Suppression of transforming growth factor β signalling aborts caerulein induced pancreatitis and eliminates restricted stimulation at high caerulein concentrations

Stefan Wildi, Jörg Kleeff, Julia Mayerle, Arthur Zimmermann, Erwin P. Böttinger, Lalage Wakefield, Markus W. Büchler, Helmut Friess, Murray Korc

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Background: Transforming growth factors βs (TGF-βs) are implicated in pancreatic tissue repair but their role in acute pancreatitis is not known. To determine whether endogenous TGF-βs modulate the course of caerulein induced acute pancreatitis, caerulein was administered to wild-type (FVB-/-) and transgenic mice that are heterozygous (FVB+/-) for expression of a dominant negative type II TGF-β receptor. Methods: After 7 hourly supramaximal injections of caerulein, the pancreas was evaluated histologically and serum was assayed for amylase and lipase levels. Next, the effects of caerulein on amylase secretion were determined in mouse pancreatic acini, and cholecystokinin (CCK) receptor expression was assessed. Results: The normal mouse pancreas was devoid or inflammatory cells whereas the pancreas from transgenic mice contained lymphocytic infiltrates. Caerulein injection in wild-type mice resulted in 6- and 36-fold increases in serum amylase and lipase levels, respectively, increased serum trypsinogen activation peptide (TAP) levels, gross oedema and a marked inflammatory response in the pancreas that consisted mainly of neutrophils and macrophages. By contrast, FVB+/- mice exhibited minimal alterations in response to caerulein with attenuated neutrophil-macrophage infiltrates. Moreover, acini from FVB+/- mice did not exhibit restricted stimulation at high caerulein concentrations, even though CCK receptor mRNA levels were not decreased. Conclusion: Our findings indicate that a functional TGF-β signalling pathway may be required for caerulein to induce acute pancreatitis and for the CCK receptor to induce acinar cell damage at high ligand concentrations. Our results also support the concept that restricted stimulation at high caerulein concentrations contributes to the ability of caerulein to induce acute pancreatitis.

Original languageEnglish (US)
Pages (from-to)685-692
Number of pages8
JournalGut
Volume56
Issue number5
DOIs
StatePublished - May 2007
Externally publishedYes

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Ceruletide
Transforming Growth Factors
Pancreatitis
Cholecystokinin Receptors
Pancreas
Amylases
trypsinogen activation peptide
Lipase
Transgenic Mice
Neutrophils
Serum
Macrophages
Injections
Acinar Cells
Edema
Ligands

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Suppression of transforming growth factor β signalling aborts caerulein induced pancreatitis and eliminates restricted stimulation at high caerulein concentrations. / Wildi, Stefan; Kleeff, Jörg; Mayerle, Julia; Zimmermann, Arthur; Böttinger, Erwin P.; Wakefield, Lalage; Büchler, Markus W.; Friess, Helmut; Korc, Murray.

In: Gut, Vol. 56, No. 5, 05.2007, p. 685-692.

Research output: Contribution to journalArticle

Wildi, S, Kleeff, J, Mayerle, J, Zimmermann, A, Böttinger, EP, Wakefield, L, Büchler, MW, Friess, H & Korc, M 2007, 'Suppression of transforming growth factor β signalling aborts caerulein induced pancreatitis and eliminates restricted stimulation at high caerulein concentrations', Gut, vol. 56, no. 5, pp. 685-692. https://doi.org/10.1136/gut.2006.105833
Wildi, Stefan ; Kleeff, Jörg ; Mayerle, Julia ; Zimmermann, Arthur ; Böttinger, Erwin P. ; Wakefield, Lalage ; Büchler, Markus W. ; Friess, Helmut ; Korc, Murray. / Suppression of transforming growth factor β signalling aborts caerulein induced pancreatitis and eliminates restricted stimulation at high caerulein concentrations. In: Gut. 2007 ; Vol. 56, No. 5. pp. 685-692.
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AU - Wildi, Stefan

AU - Kleeff, Jörg

AU - Mayerle, Julia

AU - Zimmermann, Arthur

AU - Böttinger, Erwin P.

AU - Wakefield, Lalage

AU - Büchler, Markus W.

AU - Friess, Helmut

AU - Korc, Murray

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N2 - Background: Transforming growth factors βs (TGF-βs) are implicated in pancreatic tissue repair but their role in acute pancreatitis is not known. To determine whether endogenous TGF-βs modulate the course of caerulein induced acute pancreatitis, caerulein was administered to wild-type (FVB-/-) and transgenic mice that are heterozygous (FVB+/-) for expression of a dominant negative type II TGF-β receptor. Methods: After 7 hourly supramaximal injections of caerulein, the pancreas was evaluated histologically and serum was assayed for amylase and lipase levels. Next, the effects of caerulein on amylase secretion were determined in mouse pancreatic acini, and cholecystokinin (CCK) receptor expression was assessed. Results: The normal mouse pancreas was devoid or inflammatory cells whereas the pancreas from transgenic mice contained lymphocytic infiltrates. Caerulein injection in wild-type mice resulted in 6- and 36-fold increases in serum amylase and lipase levels, respectively, increased serum trypsinogen activation peptide (TAP) levels, gross oedema and a marked inflammatory response in the pancreas that consisted mainly of neutrophils and macrophages. By contrast, FVB+/- mice exhibited minimal alterations in response to caerulein with attenuated neutrophil-macrophage infiltrates. Moreover, acini from FVB+/- mice did not exhibit restricted stimulation at high caerulein concentrations, even though CCK receptor mRNA levels were not decreased. Conclusion: Our findings indicate that a functional TGF-β signalling pathway may be required for caerulein to induce acute pancreatitis and for the CCK receptor to induce acinar cell damage at high ligand concentrations. Our results also support the concept that restricted stimulation at high caerulein concentrations contributes to the ability of caerulein to induce acute pancreatitis.

AB - Background: Transforming growth factors βs (TGF-βs) are implicated in pancreatic tissue repair but their role in acute pancreatitis is not known. To determine whether endogenous TGF-βs modulate the course of caerulein induced acute pancreatitis, caerulein was administered to wild-type (FVB-/-) and transgenic mice that are heterozygous (FVB+/-) for expression of a dominant negative type II TGF-β receptor. Methods: After 7 hourly supramaximal injections of caerulein, the pancreas was evaluated histologically and serum was assayed for amylase and lipase levels. Next, the effects of caerulein on amylase secretion were determined in mouse pancreatic acini, and cholecystokinin (CCK) receptor expression was assessed. Results: The normal mouse pancreas was devoid or inflammatory cells whereas the pancreas from transgenic mice contained lymphocytic infiltrates. Caerulein injection in wild-type mice resulted in 6- and 36-fold increases in serum amylase and lipase levels, respectively, increased serum trypsinogen activation peptide (TAP) levels, gross oedema and a marked inflammatory response in the pancreas that consisted mainly of neutrophils and macrophages. By contrast, FVB+/- mice exhibited minimal alterations in response to caerulein with attenuated neutrophil-macrophage infiltrates. Moreover, acini from FVB+/- mice did not exhibit restricted stimulation at high caerulein concentrations, even though CCK receptor mRNA levels were not decreased. Conclusion: Our findings indicate that a functional TGF-β signalling pathway may be required for caerulein to induce acute pancreatitis and for the CCK receptor to induce acinar cell damage at high ligand concentrations. Our results also support the concept that restricted stimulation at high caerulein concentrations contributes to the ability of caerulein to induce acute pancreatitis.

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