Reversible inhibition of albumin production by rat hepatocytes maintained on a laminin-rich gel (Engelbreth-Holm-Swarm) in response to secretory products of Kupffer cells and cytokines



Decreased albumin synthesis by hepatocytes in liver injury is thought to occur in response to Kupffer cell–derived acute-phase cytokines. In this study we used hepatocytes maintained in a differentiated phenotype, by culture on a laminin-rich gel substratum (Engelbreth-Holm-Swarm matrix), to investigate the effects of Kupffer cell–conditioned medium and purified cytokines (interleukin-1, interleukin-6 and tumor necrosis factor–a) on albumin synthesis. Kupffer cell–conditioned medium caused a reversible decrease in albumin synthesis to 64.7% of control (p < 0.01, Wilcoxon's rank sum test, n = 11) on day 2. Repeated doses caused further dose-dependent reversible responses. The same result was obtained when protease inhibitors (α1-antitrypsin and α2-macroglobulin) were added to Kupffer cell–conditioned medium (n = 3), thus eliminating the potential effect of matrix degradation. Pure interleukin-1, interleukin-6 and tumor necrosis factor–α also inhibited albumin synthesis (p < 0.05, Wilcoxon's rank sum test, n = 5), interleukin-6 having the greatest effect. After exposure to interleukin-1 (30 U · ml−1) and tumor necrosis factor–α (300 U · ml−1), decreased albumin synthesis was followed by a rebound increase (n = 3). Our results support the hypothesis that reduced albumin synthesis in the acute-phase response is modulated by cytokines released from Kupffer cells. Moreover, our results suggest that hepatocytes may exhibit a compensatory increase in albumin synthesis after cytokine withdrawal. These findings may be of physiological importance in the recovery from injury and the acutephase response in vivo. (HEPATOLOGY 1992;16:733–741.)