Uncovering potential new targets involved in pancreas recovery may permit the development of new therapies and lead to improved outcome of pancreatitis. One of the reported disease mechanisms of pancreatitis comprises the endoplasmic reticulum (ER) stress response, since pancreatic acini exhibit high levels of protein synthesis and subsequently, ER stress. A key regulator to prevent proteotoxic stress in an inflammatory context is the immunoproteasome, an induced form of the constitutive proteasome. Our aim was therefore to investigate the role of the immunoproteasome in acute pancreatitis. In this study, we demonstrate that immunoproteasome-deficiency by deletion of the β5i/LMP7-subunit correlates with persistent pancreatic damage. Interestingly, immunoproteasome -deficient mice unveil increased activity of pancreatic enzymes in the acute disease phase as well as higher secretion of Interleukin-6 and transcript expression of the Interleukin IL-1β, IFN-β cytokines and the CXCL-10 chemokine. Cell death was increased in immunoproteasome-deficient mice, which appears to be due to the greater accumulation of ubiquitin-protein conjugates and prolonged unfolded protein response. Accordingly, our findings suggest that the immunoproteasome plays a protective role in acute pancreatitis via its role in the clearance of damaged proteins and the balance of ER-stress responses in pancreatic acini as well as in macrophages cytokine production.

中文翻译：

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免疫蛋白酶体缺乏症会导致持续的胰腺损伤并延迟实验性胰腺炎的恢复

揭示涉及胰腺恢复的潜在新靶点可能允许开发新疗法，并导致胰腺炎转归改善。胰腺炎的一种发病机理包括内质网应激反应，因为胰腺痤疮表现出高水平的蛋白质合成和内质网应激。免疫蛋白酶体是组成型蛋白酶体的诱导形式，它在炎性环境中可防止蛋白毒性应激的关键调节因子。因此，我们的目的是研究免疫蛋白酶体在急性胰腺炎中的作用。在这项研究中，我们证明了通过删除β5i/ LMP7亚基引起的免疫蛋白酶体缺乏与持续性胰腺损害相关。有趣的是 免疫蛋白酶体缺陷小鼠揭示了在急性疾病阶段胰腺酶的活性增加，以及白细胞介素6的分泌增多以及白细胞介素IL-1β，IFN-β细胞因子和CXCL-10趋化因子的转录表达。免疫蛋白酶体缺乏症小鼠的细胞死亡增加，这似乎是由于遍在蛋白-蛋白质结合物的积累更多以及未折叠的蛋白质反应延长。因此，我们的发现表明免疫蛋白酶体通过其在清除受损蛋白质中的作用以及在胰腺腺泡蛋白以及巨噬细胞细胞因子产生中的ER-应激反应的平衡中在急性胰腺炎中起保护作用。免疫蛋白酶体缺乏症小鼠的细胞死亡增加，这似乎是由于遍在蛋白-蛋白质缀合物的积累更多以及未折叠的蛋白质反应延长。因此，我们的发现表明免疫蛋白酶体通过其在清除受损蛋白质中的作用以及在胰腺腺泡蛋白以及巨噬细胞细胞因子产生中的ER-应激反应的平衡中在急性胰腺炎中起保护作用。免疫蛋白酶体缺乏症小鼠的细胞死亡增加，这似乎是由于遍在蛋白-蛋白质缀合物的积累更多以及未折叠的蛋白质反应延长。因此，我们的发现表明免疫蛋白酶体通过其在清除受损蛋白质中的作用以及在胰腺腺泡蛋白以及巨噬细胞细胞因子产生中的ER-应激反应的平衡中在急性胰腺炎中起保护作用。