title: Hepatic over-expression of TGF-beta1 promotes LPS-induced inflammatory cytokine secretion by liver cells and endotoxemic shock.
abstract: Transforming growth factor-beta (TGF-beta) is an important suppressor of inflammation. However, TGF-beta has also been found to promote secretion of inflammatory cytokines, and transgenic mice, which constitutively express TGF-beta in liver, have been found to be more susceptible to endotoxemia. To approach this apparent paradox, we investigated the role of hepatic TGF-beta1 in endotoxemia by utilising inducible TGF-beta1-transgenic mice that express TGF-beta1 under control of the C-reactive protein promoter. In contrast to non-transgenic littermates, administration of lipopolysaccharide (LPS) induced strongly increased expression of TGF-beta and acute phase proteins in the TGF-beta1-transgenic mice. Hepatic TGF-beta1-expression in the transgenic mice started an inflammatory cytokine cascade, marked by increased and prolonged secretion of TNF-alpha and IL-6 by hepatocytes. The inflammatory response of the TGF-beta1-transgenic mice to LPS was associated with high rates of mortality due to endotoxemic shock, marked by systemic hypotension and hypothermia. Endotoxemic shock was primarily mediated by TNF-alpha and IL-6, since inhibitory antibody to TNF-alpha or, more effectively, to IL-6 could reduce mortality in these mice. In conclusion, while TGF-beta-signalling to immune cells may suppress inflammatory effector function, TGF-beta-signalling to liver cells seems to promote LPS-stimulated secretion of inflammatory cytokines and to predispose for lethal endotoxemic shock.
authors.affiliation: Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Martinistr. 52, Hamburg, Germany.
authors.forename: Jose Francisco
authors.initials: JF
authors.lastname: Garcia-Lazaro
authors.forename: Florian
authors.initials: F
authors.lastname: Thieringer
authors.forename: Stefan
authors.initials: S
authors.lastname: Lüth
authors.forename: Piotr
authors.initials: P
authors.lastname: Czochra
authors.forename: Erik
authors.initials: E
authors.lastname: Meyer
authors.forename: Isaias Balderas
authors.initials: IB
authors.lastname: Renteria
authors.forename: Peter R
authors.initials: PR
authors.lastname: Galle
authors.forename: Ansgar W
authors.initials: AW
authors.lastname: Lohse
authors.forename: Johannes
authors.initials: J
authors.lastname: Herkel
authors.forename: Stephan
authors.initials: S
authors.lastname: Kanzler
mesh_terms: D000210:Acute-Phase Reaction / Q000139:chemically induced; D000818:Animals; D002478:Cells, Cultured; D019446:Endotoxemia / Q000139:chemically induced* / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
chemical_list: D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1