EFFECTS OF CYTOKINES ON SYNTHESIS AND FUNCTION OF THE HEPATIC ASIALOGLYCOPROTEIN RECEPTOR

In this study we have investigated whether cytokines, critical mediato rs of the immune response, might have a direct effect on the expressio n and/or function of the human hepatic asialoglycoprotein receptor (AS GPR). Binding and uptake of asialoglycoproteins by the human hepatoma cell line, HepG2, and by freshly isolated rat hepatocytes were inhibit ed by 50% after 3-6 hours and completely abolished following a 24 hour exposure to tumor necrosis factor (TNF) alpha, interferon (INF) alpha or gamma, or interleukin-2 (IL-2). The loss of ASGPR binding activity mediated by IL-2 was reversible up to 4 hours of exposure and accompa nied by the selective phosphorylation of the cell-surface receptor. St eady-state levels of total cellular ASGPR protein remained unchanged o ver the first 6 hours of IL-2 incubation but declined in a dose depend ent manner thereafter. This down regulation of ASGPR expression was du e to reduced synthesis as a result of reduced receptor transcript leve ls. No loss was detected, however, of cell surface-associated receptor protein even after 24 hours of IL-2 incubation, suggesting that cytok ine induced phosphorylation constitutes a mechanism to regulate recept or activity. (C) 1994 Wiley-Liss, Inc.