Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1,25-Dihydroxyvitamin D3 (1,25-D3) is known to have potent inhibitory effects on human peripheral blood mononuclear cell (PBMC) functions. Previous experiments suggest that addition of interleukin-2 (IL-2) to cell cultures can reverse the antiproliferative action of 1,25-D3. Previous studies have also shown that the CD4+ T-cell subset is more sensitive to the antiproliferative actions of 1,25-D3 than are the CD8+ T-cells. The objective of this study was to determine whether exogenous IL-2 could reverse the antiproliferative and immunoinhibitory action (inhibition of Ig production) in mitogen-activated PBMC cultures and in fluorescein-activated cell sorting (FACS) experiments where CD8+ T-cells were removed from PBMCs before mitogen stimulation with/without exogenous IL-2 added. In these studies, addition of IL-2 to mitogen-activated, 1,25-D3-treated PBMCs allowed the cells to overcome the 1,25-D3 suppressive effect on cell proliferation. However, exogenous IL-2 did not overcome the 1,25-D3-mediated inhibitory effect on PBMC Ig production. Using FACS lymphocyte populations (CD4+, CD8+ and B-cells), we showed that CD4+ T-cell-directed Ig synthesis in co-culture with autologous B-cells was inhibitable by incubation of cells with 1,25-D3, but Ig synthesis was restored to near-normal levels by addition of exogenous IL-2. This clearly contrasts with the inability of Il-2 to reverse the 1,25-D3 inhibitory effect on Ig synthesis in PBMCs. In other experiments, when CD8+ cells were removed from mitogen-stimulated, 1,25-D3-treated PBMCs, addition of exogenous IL-2 resulted in a full reversal of the 1,25-D3-mediated Ig inhibition. These data suggest that the inability of IL-2 to reverse the inhibitory effects of 1,25-D3 on PBMC Ig production is probably a result of a lack of sensitivity of CD8+ T-cells to the antiproliferative and immunoregulatory actions of 1,25-D3. This is possibly because of a differential expression of 1,25-D3 receptors on CD4+ and CD8+ T-cells.
Mol Immunol 1990 Jan
PMID:Exogenous interleukin-2 does not reverse the immunoinhibitory effects of 1,25-dihydroxyvitamin D3 on human peripheral blood lymphocyte immunoglobulin production. 196 10

Although interleukin (IL)-2 may in part be responsible for lymphocyte accumulation to sites of active sarcoidosis, other cytokines that control such recruitment are not well characterized. Similarly, the pathogenic rationale for the ability of sarcoid macrophages to produce 1,25-dihydroxycholecalciferol (calcitriol) is not understood. We studied the release of chemokinetic lymphokines from human nylon wool-non-adherent tonsillar lymphocytes (HNTLs) employing a standard in vitro lymphocyte migration assay. If mitogen-stimulated HNTL supernatants were fractionated by high-performance liquid chromatography, five positive and one negative chemokinetic factors could be identified. The five lymphocyte chemoattractant factors (LCFs) ranged in mol wt from 5 to 35 kD and stimulated the in vitro migration of nonsensitized human lymphocytes by 200 to 500%. The LCFs appeared distinct from IL-2, IL-1, or gamma-interferon. Co-incubation of HNTLs with mitogen and 1 nM calcitriol prevented the production or release of two of the LCFs and significantly decreased the quantity of a third LCF. Calcitriol also resulted in the appearance of a second negative chemokinetic factor, lymphocyte migration inhibitory factor (LyMIF). Combined with our previous studies demonstrating that calcitriol interferes with IL-2-induced lymphocyte migration, these results provide a rationale for an anti-inflammatory role for calcitriol in sarcoidosis and other granulomatous disorders. These experiments also demonstrate that the control of lymphocyte recruitment to inflammatory foci is multifactorial.
Am J Respir Cell Mol Biol 1991 Jan
PMID:Lymphocyte chemokinetic factors derived from human tonsils: modulation by 1,25-dihydroxyvitamin D3 (calcitriol). 198 77

1,25-Dihydroxyvitamin D3, the hormonally active form of vitamin D (1,25(OH)2D3), plays a major role in the transcriptional regulation of the vitamin D-induced calcium binding protein calbindin-D28k in the chick intestine. Sequence-specific protein-DNA interactions within the promoter of the calbindin-D28k gene were studied by DNAse I footprinting analysis to obtain information on the mechanism by which the 1,25(OH)2D3 receptor and other transcription factors regulate its expression. Restriction fragments spanning nucleotides -679 to +44 of the calbindin-D28k gene were used as probes Intestinal nuclear extracts prepared from vitamin D-deficient chicks generated several protected regions. Two prominent areas of protection against DNase I digestion were located at nucleotides -595 to -572 (21 bp) and -372 to -337 (36 bp). The -372 to -337 protected segment includes a CACCC sequence motif. Additional protection regions (-333/-328, -319/-315 and -308/-304) were observed within and near the candidate chicken calbindin-D28k 1,25(OH)2D3-response element (-329/-313) and the CCAAT box (-326/-322). DNase I digestion patterns obtained with liver nuclear extracts, containing low levels of 1,25(OH)2D3 receptor, revealed weaker protein-DNA interactions in these regions.
Mol Cell Endocrinol 1991 Jan
PMID:Sequences near the CCAAT region and putative 1,25-dihydroxyvitamin D3-response element and further upstream novel regulatory sequences of calbindin-D28k promoter show DNase I footprinting protection. 205 Feb 66

25-Hydroxycholecalciferol (25-OHD3) is converted to 8 alpha,25-dihydroxy-3-oxoneocholecalciferol [8,25-(OH)2-3-oxoneo-D3] by liver microsomes, alveolar macrophages and myeloid leukemia cells. The characteristics of this reaction in liver microsomes have been determined. Omission of an NADPH-generating system or NADH resulted in a greater than 75% reduction in the production of 8,25-(OH)2-3-oxoneo-D3. In the absence of the cytosolic fraction, 25-OHD3 was converted to products that comigrated with 8,25-(OH)2-3-oxoneo-D3 on a silica column developed with hexane-isopropanol, thereby preventing quantitation. Production of 8,25-(OH)2-3-oxoneo-D3 was unaffected by EDTA and was stimulated by N,N'-diphenyl-p-phenylenediamine. Both progesterone and pregnenolone inhibited production of 8,25-(OH)2-3-oxoneo-D3; inhibition by progesterone was greater than that by pregnenolone. 8,25-(OH)2-3-Oxoneo-D3 did not bind the thymus receptor for 1,25-dihydroxycholecalciferol [1,25-(OH)2D3] at concentrations 10-fold higher than that of 1,25-(OH)2D3. The lack of affinity of 8,25-(OH)2-3-oxoneo-D3 for the 1,25-(OH)2D3 receptor suggests that this metabolite is a degradative product of 25-OHD3, which might be produced when 25-OHD3 concentrations in the liver are excessive. Synthesis of this metabolite in the liver may be catalyzed by enzymes that also metabolize other steroids.
J Steroid Biochem Mol Biol 1991 Jun
PMID:Synthesis and function of 8 alpha,25-dihydroxy-3-oxoneocholecalciferol in liver. 206 90

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) and dexamethasone (DEX) influence synthesis and secretion of various hormones. Recent reports concerning the interaction of the two steroids revealed opposite--agonistic as well as antagonistic--effects in different biological systems. As calcitonin (CT) gene expression is affected by both agents, inhibited by 1,25(OH)2D3 and stimulated by DEX, we utilized CT secretion and storage as a model to study the combined effects of the two hormones. A human C cell carcinoma cell line (TT) was used, incubating the cells for a period of 4 days with 1,25(OH)2D3 and DEX alone and in combination. 1,25(OH)2D3 resulted in a decrease, whereas DEX resulted in a increase of CT secretion and content. Combining the two steroids, 1,25(OH)2D3 surprisingly abolished the stimulation of DEX on CT secretion and content. The underlying mechanism is yet unclear and could be envisioned to include steroid receptor regulation or gene transcription.
Mol Cell Endocrinol 1990 Jul 09
PMID:1,25-Dihydroxyvitamin D3 suppresses dexamethasone effects on calcitonin secretion. 221 27

1,25-Dihydroxyvitamin D3, [1,25(OH)2D3], the biologically most active metabolite of vitamin D3, is involved in the regulation of calcium homeostasis and bone metabolism. Recently, receptors for 1,25(OH)2D3 have also been shown in cells and tissues not directly related to calcium homeostasis. Experimental data obtained with leukaemic and cancer cell lines, both in vitro and in vivo, showed the effects of 1,25(OH)2D3 on cell differentiation and proliferation. However, high doses of the sterol have to be used to observe these effects. Additional studies are needed to establish whether 1,25(OH)2D3 or suitable analogues have a therapeutic potential in malignant diseases without unacceptable toxicity like the development of hypercalcemia.
J Steroid Biochem Mol Biol 1990 Dec 20
PMID:Vitamin D: a modulator of cell proliferation and differentiation. 228

1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] regulates the synthesis of bone gamma-carboxyglutamic acid (Gla) protein (BGP) by osteoblastic cells. In this study we examined the effect of cAMP, alone and in combination with 1,25-(OH)2D3, on the regulation of BGP mRNA levels in ROS 17/2 rat osteosarcoma cells. Elevation of intracellular cAMP levels by cAMP analogs or by isobutylmethylxanthine (IBMX), forskolin, or PTH, resulted in increased BGP mRNA levels and BGP secretion after 1 day of treatment. The effects of these agents were additive with 1,25-(OH)2D3 in stimulating BGP gene expression. After 4 days of treatment, pertussis toxin (PT) and 1,25-(OH)2D3 were synergistic in stimulating BGP mRNA, and the effect of PT could be mimicked by (Bu)2cAMP, IBMX, forskolin, cholera toxin, and to a lesser extent by PTH. The effect of 1-day treatment with cAMP alone and the synergistic effect with 1,25-(OH)2D3 on the stimulation of BGP mRNA were dependent on cell density, while basal and 1,25-(OH)2D3-stimulated synthesis were not. Cyclic AMP inhibited ROS 17/2 cell growth after 1 day of treatment, an effect that was also dependent on initial cell density. After 4 days of treatment, 1,25-(OH)2D3, cAMP, and PT all demonstrated inhibition of cell growth. When cells were treated with actinomycin D, both 1,25-(OH)2D3 and cAMP stimulation of BGP mRNA were blocked. In addition, neither agent was effective in enhancing BGP mRNA stability when prestimulated cells were exposed to actinomycin D.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1989 Jan
PMID:Bone Gla protein messenger ribonucleic acid is regulated by both 1,25-dihydroxyvitamin D3 and 3',5'-cyclic adenosine monophosphate in rat osteosarcoma cells. 246 56

1,25-Dihydroxyvitamin D (1,25(OH)2D3) receptors appear in cultured lymphocytes after activation; 1,25(OH)2D3 has been shown to affect both the immune function and proliferation of activated cells. However, the mechanism of these effects is not completely understood. We therefore studied the effect of 1,25(OH)2D3 on forskolin-stimulated lymphocyte cAMP production during concanavalin A (ConA) activation. Purified lymphocytes were cultured with ConA; 1,25(OH)2D3 was added concurrently or 24-48 h later. To measure cAMP production, aliquots of 10(6) cells were preincubated with a phosphodiesterase inhibitor and then stimulated with the diterpene activator, forskolin (15 microM, x 10 min). The cAMP production was 4 +/- 2 pmol/10(6) cells prior to activation, increasing markedly in 48-72 h and then declining. When 1,25(OH)2D3 was added to the culture for 48 h beginning 24 h after activation, forskolin-stimulated cAMP production was consistently reduced by greater than half. This effect on cAMP production was dose dependent with half-maximal attenuation at 5 X 10(-10) M 1,25(OH)2D3. Neither 10(-8) M 24,25(OH)2D3 nor 25(OH)D3 diminished the cAMP response to forskolin. Blastic transformation was not altered by 48 h exposure to 1,25(OH)2D3 at any time during the 120 h the cultures were maintained. We conclude that 1,25(OH)2D3 can modulate cAMP production and suggest that this may contribute to other effects on T lymphocyte function. We have described the ability of 1,25(OH)2D3 to attenuate the hormone-stimulated cAMP production in other cell types and suggest that this may be a generalized mechanism through which 1,25(OH)2D3 works.
Mol Cell Endocrinol 1987 Aug
PMID:1,25-Dihydroxyvitamin D attenuates cAMP accumulation in cultured human lymphocytes. 282 Aug 13

1,25-Dihydroxyvitamin D3 (calcitriol), or vitamin D3 itself, when added to cultures of 20-day-old embryonic chick small intestine, stimulated sodium (Na+) uptake from the mucosal surface. The calcitriol-mediated increase in Na+ uptake appeared to be related to increased tight-junctional or paracellular permeability. Support for this conclusion was, first, that the uptake of other ions, potassium (K+) and rubidium (Rb+), with tight-junctional permeabilities greater than Na+, was also stimulated by calcitriol, and second, perturbation of cellular Na+ and K+ fluxes by inhibition of Na+/K+-ATPase activity did not affect calcitriol-stimulated Na+, K+, or Rb+ transport. Calcitriol stimulation of Na+ fluxes across the brush border as an alternate possibility is unlikely for the following reason: the calcium ionophore A23187, while mimicking the stimulatory action of calcitriol on calcium (Ca2+) uptake, reduced epithelial Na+ uptake. It is therefore suggested that calcitriol, by virtue of its effect on Ca2+ transport, reduces rather than stimulates cellular Na+ uptake.
Mol Cell Endocrinol 1987 Sep
PMID:Calcitriol-dependent, paracellular sodium transport in the embryonic chick intestine. 282 8

A number of vitamin D3 metabolites inhibit benzodiazepine- and dimethyl sulfoxide-induced differentiation of Friend erythroleukemia cells. The inhibition is dose dependent and occurs at nM concentrations. The order of potency of these compounds is 1,25-dihydroxycholecalciferol greater than 1,25,26-trihydroxycholecalciferol greater than 1,24R,25-trihydroxycholecalciferol greater than 1 alpha-hydroxycholecalciferol greater than 24R,25-dihydroxycholecalciferol greater than 25S,26-dihydroxycholecalciferol. The inhibition is maximal when the vitamin D3 analogs are added together with the inducer, and becomes progressively decreased with delayed addition. These results suggest that the vitamin D3 metabolites may play a regulatory role in erythropoiesis.
Mol Pharmacol 1986 Dec
PMID:Vitamin D3 derivatives inhibit the differentiation of Friend erythroleukemia cells. 302 14


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