Involvement of P-glycoprotein in the transmembrane transport of interleukin-2 (IL-2), IL-4, and interferon-gamma in normal human T lymphocytes

Abstract

The physiological role of the multidrug resistance P-glycoprotein (P- gp), which is expressed by normal human T lymphocytes, is still largely unknown. To investigate whether or not P-gp is involved in the transport of cytokines, peripheral blood lymphocytes were stimulated with phytohemagglutinin (PHA) in the absence or presence of P-gp inhibitors, and concentrations of cytokines (interleukin-2 [IL-2], IL- 4, IL-6, interferon-gamma [IFN-gamma]) in the supernatants of these cultures were quantitated by enzyme-linked immunosorbent assay. P-gp inhibitors included verapamil (Ver), tamoxifen (Tmx), and the P-gp specific monoclonal antibody UIC2. Release of IL-2 was significantly suppressed by these inhibitors at concentrations that were also effective in blocking efflux of Rhodamine-123 from normal T lymphocytes. IL-2 mRNA expression in lymphocytes was not different between PHA control and the cultures with P-gp inhibitors. Ver and Tmx did not interfere with T-cell activation as determined by CD25 and CD69 expression. In a nonhematological model, the P-gp expressing HCT-8 adenocarcinoma cell line, exogenously added IL-2 was shown to exert an inhibitory effect on P-gp mediated Rhodamine-123 efflux. In addition, transepithelial transport of IL-2 by electrophysiologically tight and polarized HCT-8 monolayers was examined. A time-dependent flux of IL-2 across dense monolayers, which was partially inhibited by Ver, was observed. We also investigated whether or not P-gp inhibitors suppressed release of other cytokines produced by activated T cells (IL- 4, IL-6, IFN-gamma). Release of IL-4 and IFN-gamma was significantly inhibited by Ver, Tmx, and UIC2; however, release of IL-6 remained unaffected. These data show P-gp mediated transmembrane flux of IL-2 in T lymphocytes and HCT-8 cells. We conclude that P-gp participates in the transport of cytokines (IL-2, IL-4, and IFN-gamma) in normal peripheral T lymphocytes.

Downregulation of mdr1a expression in the brain and liver during CNS inflammation alters the in vivo disposition of digoxin

“…(2001) demonstrated that the pentoxyfilline (an inhibitor of TNF‐ α production) prevented the loss in biliary elimination of rhodamine123 after administration of K. pneumoniae endotoxin. Alternatively, endogenous compounds that are substrates for P‐gp including inflammatory cytokines and corticosterone (Wolf & Horwitz, 1992; Drach et al ., 1996) that are released after administration of LPS may inhibit P‐gp‐mediated drug transport, especially at the earlier time points. Lastly, LPS may also decrease P‐gp transport activity through protein kinase‐mediated phosphorylation of P‐gp (Miller et al ., 1998; Tepperman et al ., 2000).…”

“…It has been suggested that the expression of P‐gp may be important in the immune response (Panwala et al ., 1998; Johnstone et al ., 2000). P‐gp and members of the oatp family transport endogenous molecules, which are involved in inflammation including steroids, leukotrienes, prostaglandins and cytokines (Schinkel et al ., 1995; Drach et al ., 1996; Meijer et al ., 1998). It should be a priority to investigate if the loss in expression of these transporters in the brain and liver are important for regulating the body disposition of inflammatory/antiinflammatory mediators during episodes of inflammation.…”

Quantitative determination of the human MRP1 and MRP2 mRNA expression in FACS‐sorted peripheral blood CD4+, CD8+, CD19+, and CD56+cells

“…Miscellaneous ABC transporters may have different function. For instance, P‐glycoprotein has been reported to be involved in the natural killer and T cell mediated cytotoxicity (11, 12) and in the transport of cytokines (13). MRP1, unlike P‐glycoprotein, facilitates the secretion of leukotrienes, the major mediators of inflammation (14).…”

MDR1 gene polymorphisms and risk of gingival hyperplasia induced by calcium antagonists

“…it was suggested that IL-2 itself can be transported by P-gp. 30 The question is how P-gp could contribute to the uncontrolled growth of the gingiva. This hyperplasia is caused by modifications of the extracellular matrix components, particularly collagen.…”