Chloroquine decreases cell‐surface expression of tumour necrosis factor receptors in human histiocytic U‐937 cells

Summary 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.