Abnormal TNF activity in Timp3−/− mice leads to chronic hepatic inflammation and failure of liver regeneration

Abstract

Tumor-necrosis factor (TNF), a pleiotropic cytokine, triggers physiological and pathological responses in several organs. Here we show that deletion of the mouse gene Timp3 resulted in an increase in TNF-alpha converting enzyme activity, constitutive release of TNF and activation of TNF signaling in the liver. The increase in TNF in Timp3(-/-) mice culminated in hepatic lymphocyte infiltration and necrosis, features that are also seen in chronic active hepatitis in humans. This pathology was prevented when deletion of Timp3 was combined with Tnfrsf1a deficiency. In a liver regeneration model that requires TNF signaling, Timp3(-/-) mice succumbed to liver failure. Hepatocytes from Timp3(-/-) mice completed the cell cycle but then underwent cell death owing to sustained activation of TNF. This hepatocyte cell death was completely rescued by a neutralizing antibody to TNF. Dysregulation of TNF occurred specifically in Timp3(-/-), and not Timp1(-/-) mice. These data indicate that TIMP3 is a crucial innate negative regulator of TNF in both tissue homeostasis and tissue response to injury.

Enhanced metastatic dissemination to multiple organs by melanoma and lymphoma cells in timp-3−/− mice

“…It is likely that similar to melanoma, higher MMP activity also plays a role in the increased extravasation of lymphoma cells in timp-3 À/À livers. We have reported that timp-3 À/À liver has constitutive release of TNF-a and activation of its signaling pathway (Mohammed et al, 2004), and it is likely that TNF-a contribute to the metastatic process in timp-3 À/À liver. Tumor cells are known to upregulate TNF-a, which in turn increases endothelial cell expression of adhesion molecules (e.g.…”

“…Unlike liver, the levels of constitutive TNF-a do not differ between timp-3 À/À and wild-type kidney (Mohammed et al, 2004); however, it remains possible that TNF-a levels rise when metastatic cells interact with the timp-3 À/À kidney endothelium. With respect to bone, timp-3 deficiency may allow greater release of cytokine and growth factors to promote metastatic growth.…”

“…Lack of inflammatory cell involvement in metastasis of timp-3 À/À tissues Increased tumor necrosis factor (TNF) bioactivity in timp-3 À/À mice leads to hepatic inflammation (Mohammed et al, 2004), and accelerated progression to heart failure in a model of heart disease (Kassiri et al, 2005). Inflammation plays a role in tumorigenesis, and infiltrating macrophages can affect metastasis (Lin et al, 2001).…”

“…Timp-3 À/À and wild-type mice were injected intravenously with B16F10 cells and mice were killed at 15 min, 48 and 96 h post-injection. Lysates from lung tissues isolated were prepared by sonication in RIPA buffer and then analysed by gelatin zymography as described previously (Mohammed et al, 2004). Zymograms were subjected to densitometry and signals representing active and latent MMP-2 bands were quantified using ImageQuant 1.11 software.…”

“…Its overexpression in tumor cell lines inhibits, (Ahonen et al, 1998;Spurbeck et al, 2002), whereas its ablation in the host stroma promotes these processes (Cruz-Munoz et al, 2006). In addition to affecting ECM degradation, loss of TIMP-3 affects cytokine homeostasis (Mohammed et al, 2004;Kassiri et al, 2005). Cytokinemediated inflammation is now recognized to be important in tumor development (Coussens and Werb, 2002), although its role in metastasis is currently not well understood.…”