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Suppression of TGF-β signaling aborts caerulein- induced pancreatitis and eliminates restricted stimulation at high caerulein concentrations
  1. Stefan Wildi (stefan.wildi{at}
  1. University of Zurich, Switzerland
    1. Jorg Kleeff (kleeff{at}
    1. University of Heidelberg, Germany
      1. Julia Mayerle (mayerle{at}
      1. University of Greifswald, Germany
        1. Arthur Zimmermann (zimmerma{at}
        1. University of Bern, Switzerland
          1. Erwin Bottinger (erwin.bottinger{at}
          1. Mount Sinai School of Medicine, United States
            1. Lalage Wakefield (wakefiel{at}
            1. NIH, United States
              1. Markus Buchler (markus.buechler{at}
              1. University of Heidelberg, Germany
                1. Helmut Friess (helmut.friess{at}
                1. University of Heidelberg, Germany
                  1. Murray Korc (murray.korc{at}
                  1. Dartmouth Medical School, United States


                    Background: Transforming growth factors-β (TGF-β) are implicated in pancreatic tissue repair, but their role in acute pancreatitis (AP) is not known. To determine whether endogenous TGF-β modulate the course of caerulein-induced AP, 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 (Tβ RII).

                    Methods: After 7 hourly supra-maximal 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 of 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 edema, 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 signaling pathway may be required for caerulein to induce AP and for the CCK receptor to induce acinar cell damage at high ligand concentrations, and support the concept that restricted stimulation at high caerulein concentrations contributes to the ability of caerulein to induce AP.

                    • TGF-beta receptor
                    • TGF-beta signaling
                    • acute pancreatitis
                    • amylase release
                    • caeruelein

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