Hepatic over-expression of TGF-beta1 promotes LPS-induced inflammatory cytokine secretion by liver cells and endotoxemic shock.
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.
Garcia-Lazaro
Jose Francisco
JF
Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Martinistr. 52, Hamburg, Germany.
Thieringer
Florian
F
Lüth
Stefan
S
Czochra
Piotr
P
Meyer
Erik
E
Renteria
Isaias Balderas
IB
Galle
Peter R
PR
Lohse
Ansgar W
AW
Herkel
Johannes
J
Kanzler
Stephan
S
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
D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1