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)

Allergen-induced emigration and maturation of dendritic cells (DC) are pivotal steps in sparking off allergic contact dermatitis. In vitro models, reflecting these steps, may provide tools for assessment of sensitizing capacities of putative contact allergens. Here, we evaluated the applicability of such models for a panel of methacrylate congeners, the sensitizing properties of which were established previously in clinical and experimental animal studies. First, using interleukin-4 (IL-4)/granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced, blood monocyte-derived DC, hapten-induced up-regulation of maturation/ activation markers, including CD80, CD83, CD86, chemokine receptors CXCR4 and CCR5, as well as the drug resistance related molecules P-glycoprotein (Pgp) and lung resistance protein (LRP), were monitored by flow cytometry. Of note, whereas CD86 and CXCR4 were most sensitive in discriminating between the contact sensitizers and irritants included in the panel, i.e. sodium dodecyl sulphate (SDS) and croton oil (CO), assessment of CD83 and LRP expression reflected the relatively lower sensitizing capacity of methyl methacrylate. Second, using ex vivo skin explant cultures, allergen-induced LC migration from epidermal to basal membranous and dermal skin structures was most reliably monitored by CDla, as compared with Pgp, LRP, HLA-DR or CD54 staining. The extent of CD1a+ LC migration was found to closely correlate with the sensitizing capacities of the panel of test compounds. These results support the view that both in vitro models can provide valuable data on contact sensitizing properties, and add chemokine receptors and drug resistance related molecules to the list of DC membrane markers revealing allergenic signaling.
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PMID:Comparison of two in vitro dendritic cell maturation models for screening contact sensitizers using a panel of methacrylates. 1470 10

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

P-glycoprotein (P-gp) is required for adaptive immunity through defined functions in T cell activation and antigen presenting cell (APC) maturation. The potential role of P-gp as an in vivo regulator of alloimmunity is currently unknown. Here we show that P-gp blockade prolongs graft survival in a murine heterotopic cardiac allotransplantation model through in vivo inhibition of the T helper 1 (Th1) cytokine IFN-gamma and the Th2 product IL-4, and via downregulation of the APC-expressed positive costimulatory molecule CD80. In vitro, the P-gp antagonist PSC833, a non-calcineurin-inhibitory cyclosporine A analogue, specifically inhibited cellular efflux of the P-gp substrate rhodamine-123 in wild-type CD3(+) T cells and MHC class II(+) APCs but not their P-gp knockout counterparts that lacked rhodamine-123 efflux capacity. Additionally, P-gp blockade significantly inhibited murine alloimmune T cell activation in a dose-dependent fashion. In vivo, P-gp blockade significantly prolonged graft survival in Balb/c recipients of C57BL/6 cardiac allografts from 8.5+/-0.5 to 11.7+/-0.5 days (P<0.01), similar in magnitude to the effects of monotherapy with cyclosporine A. Moreover, P-gp blockade, compared to controls, attenuated intragraft expression of CD3 and CD80, but not CD86, and inhibited IFN-gamma and IL-4 production (P<0.05). In the setting of systemic CD86 inhibition, P-gp blockade suppressed IFN-gamma and IL-4 production significantly further (to 98% and 89% inhibition, respectively) compared to either P-gp or anti-CD86 blockade alone, and markedly prolonged allograft survival compared to anti-CD86 blockade alone (40.5+/-4.6 versus 22.5+/-2.6 days, respectively, P<0.01). Our findings define a novel in vivo regulatory role of P-gp in alloimmunity and identify P-gp as a potential therapeutic target in allotransplantation.
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PMID:A novel in vivo regulatory role of P-glycoprotein in alloimmunity. 2023 Jul 90