Nature Genetics36, 969 - 977 (2004)
Published online: 22 August 2004; | doi:10.1038/ng1413
Abnormal TNF activity in Timp3-/- mice leads to chronic hepatic inflammation and failure of liver regeneration
Fazilat F Mohammed1, David S Smookler1, Suzanne E M Taylor1, Barbara Fingleton2, Zamaneh Kassiri1, Otto H Sanchez1, Jane L English1, Lynn M Matrisian2, Billie Au1, Wen-Chen Yeh1
& Rama Khokha1
1
Ontario Cancer Institute, University of Toronto, Toronto, Ontario, M5G 2M9, Canada.
2
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
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- 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.
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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.
