Genomic, Lipidomic And Metabolomic Analysis Of Cyclooxygenase-Null Cells: Eicosanoid Storm, Cross Talk, And Compensation By Cox-1

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 + COX-1(-/-) or COX-27(-) cells shared about 50% of the induced transcripts with WT cells treated with IL-113, 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-1 mRNA COX-27(-) 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), peroxiredox n, phospholipase, prostacyclin synthase, and prostaglandin E synthase, resulting in a significant increase in the levels of PGE(2), PGD(2), leukotriene B-4 (LTB4), PGE(1 alpha), thromboxane B-2 (TXB2), and PGE(2),. 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-27- cells generated an "eicosanoid storm". The genomic characteristics of COX-2(-/-) is similar to that of proinflammatory cells as observed in IL-113 induced WT cells. COX-1(-/-) and COX-27(-/-) cells exhibited compensation of various eicosanoids at the genomic and metabolic levels.