P-glycoprotein (MDR 1 gene product) in cells of the immune system: Its possible physiologic role and alteration in aging and human immunodeficiency virus-1 (HIV-1) infection

Gupta, Sudhir; Gollapudi, Sastry

doi:10.1007/bf00920237

Cited by 71 publications

(40 citation statements)

References 52 publications

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“…However, the expression and function of surface P-gp by the majority of CD14 ϩ cells is different from several previous reports illustrating low P-gp expression on monocytes (10,11,14). Our findings, however, are consistent with one report that used another P-gp-specific mAb (MRK16) (31). Moreover, our finding of functional inhibition of calcein-AM dye efflux from purified CD4 ϩ T cells and monocytes by specific (Hyb-241 mAb) and pharmacologic P-gp inhibitors, a well-described function of P-gp in other cell types (30,32), confirmed that P-gp is functional in CD4 ϩ T cells and monocytes.…”

Section: Discussionsupporting

confidence: 93%

Specific MDR1 P-Glycoprotein Blockade Inhibits Human Alloimmune T Cell Activation In Vitro

Frank

Denton

Alexander

et al. 2001

The Journal of Immunology

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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 μM) and the MDR1 P-gp-specific mAb Hyb-241 (1–20 μg/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-γ, and TNF-α 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-γ 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-γ 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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Section: Discussionsupporting

confidence: 93%

Specific MDR1 P-Glycoprotein Blockade Inhibits Human Alloimmune T Cell Activation In Vitro

Frank

Denton

Alexander

et al. 2001

The Journal of Immunology

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“…The level of intracellular Rh 123 accumulation can be measured by flow cytometry. P-gp is expressed at high levels in tissues like the gastrointestinal tract, liver, and kidney and on capillary endothelial cells of the brain and on PBMCs (17, 26, 44,53,61,94,128,129). P-gp was found on freshly isolated CD4 ϩ and CD8 ϩ T cells.…”

Section: Tissue Distribution Of P-gpmentioning

confidence: 99%

“…P-gp expressed in the placenta plays an important role in the protection of the developing fetus against toxic substances (81,120). P-gp expression on bone marrow stem cells might protect them from toxic substances and could also be responsible for the transport of certain growth factors and cytokines produced by stem cells (53). It is unclear whether P-gp also has this function in other cell types.…”

Section: P-gp Functionmentioning

confidence: 99%

P Glycoprotein in Human Immunodeficiency Virus Type 1 Infection and Therapy

Sankatsing

Beijnen

Schinkel

et al. 2004

Antimicrob Agents Chemother

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“…This function is illustrated elegantly in mice that lack one [Mdr1a (Ϫ͞Ϫ) or Mdr1b(Ϫ͞Ϫ)] or both drug-transporting P-gps, because these mice have profound defects in drug distribution (5,14,15). High P-gp expression also is found in hematopoietic pluripotent stem cells and specific lymphocyte lineages, including NK cells and mature single positive thymocytes (16)(17)(18). Significantly, P-gp is expressed in developing organs of the early fetus where the ordered process of cell differentiation and death is necessary for correct organogenesis.…”

mentioning

confidence: 99%

The drug efflux protein, P-glycoprotein, additionally protects drug-resistant tumor cells from multiple forms of caspase-dependent apoptosis

Smyth¹,

Krasovskis²,

Sutton³

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

335

231

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Multidrug resistance mediated by the drug eff lux protein, P-glycoprotein (P-gp), is one mechanism that tumor cells use to escape death induced by chemotherapeutic agents. However, the mechanism by which P-gp confers resistance to a large variety of structurally diverse molecules has remained elusive. In this study, classical multidrug resistant human CEM and K562 tumor cell lines expressing high levels of P-gp were less sensitive to multiple forms of caspasedependent cell death, including that mediated by cytotoxic drugs and ligation of Fas. The DNA fragmentation and membrane damage inf licted by these stimuli were defined as caspase dependent by various soluble peptide f luoromethylketone caspase inhibitors. Inhibition of P-gp function by the anti-P-gp mAb MRK-16 or verapamil could reverse resistance to these forms of cell death. Inhibition of P-gp function also enhanced drug or Fas-mediated activation of caspase-3 in drug-resistant CEM cells. By contrast, caspase-independent cell death events in the same cells, including those mediated by pore-forming proteins or intact NK cells, were not affected by P-gp expression. These observations suggest that, in addition to eff luxing drugs, P-gp may play a specific role in regulating some caspase-dependent apoptotic pathways.

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P-glycoprotein (MDR 1 gene product) in cells of the immune system: Its possible physiologic role and alteration in aging and human immunodeficiency virus-1 (HIV-1) infection

Cited by 71 publications

References 52 publications

Specific MDR1 P-Glycoprotein Blockade Inhibits Human Alloimmune T Cell Activation In Vitro

Specific MDR1 P-Glycoprotein Blockade Inhibits Human Alloimmune T Cell Activation In Vitro

P Glycoprotein in Human Immunodeficiency Virus Type 1 Infection and Therapy

The drug efflux protein, P-glycoprotein, additionally protects drug-resistant tumor cells from multiple forms of caspase-dependent apoptosis

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