The hepatic interleukin‐6 receptor Down‐regulation of the interleukin‐6 binding subunit (gp80) by its ligand

Abstract

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 (gp13O). 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 gp8O 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 ( t ≈ 15–30 min) of IL6‐binding sites at the cell surface. More than 80% of the internalized [ 125 I]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.