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

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Abstract
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.)

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