Effects of cytokines on synthesis and function of the hepatic asialoglycoprotein receptor.
In this study we have investigated whether cytokines, critical mediators of the immune response, might have a direct effect on the expression and/or function of the human hepatic asialoglycoprotein receptor (ASGPR). Binding and uptake of asialoglycoproteins by the human hepatoma cell line, HepG2, and by freshly isolated rat hepatocytes were inhibited 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 accompanied by the selective phosphorylation of the cell-surface receptor. Steady-state levels of total cellular ASGPR protein remained unchanged over the first 6 hours of IL-2 incubation but declined in a dose dependent manner thereafter. This down regulation of ASGPR expression was due to reduced synthesis as a result of reduced receptor transcript levels. No loss was detected, however, of cell surface-associated receptor protein even after 24 hours of IL-2 incubation, suggesting that cytokine induced phosphorylation constitutes a mechanism to regulate receptor activity.
Treichel
U
U
Department of Medicine and Biochemistry, Albert Einstein College of Medicine, Marion Bessin Liver Research Center, Bronx, New York 10461.
Paietta
E
E
Poralla
T
T
Meyer zum Büschenfelde
K H
KH
Stockert
R J
RJ
D000917:Antibody Formation; D037263:Asialoglycoprotein Receptor; D001212:Asialoglycoproteins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000473:pathology / Q000648:ultrastructure; D016207:Cytokines / Q000494:pharmacology*; D015536:Down-Regulation; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D008113:Liver Neoplasms / Q000737:chemistry / Q000473:pathology / Q000648:ultrastructure; D010766:Phosphorylation; D011956:Receptors, Cell Surface / Q000032:analysis / Q000378:metabolism* / Q000502:physiology*; D015375:Receptors, Interleukin-2 / Q000032:analysis; D013997:Time Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D037263:Asialoglycoprotein Receptor; D001212:Asialoglycoproteins; D016207:Cytokines; D016898:Interferon-alpha; D007376:Interleukin-2; D011956:Receptors, Cell Surface; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma