Objective: Fibroblasts in the area of fibrosis in chronic pancreatitis and of desmoplastic reaction associated with pancreatic cancer are now recognized as activated pancreatic stellate cells (PSCs). Recent studies have shown strong expression of fibrinogen, the central protein in the hemostasis pathway, in the stromal tissues of pancreatic cancer and chronic pancreatitis, suggesting that PSCs are embedded in and exposed to abundant fibrinogen in these pathological settings. We here examined the effects of fibrinogen on cell functions in PSCs.
Methods: PSCs were isolated from human pancreas tissues of patients undergoing operation for pancreatic cancer, and from rat pancreatic tissues. The effects of fibrinogen on key cell functions and activation of signaling pathways in PSCs were examined.
Results: Fibrinogen induced the production of interleukin-6, interleukin-8, monocyte chemoattractant protein-1, vascular endothelial growth factor, angiopoietin-1, and type I collagen, but not proliferation or intercellular adhesion molecule-1 expression. Fibrinogen increased the α-smooth muscle actin expression. Fibrinogen induced the activation of nuclear factor-κB, Akt, and three classes of mitogen-activated protein kinases (extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase). Fibrinogen-induced interleukin-6 and interleukin-8 production was inhibited by antibodies against αvβ3 and α5β1 integrins, suggesting that these integrins worked as counter receptors for fibrinogen in PSCs. In addition, fibrinogen-induced production of these cytokines was abolished by an inhibitor of nuclear factor-κB, and partially inhibited by inhibitors of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase.
Conclusion: Fibrinogen directly stimulated profibrogenic and proinflammatory functions in PSCs.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.