BMP-9 modulates the hepatic responses to LPS

We have 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 ameliorates liver fibrogenesis. Thereby BMP-9 acts pro-fibrogenic in liver but without directly activating isolated HSC in vitro. 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.

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 upcyte® LSEC with LPS and incubated primary human HSC with the conditioned medium of these cells. We found that LPS induced the secretion of factors from LSEC that upregulated BMP-9 expression in HSC. One of these BMP-9 stimulatory factors was found to be IL-6. High BMP-9 in turn induced expression of capillarization markers and latent TGF-β activating proteins in LSEC and enhanced the LPS-mediated induction of pro-inflammatory cytokines in primary human macrophages in vitro as well as in the livers of mice that were injected with BMP-9/LPS.

These data imply that LSEC control the hepatic response to LPS at least in part via regulating the BMP-9 levels in the neighbouring HSC. Our hypothesis is that too much BMP-9 induces fibrosis by promoting LSEC capillarization and TGF-β activity and by provoking too intense inflammatory reactions. Too little BMP-9 on the other hand might disturb liver homeostasis leading to a de-differentiated endothelium and parenchyma. Thereby the direct cross-talk between the non-parenchymal cells, fine-tunes major hepatic responses with BMP-9 being a central homoeostasis-factor.