Objective: Fibroblasts in the area of fibrosis in chronic pancreatitis and of the desmoplastic reaction associated with pancreatic cancer are now recognised as activated pancreatic stellate cells (PSCs). Recent studies have shown strong expression of fibrinogen, the central protein in the haemostasis 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. The effects of fibrinogen on cell functions in PSCs were examined here.
Methods: PSCs were isolated from human pancreas tissues of patients undergoing operations for pancreatic cancer, and from rat pancreatic tissues. The effects of fibrinogen on key cell functions and activation of signalling pathways in PSCs were examined.
Results: Fibrinogen induced the production of interleukin 6 (IL6), interleukin 8 (IL8), 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 α-smooth muscle actin expression and induced the activation of nuclear factor-κB (NF-κB), Akt and three classes of mitogen-activated protein kinases (extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase and p38 mitogen-activated protein kinase (MAPK)). Fibrinogen-induced IL6 and IL8 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 NF-κB, and partially inhibited by inhibitors of ERK and p38 MAPK.
Conclusion: Fibrinogen directly stimulated profibrogenic and proinflammatory functions in PSCs.
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Competing interests: None.
Funding: This work was supported in part by a Grant-in-Aid from the Japan Society for the Promotion of Science (to AM and KK), by the Pancreas Research Foundation of Japan (to AM and KK), by the Kanae Foundation for Life and Socio-Medical Science (to AM) and by the Uehara Memorial Foundation (to AM).
Ethics approval: This study was approved by the Ethics Committee of Tohoku University School of Medicine, Sendai, Japan.