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Regulation of hepatic endothelial cell and macrophage proliferation and nitric oxide production by GM‐CSF, M‐CSF, and IL‐1 β following acute endotoxemia
Author(s) -
Feder Lisa S.,
Laskin Debra L.
Publication year - 1994
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.55.4.507
Subject(s) - biology , lipopolysaccharide , endothelial stem cell , cytokine , macrophage , tumor necrosis factor alpha , kupffer cell , macrophage colony stimulating factor , granulocyte macrophage colony stimulating factor , nitric oxide , proinflammatory cytokine , interleukin , medicine , endocrinology , immunology , inflammation , in vitro , biochemistry
Treatment of rats with bacterially derived lipopolysaccharide (LPS), a condition that mimics acute endotoxemia, results in a significant increase in the number of endothelial cells and macrophages in the liver. This is correlated with the release of proinflammatory and cytotoxic mediators that induce liver damage. In the present studies, we analyzed the effects of various inflammatory mediators released during the pathogenesis of hepatic injury on proliferation of liver nonparenchymal cells. To induce acute endotoxemia female Sprague‐Dawley rats were injected intravenously with 5 mg/kg LPS. Endothelial cells and macrophages were isolated 48 h later by combined collagenase and pronase perfusion of the liver followed by centrifugal elutriation. Interleukin‐1 α (IL‐1 α ), interleukin‐6 (IL‐6), and tumor necrosis factor α (TNF‐ α ) had no effect on proliferation of either endothelial cells or macrophages. In contrast, whereas interleukin‐1 β (IL‐1 β ) inhibited the proliferation of endothelial cells from untreated rats, this cytokine stimulated the growth of cells from endotoxemic rats. The colony‐stimulating factors, granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and macrophage colony‐stimulating factor (M‐GSF), also markedly enhanced the proliferation of endothelial cells, as well as macrophages from endotoxemic rats. Macrophages from endotoxemic rats were more sensitive to the colony‐stimulating factors than cells from untreated rats. In contrast, the inflammatory mediators LPS and interferon‐γ (IFN‐γ) inhibited endothelial cell and macrophage growth, an effect that was partially blocked in endothelial cells by the nitric oxide synthase inhibitor N G ‐ monomethyl‐l‐aiginine (L‐NMMA). This suggests that growth inhibition in these cells is mediated, in part, by nitric oxide. Interestingly, in both endothelial cells and macrophages from endotoxemic rats, GM‐CSF, M‐CSF, and IL‐1 β synergized with LPS and IFN‐γ to induce nitric oxide production. This was correlated with a further inhibition of proliferation that was partially reversed by L‐NMMA in endothelial cells but not macrophages. Taken together these data demonstrate that endothelial cell and macrophage proliferation in the liver is controlled by a variety of mediators released during endotoxemia; however, the mechanisms regulating growth in the two cell types are distinct. J. Leukoc. Biol. 55: 507–513; 1994.