ERK pathway and sheddases play an essential role in ethanol-induced CX3CL1 release in pancreatic stellate cells

Masahiko Uchida, Tetsuhide Ito, Taichi Nakamura, Hisato Igarashi, takamasa ono, Nao Fujimori, Ken Kawabe, Koichi Suzuki, Robert T. Jensen, Ryoichi Takayanagi

研究成果: ジャーナルへの寄稿記事

13 引用 (Scopus)

抄録

The clinical course of chronic pancreatitis (CP) worsens with drinking, and pancreatic stellate cells (PSCs) have an important role in the pathogenesis of alcoholic CP. Chemokines recruit inflammatory cells, resulting in chronic pancreatic inflammation. Although serum levels of fractalkine (CX3CL1) are significantly elevated in patients with alcoholic CP, the mechanism of this elevation remains unclear. This study aims to determine the effects of cytokines, pathogen-associated molecular patterns (PAMPs), and ethanol and its metabolites on CX3CL1 secretion by PSCs. Male Wistar/Bonn Kobori (WBN/Kob) rats aged 15 to 20 weeks were used as rodent models of CP in vivo. PSCs were isolated from 6-week-old male Wistar rats. The effects of cytokines, PAMPs, and ethanol and its metabolites on chemokine production and activation of signaling pathways in PSCs in vitro were examined by real-time reverse transcription-polymerase chain reaction (RT-PCR), western blotting, and enzyme-linked immunosorbent assay. Expression of CX3CL1 and matrix metalloprotease (MMP)-2 was increased in the pancreas of WBN/Kob rats. The rat PSCs expressed CX3CL1, MMP-2, and a disintegrin and metalloprotease domain (ADAM) 17. Cytokines and PAMPs induced CX3CL1 release and activated extracellular signal-regulated kinase (ERK), MMP-9, and ADAM17. CX3CL1 release was suppressed by specific inhibitors of ERK, MMP, and ADAM, and ERK was associated with CX3CL1 transcription. Ethanol and phorbol myristate acetate synergistically increased CX3CL1 release. Real-time PCR and western blotting confirmed the synergistic activation of ERK and ADAM17. Ethanol synergistically increased CX3CL1 release via ERK and ADAM17 activation in PSCs. In conclusion, we demonstrated for the first time that ethanol synergistically increased CX3CL1 release from PSCs at least in part through activation of ERK mitogen-activated protein kinase and ADAM17. This might be one of the mechanisms of serum CX3CL1 elevation and disease progression in patients with alcoholic CP.

元の言語英語
ページ(範囲)41-53
ページ数13
ジャーナルLaboratory Investigation
93
発行部数1
DOI
出版物ステータス出版済み - 1 1 2013

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Pancreatic Stellate Cells
Extracellular Signal-Regulated MAP Kinases
Metalloproteases
Ethanol
Chronic Pancreatitis
Alcoholic Pancreatitis
Disintegrins
Cytokines
Chemokines
Western Blotting
Chemokine CX3CL1
Tetradecanoylphorbol Acetate
Mitogen-Activated Protein Kinases
Serum
Drinking
Reverse Transcription
Disease Progression
Wistar Rats
Real-Time Polymerase Chain Reaction
Pancreas

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

これを引用

ERK pathway and sheddases play an essential role in ethanol-induced CX3CL1 release in pancreatic stellate cells. / Uchida, Masahiko; Ito, Tetsuhide; Nakamura, Taichi; Igarashi, Hisato; ono, takamasa; Fujimori, Nao; Kawabe, Ken; Suzuki, Koichi; Jensen, Robert T.; Takayanagi, Ryoichi.

:: Laboratory Investigation, 巻 93, 番号 1, 01.01.2013, p. 41-53.

研究成果: ジャーナルへの寄稿記事

Uchida, M, Ito, T, Nakamura, T, Igarashi, H, ono, T, Fujimori, N, Kawabe, K, Suzuki, K, Jensen, RT & Takayanagi, R 2013, 'ERK pathway and sheddases play an essential role in ethanol-induced CX3CL1 release in pancreatic stellate cells', Laboratory Investigation, 巻. 93, 番号 1, pp. 41-53. https://doi.org/10.1038/labinvest.2012.156
Uchida, Masahiko ; Ito, Tetsuhide ; Nakamura, Taichi ; Igarashi, Hisato ; ono, takamasa ; Fujimori, Nao ; Kawabe, Ken ; Suzuki, Koichi ; Jensen, Robert T. ; Takayanagi, Ryoichi. / ERK pathway and sheddases play an essential role in ethanol-induced CX3CL1 release in pancreatic stellate cells. :: Laboratory Investigation. 2013 ; 巻 93, 番号 1. pp. 41-53.
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abstract = "The clinical course of chronic pancreatitis (CP) worsens with drinking, and pancreatic stellate cells (PSCs) have an important role in the pathogenesis of alcoholic CP. Chemokines recruit inflammatory cells, resulting in chronic pancreatic inflammation. Although serum levels of fractalkine (CX3CL1) are significantly elevated in patients with alcoholic CP, the mechanism of this elevation remains unclear. This study aims to determine the effects of cytokines, pathogen-associated molecular patterns (PAMPs), and ethanol and its metabolites on CX3CL1 secretion by PSCs. Male Wistar/Bonn Kobori (WBN/Kob) rats aged 15 to 20 weeks were used as rodent models of CP in vivo. PSCs were isolated from 6-week-old male Wistar rats. The effects of cytokines, PAMPs, and ethanol and its metabolites on chemokine production and activation of signaling pathways in PSCs in vitro were examined by real-time reverse transcription-polymerase chain reaction (RT-PCR), western blotting, and enzyme-linked immunosorbent assay. Expression of CX3CL1 and matrix metalloprotease (MMP)-2 was increased in the pancreas of WBN/Kob rats. The rat PSCs expressed CX3CL1, MMP-2, and a disintegrin and metalloprotease domain (ADAM) 17. Cytokines and PAMPs induced CX3CL1 release and activated extracellular signal-regulated kinase (ERK), MMP-9, and ADAM17. CX3CL1 release was suppressed by specific inhibitors of ERK, MMP, and ADAM, and ERK was associated with CX3CL1 transcription. Ethanol and phorbol myristate acetate synergistically increased CX3CL1 release. Real-time PCR and western blotting confirmed the synergistic activation of ERK and ADAM17. Ethanol synergistically increased CX3CL1 release via ERK and ADAM17 activation in PSCs. In conclusion, we demonstrated for the first time that ethanol synergistically increased CX3CL1 release from PSCs at least in part through activation of ERK mitogen-activated protein kinase and ADAM17. This might be one of the mechanisms of serum CX3CL1 elevation and disease progression in patients with alcoholic CP.",
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AU - Igarashi, Hisato

AU - ono, takamasa

AU - Fujimori, Nao

AU - Kawabe, Ken

AU - Suzuki, Koichi

AU - Jensen, Robert T.

AU - Takayanagi, Ryoichi

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