Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
Center for Alcohol Research, University of Heidelberg and Salem Medical Center, 69120 Heidelberg, Germany.
Cells. 2020 Mar 4;9(3):617. doi: 10.3390/cells9030617.
It was previously shown that Bone Morphogenetic Protein (BMP)-9 is constitutively produced and secreted by hepatic stellate cells (HSC). Upon acute liver damage, BMP-9 expression is transiently down-regulated and blocking BMP-9 under conditions of chronic damage ameliorated liver fibrogenesis in C57BL/6 mice. Thereby, BMP-9 acted as a pro-fibrogenic cytokine in the liver but without directly activating isolated HSC in vitro. Lipopolysaccharide (LPS), an endotoxin derived from the membrane of Gram-negative bacteria in the gut, is known to be essential in the pathogenesis of diverse kinds of liver diseases. The aim of the present project was therefore to investigate how high levels of BMP-9 in the context of LPS signalling might result in enhanced liver damage. For this purpose, we stimulated human liver sinusoidal endothelial cells (LSEC) with LPS and incubated primary human liver myofibroblasts (MF) with the conditioned medium of these cells. We found that LPS led to the secretion of factors from LSEC that upregulate BMP-9 expression in MF. At least one of these BMP-9 enhancing factors was defined to be IL-6. High BMP-9 in turn, especially in combination with LPS stimulation, induced the expression of certain capillarization markers in LSEC and enhanced the LPS-mediated induction of pro-inflammatory cytokines in primary human macrophages. In LSEC, pre-treatment with BMP-9 reduced the LPS-mediated activation of the NfkB pathway, whereas in macrophages, LPS partially inhibited the BMP-9/Smad-1 signaling cascade. In vivo, in mice, BMP-9 led to the enhanced presence of F4/80-positive cells in the liver and it modulated the LPS-mediated regulation of inflammatory mediators. In summary, our data point to BMP-9 being a complex and highly dynamic modulator of hepatic responses to LPS: Initial effects of LPS on LSEC led to the upregulation of BMP-9 in MF but sustained high levels of BMP-9 in turn promote pro-inflammatory reactions of macrophages. Thereby, the spatial and timely fine-tuned presence (or absence) of BMP-9 is needed for efficient wound-healing responses in the liver.
先前的研究表明，骨形态发生蛋白 9（BMP-9）在肝星状细胞（HSC）中持续产生和分泌。在急性肝损伤时，BMP-9 的表达短暂下调，而在慢性损伤条件下阻断 BMP-9 可改善 C57BL/6 小鼠的肝纤维化。因此，BMP-9 在肝脏中作为一种促纤维化细胞因子发挥作用，但在体外不能直接激活分离的 HSC。脂多糖（LPS），一种源自肠道革兰氏阴性菌膜的内毒素，被认为是多种肝脏疾病发病机制中的关键因素。本研究的目的是探讨 LPS 信号转导中 BMP-9 水平升高如何导致肝损伤加重。为此，我们用 LPS 刺激人肝窦内皮细胞（LSEC），并用这些细胞的条件培养基孵育原代人肝成纤维细胞（MF）。我们发现，LPS 导致 LSEC 分泌因子，上调 MF 中的 BMP-9 表达。这些增强 BMP-9 的因子中至少有一种是白细胞介素 6（IL-6）。高 BMP-9 水平，特别是与 LPS 刺激联合，诱导 LSEC 中某些毛细血管化标志物的表达，并增强原代人巨噬细胞中 LPS 介导的促炎细胞因子的诱导。在 LSEC 中，BMP-9 预处理可降低 LPS 介导的 NFkB 途径的激活，而在巨噬细胞中，LPS 部分抑制 BMP-9/Smad-1 信号级联。在体内，在小鼠中，BMP-9 导致肝脏中 F4/80 阳性细胞的增加，并调节 LPS 介导的炎症介质的调节。总之，我们的数据表明 BMP-9 是肝脏对 LPS 反应的复杂而高度动态的调节剂：LPS 对 LSEC 的初始作用导致 MF 中 BMP-9 的上调，但持续高水平的 BMP-9 反过来又促进巨噬细胞的促炎反应。因此，肝脏中有效的伤口愈合反应需要 BMP-9 的空间和时间精细调节。
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