and increases in their production also could contribute to age-related bone loss. Therefore, we measured serum concentrations of these cytokines in 80 normal women who were 24-87 years old. IL-6 concentration correlated highly with age (p < 0.001) and increased three-fold during life. However, multiple-regression analysis showed no significant correlation between serum IL-6 levels and menopausal status, serum estradiol concentration, or markers for bone turnover (serum bone alkaline phosphatase, osteocalcin, carboxyl-terminal telopeptide of type I collagen, or 24 h urinary free pyridinoline excretion). Serum IL-1 alpha, IL-1 beta, or IL-1ra level did not change with age and, by multiple-regression analysis, did not correlate with markers of bone turnover, except IL-1ra weakly with ICTP. We found no relationship between bone-resorbing cytokines and ovarian function. Although the large age-related increase in serum IL-6 concentration could contribute to age-related bone loss, the lack of correlation with markers for bone turnover argues against this. However, based on the strong evidence in experimental animals that these cytokines are involved in estrogen action on bone, further studies in humans are warranted.
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PMID:Circulating levels of cytokines that modulate bone resorption: effects of age and menopause in women. 797 12

We investigated expression of several cytokines and growth factors in explants of Pagetic and non-Pagetic bone samples using the technique of reverse-transcription/polymerase chain reaction (RT/PCR). Transcripts for IL-1 alpha and IL-1 beta, TNF-alpha, TNF-beta, IL-6, basic fibroblast growth factor (bFGF), transforming growth factor beta (TGF-beta) and insulin-like growth factor-I (IGF-I) were found to a variable degree in both Pagetic and non-Pagetic bone samples, but there was no significant difference in the patterns of expression for these factors in Pagetic bone (n = 18) as compared with non-Pagetic bone (n = 51). There was furthermore, no significant difference in the patterns of expression for the various factors studied when patients were subdivided into mild and severe categories of disease activity using markers of bone formation (serum alkaline phosphatase) or bone resorption (osteoclast counts on adjacent biopsy specimens). Although IL-6 and IL-1 have previously been implicated as bone resorbing factors in Pagetic bone, 40% of our patients with severe disease had not detectable IL-6 transcripts, 70% had no detectable IL-1 alpha transcripts and 50% no IL-1 beta transcripts. We conclude that patterns of expression for cytokine and growth factor mRNAs are not disturbed in Paget's disease. Although we cannot exclude the possibility that post-transcriptional processing of the mRNAs may differ in Pagetic and normal bone cells, our data raise the possibility that the abnormalities of bone turnover which are characteristic of active Paget's disease may be due to local elaboration of other, possibly novel osteotropic factors, which stimulate bone formation and resorption.
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PMID:Cytokine and growth factor expression in Paget's disease: analysis by reverse-transcription/polymerase chain reaction. 801 89

Interleukin-1, a soluble polypeptide, plays an important role in inflammatory reactions by increasing prostaglandin E2 (PGE2) generation. Human recombinant IL-1 receptor antagonist (hrIL-1ra) is a natural inhibitor of IL-1 which blocks its activity in several inflammatory states. In these studies we found that hrIL-1ra (250 mg/ml) inhibits the generation of PGE2, as measured by RIA method, in minced mouse granuloma tissue (700 mg) treated overnight with LPS (10-1000 ng/ml) or hrIL-1 beta (0.1-10 ng/ml). In addition, we show that hrIL-1ra (250 ng/ml) strongly inhibited IL-1 alpha and IL-1 beta, as measured by ELISA method, in the minced granuloma tissue treated overnight with LPS 1 micrograms/ml or IL-1 beta (10 ng/ml). The granuloma tissue induced in mice by a dorsal subcutaneous injection (0.2 ml) of a saturated solution (1:40 dilution) of KMnO4 crystals, presented an alkaline phosphatase activity which was not inhibited by two intraperitoneal administrations of hrIL-1ra 20 micrograms/200 ml bolus injections (given at the same time as KMnO4 injection and one 24 h later). These results show for the first time that hrIL-1ra blocks PGE2, IL-1 alpha and IL-1 beta but not alkaline phosphatase activity, which is a marker in growing bone and in calcific and inflamed tissue.
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PMID:Human recombinant interleukin-1 receptor antagonist (hrIL-1RA) inhibits prostaglandin E2 (PGE2) generation but not alkaline phosphatase activity in in vivo chronic granulomatous tissue induced by KMnO4. 822 2

The use of primary (nontransformed) bone cell cultures is hampered by their cellular heterogeneity. Primary cultures of osteoblast-like cells have been shown to proliferate in response to several osteotropic agents, but because mixed cell populations are present it is uncertain whether a true osteoblastic response was observed. By combining (1) localization of [3H]-thymidine incorporation into the nuclei of actively dividing cells by autoradiography with (2) subsequent induction of osteoblast differentiation by 1,25(OH)2D3 to optimize the number of cells expressing high alkaline phosphatase activity and (3) its localization by histochemical staining, it is possible to measure the proliferation of cells that are capable of expressing a more mature osteoblastic phenotype in heterogeneous human trabecular bone cell cultures. Over a 72-hour incubation period, rhIL-1 alpha (0.2-2 ng/ml) exerted a dose-dependent stimulation of proliferation of cells expressing alkaline phosphatase. Purified human TGF beta 1 produced a biphasic increase in the proliferation of these cells (0.01-1 ng/ml) but 17 beta and 17 alpha-estradiol (10(-12)-10(-8) M) failed to consistently regulate cell growth. Furthermore, 17 beta-estradiol did not reproducibly modulate proliferation induced by IL-1 alpha or TGF beta when added together in cultures. This procedure represents a more accurate method for the assessment of osteoblast proliferation in primary bone cell cultures and demonstrates that estrogen is not mitogenic for human osteoblasts and does not potentiate the actions of putative local stimulators of osteoblast replication.
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PMID:Proliferative responses to estradiol, IL-1 alpha and TGF beta by cells expressing alkaline phosphatase in human osteoblast-like cell cultures. 848 37

Interleukin-1 alpha (IL-1 alpha) and IL-1 beta bind to either the p80 type I IL-1 receptor (IL-1RI) or the p68 type II IL-1R (IL-1RII) on both T and B lymphocytes. We and others have previously shown that the anterior pituitary gland also has specific high affinity binding sites for IL-1 alpha (Kd = approximately 1 nM) and expresses transcripts for both isoforms of the IL-1R. However, the identity of cells in the anterior pituitary gland that express the IL-1R and whether different populations of adenohypophyseal cells express different isoforms of the IL-1R remain unknown. Here we have used a combination of immunohistochemistry and histochemistry to localize IL-1RI and IL-1RII to specific target cells in the mouse anterior pituitary gland. Perfusion-fixed, paraffin-embedded sections of anterior pituitary gland were immunolabeled with well characterized monoclonal antibodies to either IL-1RI or IL-1RII and counterstained using a modified Gomori's method to document acidophils and basophils. Immunolabeling demonstrated that both IL-1RI and IL-1RII were abundantly expressed on a single population of anterior pituitary gland cells and that these cells could be classified on the basis of histochemical staining as a subpopulation of acidophils. The distribution, morphology, and proportion of cells immunolabeled for IL-1RI and IL-1RII were consistent with GH-synthesizing cells. To confirm this hypothesis, a modified indirect avidin-biotin complex, sequential peroxidase/alkaline phosphatase technique was used to label anterior pituitary gland cells with antibodies to IL-1RI followed by antibodies to IL-1RII, GH, PRL, or ACTH. The IL-1RI-positive cells predominately coexpressed IL-1RII and GH, but very little, if any, PRL or ACTH. These data establish that the predominant cell population in the murine anterior pituitary gland that constitutively expresses IL-1R stain as acidophils histochemically, is round to oval with dense granular cytoplasm and eccentric nuclei, synthesizes GH, and simultaneously expresses IL-1RI and IL-1RII isoforms.
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PMID:Dual expression of p80 type I and p68 type II interleukin-I receptors on anterior pituitary cells synthesizing growth hormone. 875 80

Kinetic and phenotypic heterogeneity in leukocyte subsets and adhesion-molecule expression is characteristic of many inflammatory conditions. We have studied the effect of various cytokines and inflammatory agonists on the type of leukocyte present and the adhesion molecules expressed in acute lesions (up to 3 days old) in porcine skin by immunohistology. Four major histocompatability complex-homozygous inbred pigs received replicate intradermal injections of IL-1 alpha, TNF-alpha, PMA, or PHA. Injections were timed so that lesions were obtained at 2, 4, 9, and 24 hours. Another two animals were studied at time points up to 72 hours. Leukocyte subsets and endothelial adhesion molecules were visualized on cryosections by use of monoclonal antibodies and alkaline phosphatase immunohistologic techniques. Substantial heterogeneity in leukocyte phenotypes was observed with all agonists, with lymphocyte subsets showing the greatest variation. Thus, CD2+ and gamma delta TcR+ (Null) T lymphocytes were present in all lesions, but to a varying extent such that few T cells were seen after PMA injection, approximately equal proportions of each after TNF-alpha, but substantially more gamma delta TcR+ (Null) lymphocytes were noted after PHA administration. Endothelial adhesion molecules were also variously affected, with E-selectin (CD62E) being transiently up-regulated by IL-1 alpha but CD62E showed early and sustained expression after TNF-alpha and PHA administration. The E-selectin ligand was demonstrated on infiltrating gamma delta TcR+ lymphocytes by use of a recombinant porcine E-selectin. The L-selectin ligand, identified by the mAb MECA-79, was only observed in late acute sites (< 24 hours) of TNF-alpha and PHA. Endothelial expression of class II major histocompatability complex was also variously up-regulated by all agonists. The results underline the heterogeneity of leukocyte phenotypes and endothelial adhesion molecule expression in acute cutaneous lesions dependent upon the nature of the inflammatory agonist and indicate an association between endothelial E-selectin and the presence of a gamma delta TcR+ (Null) T lymphocyte subset.
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PMID:Lymphocyte subsets and adhesion molecules in cutaneous inflammation induced by inflammatory agonists: correlation between E-selectin and gamma delta TcR+ lymphocytes. 880 66

Although the effects of interleukin-1 (IL-1) and interleukin-6 (IL-6) on articular cartilage chondrocytes have been reported, little is known concerning the effects of these cytokines on growth plate chondrocytes. In this study, we examined the effect of IL-1 alpha, IL-1 beta, and IL-6 on growth plate chondrocyte proliferation, differentiation, and matrix production as a function of cell maturation and examined the ability of these cells to produce IL-1 alpha and IL-1 beta. Confluent fourth passage cultures of rat costochondral resting zone and growth zone chondrocytes were treated with 0-100 ng/ml of IL-1 alpha, IL-1 beta, or IL-6 for 24 h and then assayed for [3H]-thymidine incorporation, alkaline phosphatase specific activity, [35S]-sulfate incorporation, and percent collagen production. Neutralizing polyclonal antibodies were used to confirm the specificity of response to each cytokine. Treatment of resting zone cells with IL-1 alpha produced a significant, dose-dependent decrease in [3H]-thymidine incorporation, while similarly treated growth zone cells were unaffected by treatment with this cytokine. IL-1 alpha also stimulated alkaline phosphatase specific activity and inhibited [35S]-sulfate incorporation by resting zone chondrocytes, but had no affect on growth zone chondrocytes. When collagen production was examined, it was observed that IL-1 alpha had a stimulatory affect on growth zone cells but no affect on resting zone cells. When the effect of IL-1 beta was examined, it was observed that this cytokine inhibited [3H]-thymidine incorporation by resting zone cells and stimulated isotope incorporation in growth zone cells. IL-1 beta also stimulated alkaline phosphatase specific activity and inhibited [35S]-sulfate incorporation by resting zone chondrocytes but had no affect on growth zone chondrocytes. In contrast to IL-1 alpha, IL-1 beta stimulated collagen production by resting zone cells but not growth zone cells. IL-6 had no affect on any of the parameters measured in either cell type. When cytokine production was measured, it was found that IL-1 alpha was produced by both cell types, while IL-1 beta was produced only by resting zone cells. Resting zone cells secreted both IL-1 alpha and IL-1 beta into the media, but 75% of the total cytokine produced by these cells was retained in the cell layer. In contrast, growth zone cells did not secrete measurable IL-1 alpha into the media. These results suggest that IL-1 alpha and IL-1 beta target resting zone cells, inducing them to differentiate and acquire a phenotype characteristic of the more mature growth zone cells. Moreover, resting zone chondrocytes produce both IL-1 alpha and IL-1 beta, suggesting the possibility of an autocrine effect of these cytokines on the cells.
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PMID:Evidence that interleukin-1, but not interleukin-6, affects costochondral chondrocyte proliferation, differentiation, and matrix synthesis through an autocrine pathway. 885 48

Osteoarthritic lesions were observed in the mandibular condyle cartilage of mice aged 7 months and older. These lesions appeared as fibrillations along the articular surface and were accompanied by reduced extracellular matrix synthesis and chondrocyte proliferation. Explants of mandibular condyle cartilage were cultured in serum-free BGJb medium supplemented with ascorbic acid (300 micrograms/ml), penicillin (100 U/ml) and streptomycin (100 micrograms/ml) for up to 72 h. Cultures were further supplemented with either hTGF-beta 1 (0.1-5.0 ng/ml) or human IL-1 alpha (40 U/ml). [3H]thymidine (2 microCi/ml) and [35S]SO4 (10 microCi/ml) were added to the culture medium for the last 24 h of culture and incorporation into DNA and sulfated proteoglycans, respectively, studied. The results indicated that protein and DNA contents, [3H]thymidine and [35S]SO4 incorporation, as well as the specific activity of alkaline phosphatase, were increased by TGF-beta 1. Addition of 1.0 or 5.0 ng/ml hTGF-beta 1 to the cultures for 48 h, had the most stimulatory effect on matrix synthesis and cell proliferation, whereas 0.1 ng/ml hTGF-beta 1 appeared to be inhibitory when compared to controls. Increased [35S]SO4 labeling of chondrocyte clusters was observed by autoradiography in tissue sections from cultures treated with TGF-beta 1 (1.0 and 5.0 ng/ml). In contrast, IL-1 alpha exerted inhibitory effects on cell proliferation and matrix synthesis. However, it induced the activity of acid phosphatase in these cultures. The results of the present study show that IL-1 alpha had catabolic effect on his tissue, while TGF-beta 1 enhanced proliferation and induced synthetic activity of the cartilage cells. Such action by TGF-beta suggests the existance of a possible repair process in osteoarthritic cartilage of the temporo-mandibular joint of aged mice.
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PMID:Effects of transforming growth factor-beta 1 and interleukin-1 alpha on matrix synthesis in osteoarthritic cartilage of the temporo-mandibular joint in aged mice. 915 64

We report a novel material that appears to stimulate cytokine production in human osteoblasts and allow good adherence of the cells to the material. We have examined cultured osteoblasts (MG-63) in the presence of mineral trioxide aggregate (MTA) as set in moist conditions; secondly, we examined the behavior of these MG-63 cells with respect to cytokine and osteocalcin production and alkaline phosphatase activity. Standard ELISA assays were used for assessment of interleukin (IL)-1 alpha, IL-1 beta, IL-6, macrophage colony stimulating factor (M-CSF), and osteocalcin. Furthermore the levels of alkaline phosphatase were measured to establish the level of differentiation of the cells. Cells without MTA served as controls. Cells also were grown in the presence of polymethylmethacrylate (PMA), the commonly used orthopedic cement. In all dishes cells were seen adhering to the base and MTA at 6 h and had increased to confluence at 144 h. IL-1 alpha (175.1 +/- 32.6 pg/mL), IL-1 beta (154.0 +/- 26.7 pg/mL), and IL-6 (214.7 +/- 21.8 pg/mL) were raised when the cells were grown in the presence of MTA at 144 h, with raised values at all time intervals. M-CSF appeared to be unaffected although the overall value was high (7,045.0 +/- 89.5 pg/mL). In contrast, cells grown in the absence of MTA produced negligible amounts of these cytokines (< pg/mL) as did those cells grown in the presence of PMA. Osteocalcin production increased when cells were grown on MTA from 3.8 +/- 0.87 ng/mL to 19.7 +/- 2.8 ng/mL. No osteocalcin could be detected with PMA. Cells in contact with MTA also appeared to have levels of alkaline phosphatase similar to those reported elsewhere (4.3 +/- 0.21 mumol/mg protein/min). No cells could be found attached to PMA and so no alkaline phosphatase activity could be measured.
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PMID:Mineral trioxide aggregate stimulates a biological response in human osteoblasts. 936 48

Interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) have been implicated in the pathogenesis of osteoporosis. These proinflammatory cytokines induce both cyclooxygenase (COX) and nitric oxide synthase (NOS) with the release of prostaglandin (PG) and NO, respectively. The present study was undertaken to examine the interaction between COX and NOS pathways and their role in the regulation of osteoblastic function in MC3T3-E1 cells. Addition of IL-1 alpha and TNF-alpha induced a marked increase in the production of both NO and PGE2. Reverse transcription-polymerase chain reaction analysis showed that the increase in NO production was preceded by the expression of inducible NOS mRNA. The temporal profile of PGE2 production revealed a biphasic pattern: the first small peak at 3 h was caused by de novo synthesis of PGE2 through inducible COX (COX-2) mRNA, while the subsequent progressive accumulation of PGE2 was mediated through the activation of COX pathway by NO since (1) aminoguanidine (AG), a selective inhibitor of inducible NOS, significantly suppressed the PGE2 production by IL-1 alpha and TNF-alpha, (2) NOC-18, an NO donor, reversed this suppression, and (3) NOC-18 increased PGE2 production by itself. The increase in NO production in response to IL-1 alpha and TNF-alpha was further stimulated by aspirin and inhibited by exogenous addition of PGE2, suggesting that PGE2 produced by the cytokines, in turn, negatively modulates NO production. IL-1 alpha and TNF-alpha inhibited alkaline phosphatase (ALP) activity, which was significantly reversed by AG. NOC-18 not only suppressed ALP activity by itself but also blocked the effect of AG, suggesting the role of NO in the inhibition of ALP activity. PGE2 decreased ALP activity, and the inhibitory effect of NOC-18 was attenuated in the presence of aspirin, suggesting the involvement of PGE2 in the negative modulation of ALP activity by NO. These results suggest that NO produced in response to proinflammatory cytokines participates in the modulation of ALP activity via the activation of COX pathway. The interaction between NO and the COX pathways may play an important role in the regulation of osteoblastic functions under physiologic as well as pathologic conditions.
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PMID:Interaction between nitric oxide synthase and cyclooxygenase pathways in osteoblastic MC3T3-E1 cells. 938 83


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