Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis

Background-The pathogenesis of pancreatic fibrosis is unknown. In the liver stellate cells play a major role in fibrogenesis by synthesising increased amounts of collagen and other extracellular matrix (ECM) proteins when act ivated by profibrogenic mediators such as cytokines and oxidant stress. Aims-To determine whether cultured rat pancreatic stellate cells produce co llagen and other ECM proteins, and exhibit signs of activation:when exposed to the cytokines platelet derived growth factor (PDGF) or transforming gro wth factor beta (TGF-beta). Methods-Cultured pancreatic stellate cells were immunostained for the ECM p roteins procollagen III, collagen I, laminin, and fibronectin using specifi c polyclonal antibodies. For cytokine studies, triplicate wells of cells we re incubated with increasing concentrations of PDGF or TGF-beta. Results-Cultured pancreatic stellate cells stained strongly positive for al l ECM proteins tested. Incubation of cells with I, 5, and 10 ng/ml PDGF led to a significant close related increase in cell counts as well as in the i ncorporation of H-3-thymidine into DNA, Stellate cells exposed to 0.25, 0.5 , and 1 ng/ml TGF-beta showed a dose dependent increase in alpha smooth-mus cle actin expression and increased collagen synthesis; In addition, TGF-bet a increased the expression of PDGF receptors on stellate cells. Conclusions-Pancreatic stellate cells produce collagen and other extracellu lar matrix proteins, and respond to the cytokines PDGF and TGF-beta by incr eased proliferation and increased collagen synthesis. These results suggest an important role for stellate cells in pancreatic fibrogenesis.