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-alpha) on albumin synthesis. Kupffer cell-conditioned medium caused a reversible decrease in albumin synthesis to 64.7% of control (p less than 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 (alpha 1-antitrypsin and alpha 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-alpha also inhibited albumin synthesis (p less than 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-alpha (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 acute-phase response in vivo.
Kowalski-Saunders
P W
PW
Medicine II, University of Southampton, Hampshire, United Kingdom.
Winwood
P J
PJ
Arthur
M J
MJ
Wright
R
R
D000418:Albumins / Q000096:biosynthesis*; D000818:Animals; D002478:Cells, Cultured; D003470:Culture Media / Q000737:chemistry; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D007728:Kupffer Cells / Q000378:metabolism*; D007797:Laminin; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000418:Albumins; D003470:Culture Media; D007375:Interleukin-1; D015850:Interleukin-6; D007797:Laminin; D014409:Tumor Necrosis Factor-alpha