Chloroquine decreases cell-surface expression of tumour necrosis factor receptors in human histiocytic U-937 cells.
Proinflammatory cytokine tumour necrosis factor (TNF) mediates its diverse effects through cell surface receptors. A variety of inflammatory signals are known to modulate TNF activities by changing expression and shedding of cell-surface TNF receptors. We have examined the effects of anti-rheumatic drug chloroquine on the expression of cell surface and soluble TNF receptors in human histiocytic U-937 cells. Chloroquine partially reduced production of soluble p55 and p75 TNF receptors in cells stimulated with phorbol 12-myristate 13-acetate (PMA). In these cells, induction of both TNF receptor mRNA was not changed and the levels of cell-associated TNF receptors were rather increased by chloroquine. Flow cytometric analysis revealed that chloroquine does not inhibit the PMA-triggered shedding of TNF receptors from cell surface, while it was suppressed by a metalloproteinase inhibitor BB-3103. Treatment of U-937 cells with chloroquine significantly reduced the level of cell surface TNF receptors and a similar effect was observed with human peripheral blood monocytes. Other weak-base amines, including hydroxychloroquine, ammonium chloride and methylamine, also induced reduction of cell surface TNF receptors, whereas lysosomal proteinase inhibitor, leupeptin, and BB-3013 were without effect. Our results suggest that chloroquine down-regulates cell surface TNF receptors by retarding their transport to the cell surface, while cleavage of cell surface receptors is not inhibited by chloroquine.
Jeong
Jae-Yeon
JY
Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
Choi
Jae Won
JW
Jeon
Kye-Im
KI
Jue
Dae-Myung
DM
D018501:Antirheumatic Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D002738:Chloroquine / Q000494:pharmacology*; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015614:Histiocytosis / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D018501:Antirheumatic Agents; C108282:BB 3103; D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D002738:Chloroquine; D013755:Tetradecanoylphorbol Acetate