Genomic,Lipidomic,and Metabolomic Analysis of Cyclooxygenase-null Cells:Eicosanoid Storm,Cross Talk,and Compensation by COX-1  

作　　者：Abul B.M.M.K.Islam Mandar Dave Sonia Amin Roderick V.Jensen Ashok R.Amin 

机构地区：[1]Department of Genetic Engineering and Biotechnology,University of Dhaka,Dhaka 1000,Bangladesh [2]Department of Rheumatology,New York University Hospital for Joint Diseases,New York,NY 10003,USA [3]Department of Biology and Chemistry,Essex County College,Newark,NJ 07102,USA [4]Department of Biological Sciences,College of Science,Virginia Tech Blacksburg,VA 24060,USA [5]Department of Pathology,New York University School of Medicine,New York,NY 10016,USA [6]RheuMatrix Inc.,Blacksburg,VA 24060,USA

出　　处：《Genomics, Proteomics & Bioinformatics》2016年第2期81-93,共13页基因组蛋白质组与生物信息学报（英文版）

基　　金：supported in part by NIH(Grant No.AR 47206-03)

摘　　要：The constitutively-expressed cyclooxygenase 1（COX-1） and the inducible COX-2 are both involved in the conversion of arachidonic acid（AA） to prostaglandins（PGs）.However,the functional roles of COX-1 at the cellular level remain unclear.We hypothesized that by comparing differential gene expression and eicosanoid metabolism in lung fibroblasts from wild-type（WT） mice and COX-2^（-/-） or COX-1^（-/-） mice may help address the functional roles of COX-1 in inflammation and other cellular functions.Compared to WT,the number of specifically-induced transcripts were altered descendingly as follows：COX-2^（-/-） 〉 COX-1^（-/-） 〉 WT ＋ IL-1β.COX-1^（-/-） or COX-2^（-/-） cells shared about 50%of the induced transcripts with WT cells treated with IL-1β,respectively.An interactive ＂anti-inflammatory,proinflammatory,and redox-activated＂ signature in the protein-protein interactome map was observed in COX-2^（-/-） cells.The augmented COX-1mRNA（in COX-2^（-/-） cells） was associated with the upregulation of mRNAs for glutathione S-transferase（GST）,superoxide dismutase（SOD）,NAD（P）H dehydrogenase quinone 1（NQO1）,aryl hydrocarbon receptor（AhR）,peroxiredoxin,phospholipase,prostacyclin synthase,and prostaglandin E synthase,resulting in a significant increase in the levels of PGE2,PGD2,leukotriene B4（LTB4）,PGF（1α）,thromboxane B2（TXB2）,and PGF（2α）.The COX-1 plays a dominant role in shifting AA toward the LTB4 pathway and anti-inflammatory activities.Compared to WT,the upregulated COX-1 mRNA in COX-2^（-/-） cells generated an ＂eicosanoid storm＂.The genomic characteristics of COX-2^（-/-） is similar to that of proinflammatory cells as observed in IL-1β induced WT cells.COX-1^（-/-） and COX-2^（-/-） cells exhibited compensation of various eicosanoids at the genomic and metabolic levels.The constitutively-expressed cyclooxygenase 1（COX-1） and the inducible COX-2 are both involved in the conversion of arachidonic acid（AA） to prostaglandins（PGs）.However,the functional roles of COX-1 at the cellular level remain unclear.We hypothesized that by comparing differential gene expression and eicosanoid metabolism in lung fibroblasts from wild-type（WT） mice and COX-2^（-/-） or COX-1^（-/-） mice may help address the functional roles of COX-1 in inflammation and other cellular functions.Compared to WT,the number of specifically-induced transcripts were altered descendingly as follows：COX-2^（-/-） 〉 COX-1^（-/-） 〉 WT ＋ IL-1β.COX-1^（-/-） or COX-2^（-/-） cells shared about 50%of the induced transcripts with WT cells treated with IL-1β,respectively.An interactive ＂anti-inflammatory,proinflammatory,and redox-activated＂ signature in the protein-protein interactome map was observed in COX-2^（-/-） cells.The augmented COX-1mRNA（in COX-2^（-/-） cells） was associated with the upregulation of mRNAs for glutathione S-transferase（GST）,superoxide dismutase（SOD）,NAD（P）H dehydrogenase quinone 1（NQO1）,aryl hydrocarbon receptor（AhR）,peroxiredoxin,phospholipase,prostacyclin synthase,and prostaglandin E synthase,resulting in a significant increase in the levels of PGE2,PGD2,leukotriene B4（LTB4）,PGF（1α）,thromboxane B2（TXB2）,and PGF（2α）.The COX-1 plays a dominant role in shifting AA toward the LTB4 pathway and anti-inflammatory activities.Compared to WT,the upregulated COX-1 mRNA in COX-2^（-/-） cells generated an ＂eicosanoid storm＂.The genomic characteristics of COX-2^（-/-） is similar to that of proinflammatory cells as observed in IL-1β induced WT cells.COX-1^（-/-） and COX-2^（-/-） cells exhibited compensation of various eicosanoids at the genomic and metabolic levels.

关 键 词：PROSTAGLANDINS Metabolomics Lung fibroblasts Genomies Inflammation 

分 类 号：R3411[医药卫生—基础医学]