The hepatic interleukin-6 receptor. Down-regulation of the interleukin-6 binding subunit (gp80) by its ligand.
Interleukin-6 (IL6) exerts its action via a cell surface receptor composed of an 80 kDa IL6-binding protein (gp80) and a 130 kDa polypeptide involved in signal transduction (gp130). We studied the role of gp80 in binding, internalization and down-regulation of the hepatic IL6-receptor (IL6R) by its ligand in human hepatoma cells (HepG2). Comparison of transfected HepG2 cells overexpressing gp80 with parental cells indicate that gp80 is responsible for low affinity binding (Kd = 500 pM) of IL6. Furthermore, gp80 is rate-limiting in internalization and degradation of IL6. Internalization resulted in a rapid down-regulation (t1/2 approximately 15-30 min) of IL6-binding sites at the cell surface. More than 80% of the internalized [125I]rhIL6 was degraded. The reappearance of IL6-binding sites at the cell surface required greater than 8 h and was sensitive to cycloheximide, suggesting that gp80 is not recycled after internalization. The down-regulation of the hepatic IL6R by its ligand might play an important role as a protection against overstimulation.
Zohlnhöfer
D
D
Institut für Biochemie RWTH Aachen, Germany.
Graeve
L
L
Rose-John
S
S
Schooltink
H
H
Dittrich
E
E
Heinrich
P C
PC
D006528:Carcinoma, Hepatocellular; D015536:Down-Regulation; D004705:Endocytosis; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008024:Ligands; D008099:Liver / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000737:chemistry / Q000378:metabolism*; D019947:Receptors, Interleukin-6; D014407:Tumor Cells, Cultured
D015850:Interleukin-6; D008024:Ligands; D011971:Receptors, Immunologic; D019947:Receptors, Interleukin-6