Regulatory effects of the JAK3/STAT1 pathway on the release of secreted phospholipase A2-IIA in microvascular endothelial cells of the injured brain

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• 作者：Guansong Wang (1)
  Pin Qian (1)
  Zhi Xu (1)
  Jiqiang Zhang (2)
  Yaoli Wang (1)
  Saiyu Cheng (2)
  Wenqin Cai (2)
  Guisheng Qian (1)
  Changzheng Wang (1)
  Mark A DeCoster (3)
  
• 关键词：Secreted phospholipase A2 ; IIA ; Brain microvascular endothelial cells ; Permeability ; Lipopolysaccharide ; Nitric oxide ; Inducible NO synthase ; JAK3 ; STAT1
• 刊名：Journal of Neuroinflammation
• 出版年：2012
• 出版时间：December 2012
• 年：2012
• 卷：9
• 期：1
• 全文大小：758KB
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• 作者单位：Guansong Wang (1)
  Pin Qian (1)
  Zhi Xu (1)
  Jiqiang Zhang (2)
  Yaoli Wang (1)
  Saiyu Cheng (2)
  Wenqin Cai (2)
  Guisheng Qian (1)
  Changzheng Wang (1)
  Mark A DeCoster (3)
  
  1. Neuronscience Program, Institute of Respiratory Diseases in Xinqiao Hospital, Chongqing, 400037, P. R. China
  2. Department of Neurobiology, The Third Military Medical University, Chongqing, 400037, P. R. China
  3. Biomedical Engineering and Institute for Micro Manufacturing, Louisiana Tech University, Ruston, LA, 71272, USA
  
• ISSN：1742-2094

文摘

Background Secreted phospholipase A2-IIA (sPLA2-IIA) is an inducible enzyme released under several inflammatory conditions. It has been shown that sPLA2-IIA is released from rat brain astrocytes after inflammatory stimulus, and lipopolysaccharide (LPS) and nitric oxide (NO) have been implicated in regulation of this release. Here, brain microvascular endothelial cells (BMVECs) were treated with LPS to uncover whether sPLA2-IIA was released, whether nitric oxide regulated this release, and any related signal mechanisms. Methods Supernatants were collected from primary cultures of BMVECs. The release of sPLA2-IIA, and the expression of inducible nitric oxide synthase (iNOS), phospho-JAK3, phospho-STAT1, total JAK3 and STAT1, β-actin, and bovine serum albumin (BSA) were analyzed by Western blot or ELISA. NO production was calculated by the Griess reaction. sPLA2 enzyme activity was measured with a fluorometric assay. Specific inhibitors of NO (L-NAME and aminoguanidine, AG), JAK3 (WHI-P154,WHI), STAT1 (fludarabine, Flu), and STAT1 siRNA were used to determine the involvement of these molecules in the LPS-induced release of sPLA2-IIA from BMVECs. Nuclear STAT1 activation was tested with the EMSA method. The monolayer permeability of BMVECs was measured with a diffusion assay using biotinylated BSA. Results Treatment of BMVECs with LPS increased the release of sPLA2-IIA and nitrite into the cell culture medium up to 24?h. Pretreatment with an NO donor, sodium nitroprusside, decreased LPS-induced sPLA2-IIA release and sPLA2 enzyme activity, and enhanced the expression of iNOS and nitrite generation after LPS treatment. Pretreatment with L-NAME, AG, WHI-P154, or Flu notably reduced the expression of iNOS and nitrite, but increased sPLA2-IIA protein levels and sPLA2 enzyme activity. In addition, pretreatment of the cells with STAT1 siRNA inhibited the phosphorylation of STAT1, iNOS expression, and nitrite production, and enhanced the release of sPLA2-IIA. Pretreatment with the specific inhibitors of NOS, JAK2, and STAT3 decreased the permeability of BMVECs. In contrast, inhibition of sPLA2-IIA release increased cell permeability. These results suggest that sPLA2-IIA expression is regulated by the NO-JAK3-STAT1 pathway. Importantly, sPLA2-IIA augmentation could protect the LPS-induced permeability of BMVECs. Conclusion Our results demonstrate the important action of sPLA2-IIA in the permeability of microvascular endothelial cells during brain inflammatory events. The sPLA2 and NO pathways can be potential targets for the management of brain MVEC injuries and related inflammation.