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:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have used a T-cell receptor transgenic mouse model to study the role of antigen in the changes that occur as T cells age. We find that the characteristic shift in the CD4 population to a predominance of memory phenotype T cells which accompanies aging in non-transgenic mice does not occur, suggesting that this shift is a result of antigenic stimulation. Thus at least one component of aging must be antigen dependent. When responses of naive CD4 T cells from aged and young mice are directly compared in vitro, the former are relatively deficient in their ability to produce IL-2 and IL-3, they express altered levels of P-glycoprotein and they proliferate less well in the absence of exogenous cytokines. When the ability of both naive populations to generate effectors is compared, the number of effectors generated from aged naive cells is much reduced and the effectors generated express lower levels of IL-2R alpha and produce reduced levels of cytokines. Importantly, addition of IL-2 restores proliferation of aged naive T cells, restores efficient effector generation and results in effectors seemingly indistinguishable from those derived from young CD4 cells. Similar phenotypic and functional changes seen with aging are also found in T-cell populations from IL-2 and IL-2R alpha knockout mice. Thus the loss of optimal IL-2 production may participate in the aging process and may represent the main antigen-independent defect in the CD4 T-cell population.
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PMID:From naive to effector--alterations with aging. 947 61

The plasma membrane transport protein P-glycoprotein (P-gp) is expressed by subsets of both CD4+ and CD8+ T cells in mice. The proportion of T cells that express P-gp goes up with age, and the P-gp-expressing subset of the CD4 memory population is hyporesponsive in many in vitro assays. The significance of P-gp expression for T cell function has not been well established, although several reports have suggested that it may promote cytokine export and/or cytotoxic T cell function. To elucidate which T cell functions may require P-gp, we have compared a variety of responses using T cells from wt and P-gp knockout mice. Protein expression and rhodamine-123 efflux studies revealed that peripheral T cells exclusively utilize the mdr1a-encoded isoform rather than the homologous mdr1b or mdr2 isoforms. Comparisons of T cells from mdr1a+/+ and mdr1a-/- mice showed no differences in proliferation or in secretion of IL-2, IL-4, IL-5, IL-10, or IFN-gamma in response to polyclonal stimulation. Moreover, mdr1a-/- T cells produced strong allospecific cytotoxic responses comparable to those of wt T cells. Our results show that P-gp is not a necessary component of peripheral T cell functional responses. Further investigation will be needed to determine the significance of P-gp expression in T lymphocytes.
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PMID:mdr1a-encoded P-glycoprotein is not required for peripheral T cell proliferation, cytokine release, or cytotoxic effector function in mice. 1045 1

The expression of P-glycoprotein (Pgp) on normal human lymphocytes, and its drug exclusion capacity, implies that Pgp might be involved in cytokine secretion. We used two-color flow cytometry to detect simultaneously Pgp expression and IL-2 accumulation in resting and mitogen-activated human lymphocytes. Among resting lymphocytes from five healthy donors less than 1% were Pgp+ as determined by reactivity with the anti-Pgp monoclonal antibody (mAb) 4E3. The percentage of Pgp+ lymphocytes increased to 3% after 24 hr of mitogenic stimulation that induced maximal production of cytoplasmic IL-2. The percentage of lymphocytes that coexpressed membrane Pgp and cytoplasmic IL-2 accounted for < 10% of the total IL-2 producing lymphocytes. Finally, mitogen-induced cytoplasmic IL-2 accumulation was enhanced by stimulation in the presence of monensin but not the Pgp functional inhibitor verapamil. Because mAb 4E3 detected lower than expected numbers of Pgp+ lymphocytes, we compared the binding of mAbs MRK16 and 4E3 concomitant with doxorubicin (DOX)-uptake by K562 and R7 tumor cells and purified CD8+ lymphocytes. The MRK16 mAb was found to be sensitive but not very specific (30%). In contrast, the sensitivity of 4E3 was equivalent to MRK16 (98%) and was highly specific (98.5%). There was also a positive association between DOX efflux and the level of Pgp expression as detected by 4E3 but not MRK16. Thus, human T cells do not markedly up-regulate their expression of functional Pgp molecules as detected by mAb 4E3 following activation, suggesting that Pgp does not play a major role in IL-2 secretion by activated T cells.
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PMID:Activation of human peripheral blood T cells does not lead to increased P-glycoprotein expression. 1047 78

Intraepithelial lymphocytes (IEL) that reside in the intestinal epithelium are known to exhibit phenotypic and functional characteristics that are distinct from other T cells. We have recently shown that peripheral T cells exclusively express an isoform of P-glycoprotein (P-gp) encoded by the mdr1a gene, but do not require mdr1a expression for normal proliferative, cytokine, or cytotoxic responses. In the present study, we have used mdr1-type knockout (KO) mice to demonstrate that IEL also utilize mdr1a, but only preferentially, in that the mdr1b isoform can be expressed in the absence of mdr1a expression. We also report that a high level of P-gp activity appears to be necessary for the normal development of certain IEL subpopulations. In specific, while the total number of IEL was relatively unaffected by the absence of mdr1a expression, the proportions of CD8 alpha beta and TCR alpha beta+ IEL increased significantly in mdr1a and mdr1a/b KO mice at the expense of CD8 alpha alpha and TCR gamma delta+ IEL, respectively. Moreover, these subset alterations also appeared to have functional consequences, in that proliferative, IL-2, and IFN-gamma responses of IEL from KO mice were distinct from those of normal IEL. In summary, our data suggest that mdr1a expression is required for the development of certain IEL subpopulations, most notably TCR gamma delta+ cells, and thereby indirectly influences the balance of T cell subsets in the intestinal epithelium.
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PMID:Altered development of intestinal intraepithelial lymphocytes in P-glycoprotein-deficient mice. 1090 91

MDR1 P-glycoprotein (P-gp), the multidrug resistance-associated transmembrane transporter, is physiologically expressed by human peripheral immune cells, but its role in cell-mediated immunity remains poorly understood. Here, we demonstrate a novel role for P-gp in alloantigen-dependent human T cell activation. The pharmacologic P-gp inhibitor tamoxifen (1-10 microM) and the MDR1 P-gp-specific mAb Hyb-241 (1-20 microg/ml), which detected surface P-gp on 21% of human CD3(+) T cells and 84% of CD14(+) APCs in our studies, inhibited alloantigen-dependent, but not mitogen-dependent, T cell proliferation in a dose-dependent manner from 40-90% (p < 0.01). The specific inhibitory effect on alloimmune T cell activation was associated with >85% inhibition (p < 0.01) of IL-2, IFN-gamma, and TNF-alpha production in 48-h MLR coculture supernatants. Addition of recombinant human IL-2 (0.1-10 ng/ml) restored proliferation in tamoxifen-treated cocultures. Pretreatment of purified CD4(+) T cells with Hyb-241 mAb before coculture resulted in inhibition of CD4(+) T cellular IFN-gamma secretion. Also, blockade of P-gp on allogeneic APCs inhibited IL-12 secretion. Taken together these results demonstrate that P-gp is functional on both CD4(+) T cells and CD14(+) APCs, and that P-gp blockade may attenuate both IFN-gamma and IL-12 through a positive feedback loop. Our results define a novel role for P-gp in alloimmunity and thus raise the intriguing possibility that P-gp may represent a novel therapeutic target in allograft rejection.
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PMID:Specific MDR1 P-glycoprotein blockade inhibits human alloimmune T cell activation in vitro. 1116 Mar 5

P-glycoprotein (encoded by multidrug resistance genes), a member of the ATP-binding cassette transporter protein superfamily, has been shown to play a role in the secretion of cytokines. This conclusion was based upon the inhibition of cytokine secretion by anti-P-gp monoclonal antibodies. In this study, we show that anti-CD3-stimulated lymphocytes from wild-type, mdr1a knock out and mdr1ab double knock out mice produce similar amounts of IL-2, IFN-gamma, IL-4, and IL-10. In addition, Jurkat T cells that lack P-gp and MDR1-transfected Jurkat T cells (JurkatP-gp) as well as purified human peripheral blood CD4+ P-gp+ and CD4+ P-gp- and CD8+ P-gp+ and CD8+ P-gp- T cell subsets produced comparable amounts of IL-2. These data show that P-gp is not required for secretion of IL-2, IFN-gamma, IL-4, and IL-10 secretion in mice and IL-2 secretion in humans.
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PMID:P-glycoprotein (encoded by multidrug resistance genes) is not required for interleukin-2 secretion in mice and humans. 1119 84

Cyclosporin is a non-cytotoxic immunomodulating drug which inhibits NF-AT-dependent IL-2 transcription in lymphocytes. Cyclosporin is, therefore, beneficial as a monotherapy or as a combined therapy with methotrexate for refractory rheumatoid arthritis (RA). We also document that cyclosporin recovers the low concentration of intracellular multidrugs in lymphocytes by competitively binding to P-glycoprotein, a product of multidrug resistance gene-1, in vitro. Thus, cyclosporin could be used for the reversal of multidrug resistance, experienced in patients with longterm treated RA.
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PMID:[Clinical implication of cyclosporin for rheumatoid arthritis]. 1251 Mar 60

We evaluated levels of intestinal expression of absorptive-barrier P-glycoprotein (PGP) and cytochrome P-450 IIIA4 (CYP3A4) and immunosuppressant therapy in a patient who underwent living donor liver transplantation (LDLT) and received a second living donor liver transplant after chronic rejection of the first. PGP and CYP3A4 expression were measured using part of a Roux-en-Y limb. After the first LDLT, the concentration-dose ratio of orally administered tacrolimus was 159.8 +/- 125.3 (average +/- SD of 32 different days), similar to the average for 46 recipients of living donor liver transplants in our hospital (161.3 +/- 88.1). However, the recipient required very large oral doses of cyclosporine (703.9 +/- 385.4 mg/d, average +/- SD of 13 different days) after the second LDLT. Although intestinal PGP level was increased markedly at the second LDLT, CYP3A4 level was decreased. In addition, levels of messenger RNA expression of several gene products related to the local inflammation, such as cyclooxygenase 2, interleukin-1beta (IL-1beta), IL-2, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha, were increased. These results suggest that hepatic failure after LDLT, including chronic rejection and/or cholangitis, was accompanied by upregulation of intestinal PGP expression, which could depress the bioavailability of the immunosuppressant.
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PMID:Enhanced expression of enterocyte P-glycoprotein depresses cyclosporine bioavailability in a recipient of living donor liver transplantation. 1452 9

P-glycoprotein, encoded by the multidrug resistance (MDR)-1 gene, expels various drugs from cells resulting in drug resistance. However, its functional relevance to lymphocytes and the regulatory mechanism remain unclear. Although MDR-1 is known to be induced by various cytotoxic stimuli, it is poorly understood whether the activation stimuli such as cytokines induce MDR-1 transcription. We investigated the transcriptional regulation of MDR-1 in lymphocytes by activation stimuli, particularly by interleukin (IL)-2. IL-2 induced translocation of YB-1, a specific transcriptional factor for MDR-1, from the cytoplasm into nucleus of lymphocytes in a dose-dependent manner and resulted in the sequential events; transcription of MDR-1, expression of P-glycoprotein on the cell surface, and excretion of the intracellular dexamethasone added in vitro. Transfection of YB-1 anti-sense oligonucleotides inhibited P-glycoprotein expression induced by IL-2. Cyclosporin A, a competitive inhibitor of P-glycoprotein, recovered intracellular dexamethasone levels in lymphocytes. We provide the first evidence that IL-2, a representative lymphocyte-activation stimulus, induces YB-1 activation followed by P-glycoprotein expression in lymphocytes. Our findings imply that lymphocytes activation by IL-2 in vivo, in the context of the pathogenesis of autoimmune diseases, results in P-glycoprotein-mediated multidrug resistance, and that P-glycoprotein could be an important target for the treatment of refractory autoimmune diseases.
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PMID:Transcriptional regulation of multidrug resistance-1 gene by interleukin-2 in lymphocytes. 1556 57

P-glycoprotein (P-gp), a product of the MDR1 gene, is an important factor in the turnover of many drugs and xenobiotics. Recent reports have suggested that P-gp can also be involved in the transport of cytokines. The aim of this study was to examine the role of P-gp in cytokine release from phytohaemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (MNCs) as well as in the release of cytokines from MNCs treated with methotrexate (MTX) and dexamethasone (DEX). The study was carried out on PHA-stimulated MNC from 10 healthy subjects. Flow cytometry was applied to measure interleukin (IL)-2, IL-4, IL-6, IL-10, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha levels in the culture supernatants. In the experiments verapamil (VER) and P-gp specific monoclonal antibodies (mAb) (clone 17F9) were used to inhibit P-gp function. P-gp inhibitors suppressed the release of IL-2, IL-4, IFN-gamma and TNF-alpha from PHA-stimulated MNC, whereas release of IL-6 and IL-10 remained unaffected. VER and mAb significantly decreased the release of IL-2, IL-4, TNF-alpha and INF-gamma in MNC cultures treated with MTX or DEX. The results of this study suggest that P-gp may be involved in the transmembrane transport of some cytokines. Moreover, it seems that blocking of P-gp function may influence the release of some cytokines from MNCs, displaying an additive inhibitory effect to DEX and MTX.
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PMID:Involvement of P-glycoprotein in the release of cytokines from peripheral blood mononuclear cells treated with methotrexate and dexamethasone. 1625 74


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