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

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）,PGF1α,thromboxane B2（TXB2）,and PGF2α.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.