Transcriptional regulation of CXC-ELR chemokines KC and MIP-2 in mouse pancreatic acini
Transcriptional regulation of CXC-ELR chemokines KC and MIP-2 in mouse pancreatic acini
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DOI：
10.1152/ajpgi.00177.2010
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发表时间：
2010-10-01
影响因子：
4.5
通讯作者：
Singh, Vijay P.
中科院分区：
文献类型：
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作者：
Orlichenko, Lidiya S.;Behari, Jaideep;Singh, Vijay P.
中性粒细胞及其趋化因子、CXC-ELR 趋化因子、角质细胞细胞因子 (KC) 和巨噬细胞炎症蛋白 2 (MIP-2) 在胰腺炎中发挥着关键作用。虽然急性胰腺炎是在腺泡细胞中引发的，但尚不清楚这些细胞是否是 CXC-ELR 趋化因子的来源。 KC 和 MIP-2 在其启动子区域具有 NF-κ B 激活蛋白 1 (AP-1) 位点。然而，之前的研究表明，在体外收获的胰腺组织中，雨伞素诱导的 AP-1 激活增加，而雨伞素诱导的 AP-1 激活减少，这限制了对雨伞素诱导反应的解释。此外，最近的研究表明，仅在腺泡细胞中沉默 NF-kappa B 可能不足以减少急性胰腺炎的炎症。因此，本研究的目的是确定腺泡细胞是否是 KC 和 MIP-2 的来源，并了解它们的转录调控。在确认其复制生理和病理腺泡细胞反应的能力后，使用原代过夜培养的小鼠胰腺腺泡。研究了导致 KC、MIP-2 上调的上游信号传导以及转录因子 NF-κ B 和 AP-1 的激活。培养的腺泡复制了对生理和病理雨蛙素浓度的关键反应。 KC 和 MIP-2 mRNA 水平随超最大剂量而非生理雨蛙素剂量而增加。这种上调依赖于钙和蛋白激酶 C (PKC)，但不依赖于 cAMP。 NF-κ B 抑制完全阻止 KC 的上调，但不能阻止 MIP-2。完全抑制 MIP-2 上调需要 NF-κ B 和 AP-1 的双重抑制。腺泡细胞可能是胰腺炎期间 KC 和 MIP-2 上调的来源。这种上调依赖于钙和 PKC。 MIP-2 上调需要这些细胞中的 NF-κ B 和 AP-1。因此，与单独靶向 NF-κ B 相比，双重抑制 NF-κ B 和 AP-1 可能是减少胰腺炎炎症更成功的策略。
Neutrophils and their chemoattractants, the CXC-ELR chemokines keratinocyte cytokine (KC) and macrophage inflammatory protein-2 (MIP-2), play a critical role in pancreatitis. While acute pancreatitis is initiated in acinar cells, it is unclear if these are a source of CXC-ELR chemokines. KC and MIP-2 have NF-kappa B, activator protein-1 (AP-1) sites in their promoter regions. However, previous studies have shown increased basal and reduced caerulein-induced AP-1 activation in harvested pancreatic tissue in vitro, which limits interpreting the caerulein-induced response. Moreover, recent studies suggest that NF-kappa B silencing in acinar cells alone may not be sufficient to reduce inflammation in acute pancreatitis. Thus the aim of this study was to determine whether acinar cells are a source of KC and MIP-2 and to understand their transcriptional regulation. Primary overnight-cultured murine pancreatic acini were used after confirming their ability to replicate physiological and pathological acinar cell responses. Upstream signaling resulting in KC, MIP-2 upregulation was studied along with activation of the transcription factors NF-kappa B and AP-1. Cultured acini replicated critical responses to physiological and pathological caerulein concentrations. KC and MIP-2 mRNA levels increased in response to supramaximal but not to physiological caerulein doses. This upregulation was calcium and protein kinase C (PKC), but not cAMP, dependent. NF-kappa B inhibition completely prevented upregulation of KC but not MIP-2. Complete suppression of MIP-2 upregulation required dual inhibition of NF-kappa B and AP-1. Acinar cells are a likely source of KC and MIP-2 upregulation during pancreatitis. This upregulation is dependent on calcium and PKC. MIP-2 upregulation requires both NF-kappa B and AP-1 in these cells. Thus dual inhibition of NF-kappa B and AP-1 may be a more successful strategy to reduce inflammation in pancreatitis than targeting NF-kappa B alone.