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.