Fibrinogen induces cytokine and collagen production in pancreatic stellate cells.
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 alpha-smooth muscle actin expression and induced the activation of nuclear factor-kappaB (NF-kappaB), 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 alpha(v)beta(3) and alpha(5)beta(1) 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-kappaB, and partially inhibited by inhibitors of ERK and p38 MAPK.


CONCLUSIONS
Fibrinogen directly stimulated profibrogenic and proinflammatory functions in PSCs.
Masamune
A
A
Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574 Japan. amasamune@int3.med.tohoku.ac.jp
Kikuta
K
K
Watanabe
T
T
Satoh
K
K
Hirota
M
M
Hamada
S
S
Shimosegawa
T
T
D000818:Animals; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis*; D016207:Cytokines / Q000096:biosynthesis*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005340:Fibrinogen / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D039081:Integrin alpha5beta1 / Q000502:physiology; D039302:Integrin alphaVbeta3 / Q000502:physiology; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010179:Pancreas / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D050500:Pancreatitis, Chronic / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000096:biosynthesis; D011347:Procollagen / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D024042:Collagen Type I; D016207:Cytokines; D039081:Integrin alpha5beta1; D039302:Integrin alphaVbeta3; D015850:Interleukin-6; D016209:Interleukin-8; D010446:Peptide Fragments; D011347:Procollagen; C042813:procollagen type I carboxy terminal peptide; D005340:Fibrinogen