| Abstract |
Kupffer cells, the resident liver macrophages, play an important role in the primary immune response of the liver by actively participating in the defense mechanism against viruses and cancer cells. Moreover, these cells are implicated in fibrosis through the production of matrix metalloproteinases and TGF-β. The role of Kupffer cells in fibrolysis remains unclear, while Kupffer cell stimulation is considered the main mechanism of liver antitumour activity. Octreotide, the synthetic analogue of somatostatin, is widely used as therapeutic agent in cirrhotic patients and it is considered to prolong survival in patients suffering from hepatocellular carcinoma, though an identified, as yet, mechanism. In the present study, we investigated the production of two profibrotic (TGF-β1 and leptin) and two antifibrotic (MMP-1 and uPA) agents, as well as the expression of apoptotic proteins in rat liver isolated primary Kupffer cell cultures stimulated by lipopolysaccharide (LPS) and/ or octreotide. We found that isolated rat Kupffer cells produce TGF-β1 and uPA, but not leptin. LPS stimulation reduces TGF-β1 production and the same effect occurs by octreotide stimulation. Octreotide causes a significant increase on MMP-1 production by Kupffer cells. The concomitant stimulation by LPS and octreotide acts synergistically on MMP-1 production. We also observed a constant uPA production by unstimulated Kupffer cells which was significantly induced following stimulation by LPS and/ or octreotide. Moreover, mRNA studies revealed that Kupffer cells express apoptotic genes. Unstimulated Kupffer cells express bax and bcl-xS mRNA in a time dependent manner and this expression is paralleled by LICE. LPS stimulation inhibited the expression of proapoptotic bax and bcl-xS, while LICE expression showed a time-dependent reduction. Stimulation by octreotide showed a constant reduction of the proapoptotic gene expression which was accompanied by early induction and a late decrease on the expression of antiapoptotic bcl-2 and bcl-xL genes with a constant reduction of LICE. Concomitant stimulation by LPS and octreotide produced a similar result with the exception of early expression of LICE mRNA, which was probably due to the paralleled increase of the proapoptotic bax and bcl-xS. In conclusion, Kupffer cells exceed their role not only to the extracellular matix accumulation through the overproduction of TGF-β1, but also to fibrolysis by producing matrix metalloproteinases and uPA. Moreover, octreotide might be a useful therapeutic agent for reducing liver fibrosis, an issue which needs to be further investigated. Kupffer cell stimulation by LPS and/ or octreotide reverse the apoptotic process on the mRNA level, by influencing the proapoptotic and antiapoptotic protein expression. These results show that the antitumour activity of octreotide on patients with hepatocellular carcinoma may be due to its antiapoptotic activity on Kupffer cells.
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Η επίδραση των συνθετικών πεπτιδίων στην πρωτογενή ανοσολογική αντίδραση του ήπατος
