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 (α 1 ‐antitrypsin and α 2 ‐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 . (H EPATOLOGY 1992;16:733–741.)