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@ARTICLE{Gaitantzi:153912,
      author       = {H. Gaitantzi and J. Karch and L. Germann and C. Cai and V.
                      Rausch and E. Birgin and N. Rahbari and T. Seitz and C.
                      Hellerbrand and C. König$^*$ and H. Augustin$^*$ and C.
                      Mogler and C. de la Torre and N. Gretz and T. Itzel and A.
                      Teufel and M. P. A. Ebert and K. Breitkopf-Heinlein},
      title        = {{BMP}-9 {M}odulates the {H}epatic {R}esponses to {LPS}.},
      journal      = {Cells},
      volume       = {9},
      number       = {3},
      issn         = {2073-4409},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DKFZ-2020-00522},
      pages        = {E617},
      year         = {2020},
      note         = {DKFZ-ZMBH Alliance},
      abstract     = {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.},
      cin          = {A190},
      ddc          = {570},
      cid          = {I:(DE-He78)A190-20160331},
      pnm          = {321 - Basic Concepts (POF3-321)},
      pid          = {G:(DE-HGF)POF3-321},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:32143367},
      doi          = {10.3390/cells9030617},
      url          = {https://inrepo02.dkfz.de/record/153912},
}