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Interleukin 6 (IL6) is the new definition of a group of cytokines previously named according to their biological activity, e.g. B cell stimulatory factor 2 (BSF-2), hybridoma plasmocytoma-growth factor (HGF), interferon-beta 2 (IFN-beta 2), hepatocyte stimulating factor (HSF). It has recently been suggested that IL6 may represent the major mediator of acute-phase protein response whereas IL1 beta and TNF-alpha could play a minor role. We compared the effect of the three cytokines on hepatic protein synthesis by performing in vitro as well as in vivo experiments. Human hepatoma cells (PLC/PRF5) were exposed to each cytokine separately for 20 h, and the effect was then studied at the protein and RNA level. All three cytokines reduced albumin and increased C3 and ceruloplasmin biosynthesis. The cytokines induced the same effect at the RNA level indicating that the modulation was pretranslational. The effect of the cytokines was specific since actin gene expression was not changed; furthermore the effect was blocked by specific antibodies against the cytokines. The effect of the single cytokines was dose and time dependent, and quantitatively comparable. None of the cytokines was able to alter alpha 1-anti-trypsin synthesis. In vivo experiments with mice showed that IL1 beta and TNF-alpha both induce serum amyloid A (SAA) mRNA in the mouse liver and increase factor B (Bf) gene expression. Human recombinant IL6 induced SAA gene expression and it also had a weak positive effect on Bf gene expression after i.p. injection. These data demonstrate that the three cytokines studied are quantitatively and qualitatively comparable, and that all three are probably involved in acute-phase protein response.

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Endothelin is the most potent vasoconstrictor peptide known today. Using a radioimmunoassay for endothelin, we measured immunoreactive endothelin in culture media of guinea pig sinusoidal endothelial liver cells and human umbilical vein endothelial cells. A time-dependent release of immunoreactive endothelin by confluent sinusoidal endothelial liver cells in culture was found. Sinusoidal endothelial liver cells produced similar amounts of immunoreactive endothelin as umbilical vein endothelial cells, about 900 pg/microgram DNA per 24 h. In the presence of transforming growth factor beta a dose-dependent increase of immunoreactive endothelin release was measured. The maximal increase of 50% was found at a concentration of 1 ng transforming growth factor per ml. To a similar extent Kupffer cell-conditioned media augmented the release of immunoreactive endothelin by sinusoidal endothelial liver cells, especially when Kupffer cells had been stimulated by endotoxin. Endotoxin itself did not alter the release of immunoreactive endothelin. Endothelin released by sinusoidal endothelial liver cells might influence the pericytes of the liver, i.e., the Ito-cells.

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To analyse the relationship between the presence of liver cirrhosis and hepatic inflammation and the serum concentrations of the aminoterminal propeptide of procollagen type III (P-III-NP) and of hyaluronic acid (HA) in chronic liver disease, we measured P-III-NP and HA concentrations in paired serum samples from 133 patients with various chronic liver diseases, from 22 patients with acute hepatitis and from 50 healthy age-matched controls. In 24 (of the 133) patients with autoimmune chronic liver disease, follow-up determination was performed during therapeutic treatment with immunosuppressive drugs. Compared with controls P-III-NP concentrations (medians) were significantly elevated in 65% of patients with chronic active hepatitis (P = 0.00097) and in 79% of patients with active liver cirrhosis (P = 0.0126) but not in patients with chronic persistent hepatitis (P = 0.06). Serum concentrations (medians) of HA were increased (P = 0.0058) in 32% of patients with chronic active hepatitis and in 91% of patients with active cirrhosis (P less than 6 x 10(-7)). The difference of HA serum concentrations but not that of P-III-NP serum concentrations in patients with chronic active hepatitis and in patients with active cirrhosis was statistically significant. HA and P-III-NP serum concentrations were significantly elevated in 22 patients with acute hepatitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract. Soluble serum P2-microglobulin has been thought to result from membrane shedding by activated T-lymphocytes. This hypothesis could explain the increase of P2-microglobulin serum levels during virally induced mononucleosis, but not elevated levels as observed in other virally induced and in malignant diseases. In this paper we demonstrate that P2-microglobulin is a true secretory protein, and that its synthesis in hepatocytes is modulated by IFNs but not by IL-I. While the 45 000 MW HLA antigen can be found only in cell lysates, Pz-microglobulin is shown to be secreted also into the culture medium like other secretory proteins (e.g. albumin-factor B-complement C3). Furthermore, interferon alpha (IFNa) as well as interferon gamma (IFNy) directly stimulate, in a doseand time-dependent manner, P2-microglobulin synthesis by human hepatoma cells (Mz-Hep-1 and PLC/ PRF5) and murine hepatocyte primary cultures. The increase of P2-microglobulin production induced by interferons is demonstrated at both the protein and the RNA level, indicating that interferon acts at a pretranslational level. The interferon effect on P2-microglobulin synthesis is specific since synthesis of secretory proteins like complement C3 or albumin, and of a structural protein like actin, remains unchanged. In contrast to IFN, IL-1, the main mediator of acute phase response, does not change P2-M biosynthesis rate. These data indicate that (i) 82-microglobulin is a secretory protein, (ii) IFNs but not IL-I can mediate increased P2-M serum levels, and (iii) the liver may be its primary source.