IL-1 RECEPTOR ANTAGONIST (IL-1RA) DOES NOT INHIBIT THE PRODUCTION OF C-REACTIVE PROTEIN OR SERUM AMYLOID-A PROTEIN BY HUMAN PRIMARY HEPATOCYTES - DIFFERENTIAL REGULATION IN NORMAL AND TUMOR-CELLS

The synthesis of some class 1 acute-phase proteins (APP), including C- reactive protein (CRP) and serum amyloid A (SAA) protein is completely blocked by the IL-1 receptor antagonist (IL-1Ra), whereas the product ion of fibrinogen, a class 2 APP, is increased by IL-1Ra in hepatoma c ells, but this has never been tested in human hepatocytes in primary c ulture. Since previous studies on the contributions of cytokine inhibi tors in connective tissues diseases suggested that IL-1 and tumour nec rosis factor-alpha (TNF-alpha) might play an important role in the reg ulation of CRP, we decided to examine in more detail the respective ro les of IL-1 beta, IL-6, and TNF-alpha and their inhibitors in the prod uction of APP by human primary hepatocytes versus the hepatoma cell li ne PLC/PRF/5. In the hepatoma cell line, IL-1 beta and/or TNF-alpha ha d synergistic effects with IL-6 on the production of CRP and SAA. In c ontrast, these cytokines were devoid of effect in normal hepatocytes. The production of fibrinogen was increased by IL-6 and decreased by IL -1 (and TNF-alpha) in both cell types. The secretion of CRP and SAA by primary hepatocytes incubated with a cytokine-rich mononuclear cell-c onditioned medium was totally unaffected by IL-1Ra or anti-TNF-alpha a ntibodies. In contrast, the addition of IL-1Ra increased the productio n of fibrinogen by both hepatoma cells and primary hepatocytes incubat ed with the mononuclear cell-conditioned medium. We therefore conclude that IL-1 beta and TNF-alpha do not exert any significant effect on t he synthesis of CRP and SAA by human primary hepatocytes.