Regulation of the synthesis of tissue inhibitors of metalloproteinase-1 and -2 by hepatic and pancreatic stellate cells

Abstract

Hepatic stellate cells (HSC) play a central role in fibrosis development by production of extracellular matrix and also by secretion of matrix metalloproteinases (MMPs) and Tissue inhibitors of metalloproteinases (TIMPs) including TIMP-2 and MMP-2. TIMP-2 has been shown to interact with Gelatinase A in conjunction with MT1-MMP (MMP-14). TIMP-2 has been traditionally considered to be constitutively expressed. There is some evidence that TIMP-2 expression is slightly enhanced in fibrotic disease and activation in tissue culture. Little is known in terms of TIMP-2 expression in the recently described pancreatic stellate cells (PSC). HSC were cultured on plastic having been isolated from rat and human liver resections. After culture on plastic northern analysis was performed for TIMP-2 mRNA expression. TIMP-2 promoter activity was examined in rat pancreatic stellate cells (PSC) and rat hepatic stellate cells. Early work led to subcloning the promoter into a different vector though subsequent promoter studies were unsuccessful. In vivo work in immunohistochemistry studies suggest there is increased TIMP-2 expression in evaluation of rat pancreas and liver in addition to human liver and pancreas specimens. By ribonuclease protection assay TIMP-2 was noted to be upregulated in human fibrotic liver compared to normal human liver tissue. In conclusion there is some evidence that TIMP-2 regulation may be altered in fibrotic liver states as well as in pancreatic inflammatory disease