Expression patterns of matrix metalloproteinases and their inhibitors in parenchymal and non-parenchymal cells of rat liver: regulation by TNF-alpha and TGF-beta 1

Background/Aims: Although matrix metalloproteinases (MMPs) and their specif ic inhibitors (TIMPs) play an essential role in liver injury associated wit h tissue remodeling, the cellular origin of MMPs/TMPs within the liver rema ins to be clarified. Methods: Different liver cell populations were analysed with respect to the ir expression by reverse transcription-polymerase chain reaction, Northern blot analysis and zymography. Results: MMP and TIMP coding transcripts were detectable in all liver cell types by reverse transcription-polymerase chain reaction; however, the cell ular expression levels were markedly different as assessed by Northern blot analysis, Gelatinase-B was predominantly expressed in Kupffer cells, gelat inase-A in hepatic stellate cells and rat liver myofibroblasts and stromely sins-1, -2 as well as collagenase in hepatic stellate cells. Membrane type- 1 MMP (MMP-14) was found in significant amounts in all liver cells. TIMP-1 coding m-RNAs were present mainly in hepatic stellate cells and rat liver m yofibroblasts, TIMP-2 additionally in Kupffer cells, while TIMP-3 expressio n was detectable only in hepatocytes, During in vitro activation of hepatic stellate cells. MMP expression was mostly downregulated, while TIMP expres sion was enhanced, thereby providing an explanation for matrix accumulation co-localised with these cells during chronic liver injury. In general, TNF -alpha stimulated both MMP and TIMP expression of hepatic stellate cells, w hile TGF-beta 1 induced TIMP expression only. Conclusions: Collectively these data demonstrate that all resident liver ce lls are involved in matrix degradation to some extent and that hepatic stel late cells play an important role in matrix breakdown in addition to matrix synthesis. The cytokine-specific regulation of MMP/TIMP expression in hepa tic stellate cells suggests that the initial matrix breakdown following liv er injury might be enhanced by TNF-alpha, while diminished matrix degradati on during chronic tissue injury might be due to the action of TGF-beta 1 th rough TIMP induction.