Soluble interleukin‐6 receptor strongly increases the production of acute‐phase protein by hepatoma cells but exerts minimal changes on human primary hepatocytes

Interleukin‐6 (IL‐6) interacts with a system of receptors, which include a 80‐kDa IL‐6‐binding subunit (IL‐6R) and a transducing element (gp130). The soluble form of IL‐6R (sIL‐6R) can bind its ligand and induce cellular responses by association with gp130, thus acting as an IL‐6 agonist. We and others have previously shown that the responsiveness to IL‐6 is different in hepatoma and human primary hepatocytes. We therefore compared the effects of sIL‐6R on the two types of cells, and on the B9 hybridoma, another IL‐6‐sensitive cell line. Human primary hepatocytes, hepatoma cells PLC/PRF/5, and B9 cells were incubated with different concentrations of IL‐6, sIL‐6‐R, or both. The hepatocyte culture supernatants were tested for their content of acute‐phase proteins (APP). The proliferation of B9 cells was assessed by a colorimetric method. Results showed that sIL‐6R alone markedly increases the production of APP by hepatoma cells in a dose‐dependent manner, but affects only minimally primary hepatocytes and the proliferation of B9 cells. The combinations of IL‐6R and its ligand enhanced the effects of IL‐6 alone in both PLC/PRF/5 and B9 cells, but had no effect on primary hepatocytes. An immunohistochemical study indicated that the cell‐surface expression of IL‐6R was dramatically lower in hepatoma cells than in primary hepatocytes. In conclusion, our results show that the expression of IL‐6R is low in the hepatoma cell PLC/PRF/5 when compared with primary hepatocytes and that this difference can, at least partly, explain their deficient responsiveness to IL‐6. On the other hand, it appears that IL‐6R expression by primary hepatocytes is sufficient and that circulating sIL‐6R is unlikely to play a significant role in the modulation of IL‐6 effects.