Interferon-gamma up-regulates expression and activity of P-glycoprotein in human peripheral blood monocyte-derived macrophages.
P-glycoprotein (Pgp), the product of the multidrug resistance (MDR1) gene, is expressed in a variety of normal tissues but very little is known about its expression and function in cells of the immune system. In this study, we investigated the effect of interferon-gamma (IFN-gamma) on the expression and activity of Pgp in human peripheral blood monocyte-derived macrophages (MDM). We report that IFN-gamma up-regulated Pgp expression in a dose- and time-dependent manner. We show that IFN-gamma slightly increased the accumulation of MDR1 mRNA and induced a polarized redistribution of Pgp, as well as of some cytoskeletal proteins (ie, ezrin, actin, and alpha-actinin) on cell pseudopodia. Notably, confocal microscopy studies showed that Pgp and ezrin colocalized in these cellular structures. The IFN-gamma-induced Pgp up-modulation was a specific response of primary macrophages, as IFN-gamma treatment of primary lymphocytes and monocytic cell lines did not result in any increase of Pgp expression. Finally, IFN-gamma stimulated the Pgp transport activity in MDM, as rhodamine 123-efflux increased in treated cells as compared with control cultures. These results indicate that Pgp expression and activity can be up-regulated in human MDM in response to IFN-gamma. We suggest that IFN-gamma may be involved in the induction of multidrug resistance in macrophages.
Puddu
P
P
Laboratory of Immunology, Istituto Superiore di Sanità, Rome, Italy. puddu@iss.it
Fais
S
S
Luciani
F
F
Gherardi
G
G
Dupuis
M L
ML
Romagnoli
G
G
Ramoni
C
C
Cianfriglia
M
M
Gessani
S
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000097:blood* / Q000235:genetics; D019070:Cell Lineage; D002478:Cells, Cultured; D005456:Fluorescent Dyes; D019450:Genes, MDR; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005456:Fluorescent Dyes; D007371:Interferon-gamma