Institute of Molecular Animal Breeding and Biotechnology, Gene Center of the LMU Munich, Feodor-Lynen-Str. 25, 81377, Munich, Germany.
Laboratory for Functional Genome Analysis (LAFUGA), Gene Center of the LMU Munich, Munich, Germany.
J Gastroenterol. 2020 Mar;55(3):317-329. doi: 10.1007/s00535-019-01613-6. Epub 2019 Aug 27.
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.
AP was induced with cerulein or L-arginine and investigated in a pancreas-specific ERBB4 knockout and in an EGFR knockdown mouse model (Egfr). 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.
While the pancreas of BTC transgenic mice in the background of Egfr 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.
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.
表皮生长因子受体配体β细胞素（BTC）先前已被证明可保护小鼠免受实验性急性胰腺炎（AP）的侵害。BTC 可结合自主 ERBB 受体 EGFR 和 ERBB4。在这项研究中，我们详细评估了其对 AP 相关炎症的保护作用的机制。
用胆酸钠或 L-精氨酸诱导 AP，并在胰腺特异性 ERBB4 敲除和 EGFR 敲低小鼠模型（Egfr）中进行研究。通过评分炎症、坏死和水肿来评估胰腺炎，同时进行微阵列分析以分析 AP 小鼠和预防 AP 的动物之间转录组的变化。分析 ERBB4 的细胞内结构域（ICD）在不同细胞区室中的变化。
尽管 BTC 转基因小鼠在 Egfr 的背景下仍能抵抗 AP，但在没有 ERBB4 的情况下，BTC 介导的保护作用不再存在。我们进一步证明，BTC 激活 ERBB4 的 ICD，并增加细胞外基质（ECM）蛋白骨桥蛋白和基质 Gla 蛋白以及 ECM 调节剂基质金属蛋白酶 2 和 3 的表达，但仅在存在 ERBB4 的情况下。值得注意的是，这些蛋白表达的增加并不伴随着 ECM 量的增加。
这些发现表明，BTC 衍生物作为一种药物，或 ERBB4 受体作为一种可用药靶蛋白，可能在调节 AP 的病程中发挥重要作用，甚至可以预防人类的 AP。
