Lipopolysaccharide-activated macrophages stimulate the synthesis of collagen type I and C-fibronectin in cultured pancreatic stellate cells

We have recently identified and characterized pancreatic stellate cells (PS C) in rats and humans (Gastroenterology 1998, 15:421-435). PSC are suggeste d to represent the main cellular source of extracellular matrix in chronic pancreatitis. Now We describe a paracrine stimulatory loop between human ma crophages and PSC (rat and human) that results in an increased extracellula r matrix synthesis. Native and transiently acidified supernatants of cultur ed macrophages were added to cultured PSC in the presence of 0.1% fetal cal f serum. Native supernatants of lipopolysaccharide-activated macrophages st imulated the synthesis of collagen type I 1.38 +/- 0.09-fold of control and c-fibronectin 1.89 +/- 0.18-fold of control. Transiently acidified superna tants stimulated collagen type I and c-fibronectin 2.10 +/- 0.2-fold and 2. 80 +/- 0.05-fold of control, respectively. Northern blot demonstrated an in creased expression of the collagen-I-(alpha-1)-mRNA and fibronectin-mRNA in PSC 10 hours after addition of the acidified macrophage supernatants, Cell proliferation measured by bromodeoxyuridine incorporation was not influenc ed by the macrophage supernatants. Unstimulated macrophages released 1.97 p g TGF beta 1/mu g of DNA over 24 hours and lipopolysaccharide-activated mac rophages released 6.61pg TGF beta 1/mu g of DNA over 24 hours. These data t ogether with the results that, in particular, transiently acidified macroph age supernatants increased matrix synthesis, identify TGF beta as the respo nsible mediator. In conclusion, our data demonstrate a paracrine stimulatio n of matrix synthesis of pancreatic stellate cells via TGF beta 1 released by activated macrophages. We suggest that macrophages might play a pivotal role in the development of pancreas fibrosis.