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Open AccessArticle

BMP-9 Modulates the Hepatic Responses to LPS

1
Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
2
Center for Alcohol Research, University of Heidelberg and Salem Medical Center, 69120 Heidelberg, Germany
3
Department of Surgery, University Medicine Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
4
Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
5
Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany
6
European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
7
Institute of Pathology, Technical University of Munich, 80333 Munich, Germany
8
Medical Faculty Mannheim, Medical Research Center, Heidelberg University, 68167 Mannheim, Germany
*
Author to whom correspondence should be addressed.
Cells 2020, 9(3), 617; https://doi.org/10.3390/cells9030617
Received: 29 October 2019 / Revised: 25 February 2020 / Accepted: 2 March 2020 / Published: 4 March 2020
(This article belongs to the Special Issue TGF-beta/BMP Signaling Pathway)
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. View Full-Text
Keywords: LPS; BMP-9; HSC; LSEC; kupffer cells; liver; capillarization; IL-6; macrophages; myofibroblasts LPS; BMP-9; HSC; LSEC; kupffer cells; liver; capillarization; IL-6; macrophages; myofibroblasts
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Gaitantzi, H.; Karch, J.; Germann, L.; Cai, C.; Rausch, V.; Birgin, E.; Rahbari, N.; Seitz, T.; Hellerbrand, C.; König, C.; Augustin, H.G.; Mogler, C.; de la Torre, C.; Gretz, N.; Itzel, T.; Teufel, A.; Ebert, M.P.A.; Breitkopf-Heinlein, K. BMP-9 Modulates the Hepatic Responses to LPS. Cells 2020, 9, 617.

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