TNF-ALPHA, IL-1-BETA, AND HEPATOCYTE GROWTH-FACTOR COOPERATE IN STIMULATING SPECIFIC ACUTE-PHASE PLASMA-PROTEIN GENES IN RAT HEPATOMA-CELLS

In rat hepatoma H-35 cells, TNF-alpha, like IL-1beta, stimulates the s ynthesis and secretion of type 1 acute phase plasma proteins, includin g alpha1-acid glycoprotein (AGP), complement component 3 (C3), hemopex in, and haptoglobin. TNF and IL-1 in combination act additively to syn ergistically on the expression of AGP and C3 but not on hemopexin and haptoglobin. The cytokine stimulation of AGP and C3 genes is further e nhanced by hepatocyte growth factor. The effect of TNF is mediated by the type I TNF receptor as judged from the TNF-like effect elicited by the agonist antibodies to type I but not type II TNF receptor. The da ta suggest that, although TNF and IL-1 share considerable overlap in t heir signal transduction mechanism, cytokine-specific signal pathways exist that affect a subset of acute phase plasma protein genes. A pote ntial regulatory role is attributed to the transcription factors C/EBP beta and NF-kB based on studies on transiently transfected H-35 cells.