Department of Pathophysiology, School of Medicine, Tongji University, Shanghai, China.
Am J Physiol Gastrointest Liver Physiol. 2009 Nov;297(5):G981-9. doi: 10.1152/ajpgi.00225.2009.
The objective of this study was to investigate the role of MAPKAP kinase 2 (MK2) and heat shock protein (HSP) HSP60 in the pathogenesis of a new model of severe acute pancreatitis (AP). MK2 plays a significant role in the regulation of cytokines. It has been shown that induction and expression of several HSPs can protect against experimental pancreatitis. Interplay between both systems seems of high interest. Mice with a homozygous deletion of the MK2 gene were used. Severe AP was induced by combined intraperitoneal injections of cerulein with lipopolysaccharide (LPS). Severity of AP was assessed by biochemical markers and histology. The serum IL-6 and lung myeloperoxidase (MPO) levels were determined for assessing the extent of systemic inflammatory response. Expression of HSP25, HSP60, HSP70, and HSP90 was analyzed by Western blotting. Repeated injections of cerulein alone or cerulein plus LPS (Cer+LPS) resulted in local inflammatory responses in the pancreas and corresponding systemic inflammatory changes with pronounced severity in the Cer+LPS group. Compared with the C57Bl wild-type mice, the MK2-/- mice presented with significant milder pancreatitis and attenuated responses of serum amylase and trypsinogen activity. Furthermore, serum IL-6 was decreased as well as lung MPO activity. Injection of LPS alone displayed neither pancreatic inflammatory responses nor alterations of pancreatic enzyme activities but evidently elevated serum IL-6 levels and increased lung MPO activity. In contrast hereto, in the MK2-/- mice, these changes were much milder. Increased expression of HSP25 and HSP60 occurred after induction of AP. Especially, HSP60 was robustly elevated after Cer+LPS treatment, in both MK2-/- and wild-type mice. Thus the homozygous deletion of the MK2 gene ameliorates the severity of acute pancreatitis and accompanying systemic inflammatory reactions in a new model of severe acute pancreatitis. Our data support the hypothesis that MK2 participates in the multifactorial regulation of early inflammatory responses in AP, independently of the regulation of stress proteins like HSP25 and HSP60 and most likely due to its effect on cytokine regulation.
本研究旨在探讨丝裂原活化蛋白激酶激活蛋白激酶 2（MK2）和热休克蛋白（HSP）HSP60 在一种新的重症急性胰腺炎（AP）模型发病机制中的作用。MK2 在细胞因子调节中起着重要作用。已经表明，几种 HSP 的诱导和表达可以保护实验性胰腺炎。这两个系统之间的相互作用似乎非常有趣。使用 MK2 基因纯合缺失的小鼠。通过腹腔内注射细胞松弛素与脂多糖（LPS）联合诱导重症 AP。通过生化标志物和组织学评估 AP 的严重程度。通过测定血清白细胞介素 6（IL-6）和肺髓过氧化物酶（MPO）水平来评估全身炎症反应的程度。通过 Western 印迹分析 HSP25、HSP60、HSP70 和 HSP90 的表达。单独重复注射细胞松弛素或细胞松弛素加 LPS（Cer+LPS）导致胰腺局部炎症反应和相应的全身炎症变化，Cer+LPS 组明显严重。与 C57Bl 野生型小鼠相比，MK2-/- 小鼠的胰腺炎明显较轻，血清淀粉酶和胰蛋白酶原活性的反应减弱。此外，血清 IL-6 降低，肺 MPO 活性降低。单独注射 LPS 既不会引起胰腺炎症反应，也不会改变胰腺酶活性，但明显升高血清 IL-6 水平并增加肺 MPO 活性。相比之下，在 MK2-/- 小鼠中，这些变化要温和得多。AP 诱导后 HSP25 和 HSP60 的表达增加。特别是在 Cer+LPS 处理后，MK2-/- 和野生型小鼠的 HSP60 均显著升高。因此，MK2 基因的纯合缺失可改善一种新的重症急性胰腺炎模型中急性胰腺炎的严重程度和伴随的全身炎症反应。我们的数据支持 MK2 参与 AP 早期炎症反应的多因素调节的假说，独立于 HSP25 和 HSP60 等应激蛋白的调节，很可能是由于其对细胞因子调节的影响。
