Tissue inhibitors of metalloproteinases (TIMPS) in hepatic regeneration and tissue homeostasis.
Published: 2004
Language: eng
Number of pages: 185
Description: TNFalpha is released from cell surfaces by the metalloproteinase, TNFalpha converting enzyme (TACE). Deletion of the murine Timp-3 gene resulted in increased TACE activity and constitutive release of TNFalpha culminating in hepatic lymphocyte infiltration also seen in human chronic hepatitis. This pathology was prevented when loss of Timp-3 was combined with TNF receptor 1 deficiency. Further, in a liver regeneration model that requires TNFalpha signaling, Timp-3-/-  mice succumbed to liver failure. Timp-3-/-  hepatocytes completed the cell cycle but subsequently underwent cell death due to sustained TNFalpha activation. This hepatocyte cell death was completely rescued by a neutralizing anti-TNFalpha antibody. This dysregulation did not occur in Timp-1 null mice. These data establish TIMP-3 as a critical innate negative regulator of TNFalpha, both in tissue homeostasis and tissue response to injury. Overall, extracellular proteolysis presents a key mechanism for modifying growth factor/cytokine activity and hepatocellular proliferation.Liver regeneration depends on timely restoration of cellular mass and is a powerful tool to study cell proliferation. Induction of the key molecules, hepatocyte growth factor (HGF) and tumor necrosis factor alpha (TNFalpha), causes quiescent hepatocytes to proliferate. These factors are made immediately available by proteolysis resulting in their release from the extracellular matrix (HGF) or the cell surface (TNFalpha).Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are known to regulate ECM turnover, and more recently, the processing of growth factors and cytokines. Comprehensive real-time RT-PCR analyses of regenerating livers revealed significant inductions in the mRNA of TIMP-1, TIMP-3, TIMP-4, MMP-2, MMP-9, MMP-13, MMP-14 and MMP-24. Induction of TIMP-1 occurred during the peak of hepatocyte DNA synthesis. Studies using genetically altered mice revealed that TIMP-1 loss-of-function accelerated hepatocyte cell cycle progression while TIMP-1 gain-of-function delayed this event. This was demonstrated by altered cyclin D1, proliferating cell nuclear antigen and phosphorylated histone H3 expression that mark the G1 to S transition, S and M phase, respectively. MMP activity was increased in the absence of  Timp-1. Active HGF levels were elevated in Timp-1 -/- livers along with increased phosphorylation of Met, and a downstream effector, p38, demonstrating that TIMP-1 is a novel negative regulator of HGF activity.
Notes: Adviser: Rama Khokha.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-10, Section: B, page: 4998.