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The protective effect of betacellulin against acute pancreatitis is ERBB4 dependent

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

The EGFR ligand betacellulin (BTC) has been previously shown to protect mice against experimentally induced acute pancreatitis (AP). BTC binds both autonomous ERBB receptors EGFR and ERBB4. In this study, we evaluated the mechanism underlying the protection from AP-associated inflammation in detail.

Methods

AP was induced with cerulein or l-arginine and investigated in a pancreas-specific ERBB4 knockout and in an EGFR knockdown mouse model (EgfrWa5/+). Pancreatitis was evaluated by scoring inflammation, necrosis, and edema, while microarrays were performed to analyze alterations in the transcriptome between mice with AP and animals which were protected against AP. The intracellular domain (ICD) of ERBB4 was analyzed in different cell compartments.

Results

While the pancreas of BTC transgenic mice in the background of EgfrWa5/+ is still protected against AP, the BTC-mediated protection is no longer present in the absence of ERBB4. We further demonstrate that BTC activates the ICD of ERBB4, and increases the expression of the extracellular matrix (ECM) proteins periostin and matrix gla protein as well as the ECM modulators matrix metalloproteinases 2 and 3, but only in the presence of ERBB4. Notably, the increased expression of these proteins is not accompanied by an increased ECM amount.

Conclusions

These findings suggest that BTC derivates, as a drug, or the ERBB4 receptor, as a druggable target protein, could play an important role in modulating the course of AP and even prevent AP in humans.

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Abbreviations

AP:

Acute pancreatitis

BTC:

Betacellulin

ECM:

Extra cellular matrix

EGF:

Epidermal growth factor

EGFR:

EGF receptor

H&E:

Haemotoxylin and eosin

ICD:

Intracellular domain

MDM2:

Mouse double minute 2 homolog

MGP:

Matrix gla protein

MMP:

Metalloproteinase

PBS:

Phosphate-buffered saline

PCR:

Polymerase chain reaction

PDAC:

Pancreatic ductal adenocarcinoma

POSTN:

Periostin

SAPK:

Stress-activated protein kinase

YAP1:

Yes-associated protein 1

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Acknowledgements

We thank Dr. Ingrid Renner-Müller and Petra Renner for excellent animal care, Stefanie Riesemann for assistance with Western blot analysis, Josef Millauer for mouse genotyping and Maximilian Marschall for immunohistochemistry. This work was supported by the Else Kröner-Fresenius-Stiftung.

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Authors and Affiliations

  1. Institute of Molecular Animal Breeding and Biotechnology, Gene Center of the LMU Munich, Feodor-Lynen-Str. 25, 81377, Munich, Germany

    Kathrin Hedegger, Franziska Stumpf, Marlon Roberto Schneider & Maik Dahlhoff

  2. Second Department of Internal Medicine, Klinikum Rechts Der Isar, Technical University of Munich, Munich, Germany

    Roland Michael Schmid, Marina Lesina & Hana Algül

  3. Laboratory for Functional Genome Analysis (LAFUGA), Gene Center of the LMU Munich, Munich, Germany

    Helmut Blum & Alexander Graf

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  1. Kathrin Hedegger
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Correspondence to Maik Dahlhoff.

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Hedegger, K., Stumpf, F., Blum, H. et al. The protective effect of betacellulin against acute pancreatitis is ERBB4 dependent. J Gastroenterol 55, 317–329 (2020). https://doi.org/10.1007/s00535-019-01613-6

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  • DOI: https://doi.org/10.1007/s00535-019-01613-6

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