Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Multidrug resistance proteins (MRPs) such as MRP1, MRP2 and MRP3 are membrane efflux pumps involved in multidrug resistance and handling organic anions. In the present study, MRP activity was investigated in normal mature leucocytes and CD34-positive hematopoietic cells from peripheral blood using the flow cytometric carboxy-2',7'-dichlorofluorescein (CF) efflux assay. Basal and similar cellular exports of CF, an anionic fluorescent dye substrate for MRP1 and MRP2 transporters, were evidenced in lymphocytes whatever their subsets (CD3, CD4, CD8, CD20 and CD56 cells), in CD14 monocytes and in CD15 granulocytes whereas higher CF efflux was found in CD34 cells. Such outwardly-directed transports of CF were inhibited by known blockers of MRP function such as probenecid whereas the P-glycoprotein modulator verapamil did not alter the retention of the dye in the blood leukocytes. Peripheral mature blood leukocytes were moreover found to express MRP1 mRNAs and MRP1 protein as assessed by Northern-blot and Western-blot analyses, whereas MRP2 and MRP3 transcripts were not present or only at very low levels. Mature leukocytes therefore display basal constitutive MRP-related transport activity regardless of cell lineage and likely related to MRP1 expression whereas higher MRP-related efflux can be detected in peripheral CD34 hematopoietic cells.
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PMID:Multidrug resistance protein (MRP) activity in normal mature leukocytes and CD34-positive hematopoietic cells from peripheral blood. 1123 99

Overexpression of P-glycoprotein, a transmembrane drug efflux pump that mediates efflux of chemotherapeutic agents contributes to drug resistance in many leukaemia and other cancerous cells. Non-malignant cells including leukocytes also express P-glycoprotein, but physiologic functions for P-glycoprotein are poorly defined. Recently, P-glycoprotein expression has been described in human mononuclear phagocytes and Langerhans cells. It has been shown to play a role in phagocytic cell transmigration through endothelial-lined vessels in an ablumenal-lumenal direction, a process that mimics their migration into lymphatic vessels. Using the monoclonal antibody 4E3, and the P-glycoprotein antagonist, verapamil, the expression of P-glycoprotein on human monocyte-derived dendritic cells was evaluated. Dendritic cells used in this study were CD1a+, CD11c+, CD14-, CD80+, CD83+, CD86+ and MHC-II(High). The expression of these markers increased significantly as the cells matured. P-glycoprotein expression was upregulated as the dendritic cells matured as well as in the presence of the "inflammatory stress" of the pathogenic bacteria Strept. pyogenes. Addition of verapamil or Strept. pyogenes to the culture medium during the final 24 hours significantly upregulated P-glycoprotein expression. Immortalized cell lines did not upregulate P-glycoprotein in the presence of verapamil. Evaluation of other normal cells showed that P-glycoprotein upregulation in the presence of verapamil was also a characteristic of macrophages. This novel observation of the upregulation of P-glycoprotein in the presence of verapamil appears to be a characteristic of activated myeloid derived antigen presenting cells and suggest that P-glycoprotein is essential for these cells as when it is blocked, they respond by increasing expression of this protein. In summary, this work describes that human dendritic cells generated from plastic-adherent monocytes rapidly upregulate expression of P-glycoprotein as they mature, and in the presence of inflammatory stress and the pharmacological agent verapamil, which blocks P-glycoprotein activity, suggesting that P-glycoprotein may play a role in activation as well as in migration of dendritic cells.
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PMID:Verapamil induces upregulation of P-glycoprotein expression on human monocyte derived dendritic cells. 1653 26

Dendritic cells (DC) express the ATP-binding cassette (ABC) transporters P-glycoprotein (ABCB1) and multidrug resistance protein 1 (MRP1; ABCC1). Functionally, both these transporters have been described to be required for efficient DC and T cell migration. In this study, we report that MRP1 activity is also crucial for differentiation of DC. Inhibition of MRP1, but not P-glycoprotein, transporter activity with specific antagonists during in vitro DC differentiation interfered with early DC development. Impaired interstitial and Langerhans DC differentiation was characterized by 1) morphological changes, reflected by dropped side scatter levels in flow cytometric analysis and 2) phenotypic changes illustrated by maintained expression of the monocytic marker CD14, lower expression levels of CD40, CD86, HLA-DR, and a significant decrease in the amount of cells expressing CD1a, CD1c, and Langerin. Defective DC differentiation also resulted in their reduced ability to stimulate allogeneic T cells. We identified the endogenous CD1 ligands sulfatide and monosialoganglioside GM1 as MRP1 substrates, but exogenous addition of these substrates could not restore the defects caused by blocking MRP1 activity during DC differentiation. Although leukotriene C(4) was reported to restore migration of murine Mrp1-deficient DC, the effects of MRP1 inhibition on DC differentiation appeared to be independent of the leukotriene pathway. Though MRP1 transporter activity is important for DC differentiation, the relevant MRP1 substrate, which is required for DC differentiation, remains to be identified. Altogether, MRP1 seems to fulfill an important physiological role in DC development and DC functions.
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PMID:Dendritic cells require multidrug resistance protein 1 (ABCC1) transporter activity for differentiation. 1662 83

P-glycoprotein (P-gp) expressed on human antigen presenting cells (APC) regulates alloantigen-dependent T-cell activation, but the associated mechanisms are not well understood. Here we demonstrate that P-gp functions in IL-12-dependent monocyte differentiation into dendritic cell (DC) lineages during APC maturation, thereby regulating the capacity of myeloid-derived APCs to elicit alloimmune Th1 responses. Human CD14+ monocytes cultured in vitro in the presence of IL-4/GM-CSF differentiated into CD14(-) CD1A+ APCs of the immature DC phenotype. In contrast, P-gp blockade during differentiation inhibited CD1a induction, down-regulated CD80 expression, enhanced CD86 expression and induced CD68 expression. APCs differentiated in the presence of P-gp blockade stimulated alloimmune T-cell proliferation significantly less than controls and this effect was associated with 97% inhibition of Th1 IFN-gamma production, but preserved Th2 IL-5 secretion. MAb-mediated blockade of the P-gp transport substrate IL-12 in the course of APC differentiation also inhibited IFN-gamma production, while addition of rIL-12 to P-gp-blocked APC differentiation cultures significantly reversed this effect, demonstrating that P-gp functions in APC differentiation in part via IL-12 regulation. Our findings define a novel role for P-gp as a differentiation switch in APC maturation and resultant alloimmune Th1 responses, thereby identifying P-gp as a potential novel therapeutic target in allotransplantation.
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PMID:P-glycoprotein functions as a differentiation switch in antigen presenting cell maturation. 1708 70

For drug absorption, intestinal drug permeability's through both the paracellular and transcellular routes were analyzed. Absorption enhancers, such as sodium caprate (C10), decanoylcarnitine (DC) and tartaric acid (TA), increased the paracellular permeability of water-soluble, low lipophilic and poorly absorbable drugs by enlargement of tight junction (TJ) adhering to the intercellular portion; that is, expansion of the paracellular routes. C10 increased the intracellular calcium level to induce contraction of calmodulin-dependent actin filaments. Although DC also increased the intracellular calcium level, the action was independent of calmodulin, and thus the action mechanism of DC was considered to differ from that of C10. DC and TA decreased the intracellular ATP level and the intracellular pH, suggesting that intracellular acidosis increases the calcium level through decrease in ATP level followed by opening TJ. TA had no effect on Western blot analysis, but TA significantly inhibited excretion of rhodamine 123, one of the P-glycoprotein (P-gp) substrates, from the serosal to mucosal side, suggesting that TA increases the intestinal absorption of P-gp substrates, possibly by inhibiting the P-gp function without changing the expression of P-gp. During ischemia/reperfusion (I/R) injury during small intestine grafting, TJ opening and decrease in P-gp function simultaneously occurred. The in vitro model of I/R showed that lipid peroxidation is a trigger of the injury, and superoxide and iron ion participate in TJ opening and decrease in P-gp function. Colonic epithelial cells have the specific transcellular transport systems for lipopolysaccharide (LPS), one of which shows substrate specificity in the interaction with CD14 and/or that of TLR4. In the infective disease induced by LPS, the mucosal LPS sensitive transport capability was decreased and in the secretory direction, the receptor-mediated uptake mechanism disappeared. LPS taken up into the cells can be excreted by P-gp or mrp. The expression levels and function of the secretory transporters were considered to be increased in the infective condition. In conclusion, changes in TJ as the membrane structure and P-gp as the membrane function are important factors controlling intestinal membrane transport.
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PMID:Mechanistic analysis for drug permeation through intestinal membrane. 1749 13

A total of 49 newly diagnosed patients with acute leukemia were studied in order to assess the diagnostic value of clone AC141 of CD133 antibody by flow cytometry. AC141 expression was further compared to CD34 and P-glycoprotein, immunophenotype, morphology and cytogenetic/molecular data. Flow cytometry allowed for the detection of AC141 expression in 42.8% of the patients. A strong correlation with myeloid lineage was observed. All AC141(+) acute myeloid leukemia (AML) cases were of immature morphology and a strong concordance with CD34 expression was found. However, discordant patterns were also observed. Besides, AC141 expression correlated with CD7 in the absence of mature markers (CD14, CD15 and CD64). Similarly to CD34, P-glycoprotein levels were also significantly higher in AC141(+) AML cases. No correlation was found with cytogenetic/molecular data of the patients. In conclusion, membrane expression of AC141, in combination with other antigens, might facilitate a more precise immunologic characterization of acute leukemias and may serve as an alternative to CD34 for purging purposes in selected patients.
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PMID:CD133-2 (AC141) expression analysis in acute leukemia immunophenotyping in correlation to CD34 and P-glycoprotein. 1870 70


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