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-5 (IL-5) was shown to enhance, in a dose-dependent fashion, the expression of alkaline phosphatase (APase) activity in splenic B cells stimulated with dextran sulphate (DXS). The potentiating effect of IL-5 was still more evident when assayed in large B cells than in small resting B cells, whereas IL-2, IL-4 and IL-6 were devoid of activity. Concomitant with increased APase expression, cell-cycle analysis by flow cytometry showed that large B cells in the early G1 phase were stimulated by IL-5, in conjunction with DXS, to enter G1B and to progress further through S and G2/M. A phosphorylation-dephosphorylation pathway could, thus, be involved in IL-5 transmembrane signalling.
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PMID:Interleukin-5 increases the expression of alkaline phosphatase activity in murine B lymphocytes. 138 38

Leukemia inhibitory factor/differentiation-stimulating factor (LIF/D-factor), expression of its mRNA, and possible roles in bone metabolism were studied in murine primary and clonal osteoblast-like cells. Local bone-resorbing factors such as IL-1, TNF alpha, and LPS strongly induced expression of LIF/D-factor mRNA in both clonal MC3T3-E1 cells and primary osteoblast-like cells. Neither parathyroid hormone nor 1 alpha,25-dihydroxyvitamin D3 stimulated expression of LIF/D-factor mRNA. LIF/D-factor per se did not stimulate expression of its own mRNA. Appreciable amounts of LIF/D-factor were detected in synovial fluids from rheumatoid arthritis (RA) patients but not in those with osteoarthritis (OA). Simultaneous treatment with LIF/D-factor, IL-1, and IL-6 at the concentrations found in synovial fluids from RA patients greatly enhanced bone resorption, though these cytokines did not stimulate bone resorption when separately applied. This suggests that LIF/D-factor produced by osteoblasts is in concert with other bone-resorbing cytokines such as IL-1 and IL-6 involved in the bone resorption seen in the joints of RA patients. LIF/D-factor specifically bound to MC3T3-E1 cells with an apparent dissociation constant of 161 pM and 1,100 binding sites/cell. LIF/D-factor dose-dependently suppressed incorporation of [3H]thymidine into MC3T3-E1 cells. In addition, it potentiated the alkaline phosphatase activity induced by retinoic acid, though LIF/D-factor alone had no effect on enzyme activity. These results suggest that LIF/D-factor is involved in not only osteoclastic bone resorption but also osteoblast differentiation in conjugation with other osteotropic factors.
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PMID:Leukemia inhibitory factor/differentiation-stimulating factor (LIF/D-factor): regulation of its production and possible roles in bone metabolism. 161 24

To examine the possible involvement of IL-6 in bone metabolism, a mouse osteoblastic cell line (MC3T3-E1) and primary osteoblast-like cells from fetal mouse calvaria were cultured with several systemic and local bone-resorbing agents and their expression of IL-6 mRNA was determined. Local bone-resorbing agents such as IL-1 alpha, IL-1 beta, TNF-alpha, and LPS greatly induced IL-6 mRNA expression in both MC3T3-E1 cells and primary osteoblast-like cells. Parathyroid hormone slightly increased expression of IL-6 mRNA in primary osteoblast-like cells but not in MC3T3-E1 cells. Neither IL-6 nor 1 alpha,25-dihydroxyvitamin D3 increased expression of IL-6 mRNA in either of the osteoblast-like cells. In agreement with the expression of IL-6 mRNA, biologically active IL-6 was produced in response to the treatment with IL-1 alpha, TNF-alpha, and LPS in MC3T3-E1 cells. Adding IL-6 dose dependently stimulated the release of 45Ca from prelabeled fetal mouse calvaria. Simultaneously adding suboptimal concentrations of IL-6 and IL-1 alpha induced bone resorption cooperatively. In accord with the increase in the release of 45Ca by IL-6, there were three times as many osteoclasts in the bone sections of calvaria cultured with IL-6 for 5 days as in the controls. IL-6 slightly suppressed alkaline phosphatase activity and collagen synthesis in MC3T3-E1 cells. These results indicate that IL-6 is also produced by osteoblasts, preferentially in response to local bone-resorbing agents, and it induces bone resorption both alone and in concert with other bone-resorbing agents.
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PMID:IL-6 is produced by osteoblasts and induces bone resorption. 212 24

Proximal tubular (PT) epithelial cells express MHC class II (Ia) antigens in immunologically-mediated renal injury. To study the role of PT as accessory cells, we generated several murine PT-like epithelial cell lines by transformation with origin-defective SV40 DNA. These transformed cell lines display typical alkaline phosphatase and gamma-glutamyl-transpeptidase enzyme activity, proliferation to epidermal growth factor (EGF) and sodium-dependent glucose uptake. Clonal lines of transformed tubular cells from both normal C3H/FeJ and autoimmune MRL-lpr mice do not constitutively express Ia antigens or mRNA for class II. However, stimulation with recombinant interferon-gamma(rIFN-gamma) induces Ia mRNA and surface product in the cell lines. These Ia-positive cells can process and present hen egg-white lysozyme (HEL) to antigen-specific Iak-restricted T cell hybrids. Unstimulated tubular cells do not express detectable IL-1 alpha, IL-1 beta, TNA-alpha, or IL-6 mRNA. However, stimulation with IL-1 alpha or LPS induces TNF-alpha transcripts. We conclude that these cell lines have characteristics most consistent with a proximal tubular origin. They also bear characteristics of accessory cells such as processing and presentation of antigen and TNF-alpha gene expression. We speculate that PT have the capacity to participate in the pathogenesis of immune renal injury.
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PMID:MHC class II, antigen presentation and tumor necrosis factor in renal tubular epithelial cells. 240 90

To evaluate the hematologic effects of recombinant human interleukin-6 (rhIL-6, Escherichia coli, SDZ ILS 969, IL-6), and determine its toxicity profile, we performed a phase I trial of IL-6 in 22 patients with various myelodysplastic syndromes (MDS), platelet counts < 100,000/microL, and < 5% bone marrow (BM) blasts. Patients received one of four doses of IL-6 (1.0, 2.5, 3.75, and 5.0 micrograms/kg/d) as a subcutaneous injection on day 1, followed by a 7-day wash-out period, and then 28 days of IL-6 therapy. Dose-limiting toxicities of fatigue, fever, and elevated alkaline phosphatase were seen at 5.0 micrograms/kg/d; the maximum tolerated dose was 3.75 micrograms/kg/d. All patients experienced at least grade II fever and all had an increase in acute phase proteins. Eight patients (36%) experienced at least a transient improvement in platelet counts; three fulfilled the criteria for response, whereas five others had clinically significant increases that failed to meet response criteria. Various IL-6-related toxicities prevented more than three patients from receiving maintenance therapy. Two of the three patients who received maintenance IL-6 therapy had a persistent increase in platelet counts, during 3 and 12 months of IL-6 therapy, respectively. Laboratory studies indicated that IL-6 increased the frequency of higher ploidy megakaryocytes but did not significantly increase the number of assayable megakaryocytic progenitor cells, suggesting that IL-6 acts as a maturational agent rather than a megakaryocyte colony-stimulating factor. Although IL-6 therapy can promote thrombopoiesis in some MDS patients, its limited activity and significant therapy-related toxicity preclude its use as a single agent in this patient population. Further studies, combining low doses of IL-6 with other hematopoietic growth factors, are underway.
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PMID:A phase I trial of recombinant human interleukin-6 in patients with myelodysplastic syndromes and thrombocytopenia. 753 15

Bone remodelling is regulated at the local level by an incompletely elucidated cytokine network. In the present study we have determined the effect of interleukin-4 (IL-4), a cytokine produced by T lymphocytes and other cells, on the activity of murine osteoblasts. IL-4 (0.1-10 ng/ml) did not influence the proliferation rate of the osteoblast-like cell line MC3T3, but inhibited the expression of alkaline phosphatase. In long-term cultures supplemented with ascorbic acid and glycerophosphate such an effect was accompanied by a retardation of matrix mineralization. IL-4 also stimulated M-CSF expression by MC3T3 cells, both at the RNA and bioactivity levels. However, no stimulation of IL-1, IL-6, GM-CSF or PGE2 production was observed. An IL-4-induced inhibition of alkaline phosphatase expression and retardation of mineralization was also found in cultures of primary osteoblast-like cells isolated from neonatal mice calvariae. These results suggest that IL-4, probably released by cells within the bone marrow, may locally influence the activity of bone-forming cells.
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PMID:Interleukin-4 as a bone regulatory factor: effects on murine osteoblast-like cells. 754 94

Although 17 beta-estradiol (E2) replacement therapy has been shown to be effective in treating postmenopausal osteoporosis, the underlying mechanism remains unclear. The presence of low levels of functional endogenous estrogen receptor (ER) in some osteoblastic cells has been demonstrated, and the suggestion that the abundance of ER may be rate-limiting in the action of E2 on these cells has been made. To study the mechanism of ER in regard to E2-mediated effects, we stably transfected a human osteosarcoma cell line, SaOS-2, with an expression vector, pMV-7-ER, containing the human ER gene. We characterized six of the stably transfected clones. One of the stable clones, SaOS-2-ER, expressed extra copies of ER genes integrated into the genome as detected by Southern blot analysis, showed a significantly increased level of ER mRNA by RT-PCR, and contained an increased level of ER cytosolic protein as detected by an ER-specific EIA. The overexpressed ER was functional and sensitive to E2 in a dose-dependent fashion after transient transfection with a vector containing an estrogen response element (ERE) linked to a chloramphenicol acetyltransferase (CAT) reporter gene. Scatchard analysis revealed a single high-affinity binding site with a Kd similar to values obtained for the ER in MCF-7 breast cancer cells. These SaOS-2-ER cells had altered osteoblast phenotypic features including growth inhibition, decreased basal alkaline phosphatase activity, and decreased IL-6 expression and secretion. In response to E2, a greater than 2-fold increase in TGF-beta 1 mRNA was quantitatively measured in these ER-overexpressing osteoblasts. These cells may provide a sensitive and unique model for understanding the mechanism of E2 and ER in overall bone metabolism.
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PMID:Generation and characterization of a human osteosarcoma cell line stably transfected with the human estrogen receptor gene. 763 12

We have investigated the effect of a number of cytokines on the human acute myelomonocytic leukemic cell line, ML-1. The differentiation inducing effects of interleukins (IL-1 beta, IL-3 and IL-6), colony stimulating factors (GCSF and GMCSF), TNF, LIF and IFNg, were studied either individually or in combination. Criteria for monocytic differentiation were as follows: an increase in the percentage of cells reducing nitroblue tetrazolium (NBT) salt, an increase in the alkaline phosphatase activity as well as the appearance of macrophagic phenotype. Among all the cytokines tested, only TNF was found to induce differentiation and to inhibit growth of ML-1 cells. IL-3, IL-6, interferon gamma, GCSF and to a smaller extent IL-1 beta and GMCSF synergized the differentiation inducing activity of TNF.
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PMID:Comparative analysis of the effects of recombinant cytokines on the growth and differentiation of ML-1, a human myelogenous leukemic cell line. 768 36

The role of interleukin-6 in the bone microenvironment is controversial. We studied the effect of recombinant human interleukin-6 (rhIL-6) administration on bone metabolism in 10 adult female rhesus monkeys (age 12-27 years). Monkeys received rhIL-6 (15 micrograms/kg/day) daily by subcutaneous injection for 28 days. Serum alkaline phosphatase, osteocalcin, and 24 h urinary calcium excretion were determined before, during (at weeks 2 and 4), and after (at week 6) treatment. Transilial biopsies (right and left) were obtained before treatment was initiated and just after the final (28th) dose at week 4. The serum alkaline phosphatase significantly increased at 2 and 4 weeks of rhIL-6 administration. Osteocalcin and urinary calcium excretion significantly decreased at week 2. Upon treatment with rhIL-6 significant reductions in OS/BS and Ob.S/BS were observed without changes in other static histomorphometry parameters. The reductions in urinary calcium excretion, serum osteocalcin, and the static bone parameters are consistent with an IL-6 induced reduction in bone formation or turnover. Whether this pharmacologic effect is relevant at the physiologic level remains to be determined.
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PMID:Effects of recombinant human interleukin-6 administration on bone in rhesus monkeys. 799 21

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


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