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 (K(d) = 500 pM) of IL6. Furthermore, gp80 is rate-limiting in internalization and degradation of IL6. Internalization resulted in a rapid down-regulation (t1/2 almost-equal-to 15-30 min) of IL6-binding sites at the cell surface. More than 80% of the internalized [I-125]rhIL6 was degraded. The reappearance of IL6-binding sites at the cell surface required >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.