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
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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DOI：
10.1002/hep.1840160320
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发表时间：
1992-09-01
期刊：
影响因子：
13.5
通讯作者：
WRIGHT, R
中科院分区：
文献类型：
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作者：
KOWALSKISAUNDERS, PWJ;WINWOOD, PJ;WRIGHT, R
肝损伤中肝细胞白蛋白合成减少被认为是对枯否细胞衍生的急性期细胞因子的反应。在这项研究中，我们使用的肝细胞保持在分化的表型，通过培养层粘连蛋白丰富的凝胶基质（恩格尔布雷思-霍尔姆-群矩阵），研究枯否细胞条件培养基和纯化的细胞因子（白细胞介素-1，白细胞介素-6和肿瘤坏死因子-α）对白蛋白合成的影响。在第2天，枯否细胞条件培养基导致白蛋白合成可逆性降低至对照的64.7%（p < 0.01，Wilcoxon秩和检验，n = 11）。重复给药引起进一步的剂量依赖性可逆反应。当将蛋白酶抑制剂（α-1-抗胰蛋白酶和α-2-巨球蛋白）加入枯否细胞条件培养基（n = 3）时，获得了相同的结果，从而消除了基质降解的潜在影响。纯白细胞介素-1、白细胞介素-6和肿瘤坏死因子-α也抑制白蛋白合成（p < 0.05，Wilcoxon秩和检验，n = 5），白细胞介素-6的作用最大。暴露于白细胞介素-1（30 U.ml-1）和肿瘤坏死因子-α（300 U.ml-1）后，白蛋白合成减少，随后反弹增加（n = 3）。我们的研究结果支持这一假设，即减少白蛋白合成的急性期反应是由库普弗细胞释放的细胞因子调制。此外，我们的研究结果表明，肝细胞可能会表现出代偿性增加白蛋白合成细胞因子撤出后。这些发现可能在体内损伤恢复和急性期反应中具有生理学意义。
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 < 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 < 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.