title: Genomic, Lipidomic and Metabolomic Analysis of Cyclooxygenase-null Cells: Eicosanoid Storm, Cross Talk, and Compensation by COX-1.
abstract: 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-1 mRNA (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.
authors.affiliation: Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka 1000, Bangladesh.
authors.forename: Abul B M M K
authors.initials: AB
authors.lastname: Islam
authors.affiliation: Department of Rheumatology, New York University Hospital for Joint Diseases, New York, NY 10003, USA; Department of Biology and Chemistry, Essex County College, Newark, NJ 07102, USA.
authors.forename: Mandar
authors.initials: M
authors.lastname: Dave
authors.affiliation: Department of Biological Sciences, College of Science, Virginia Tech Blacksburg, VA 24060, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Amin
authors.affiliation: Department of Biological Sciences, College of Science, Virginia Tech Blacksburg, VA 24060, USA.
authors.forename: Roderick V
authors.initials: RV
authors.lastname: Jensen
authors.affiliation: Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka 1000, Bangladesh; Department of Rheumatology, New York University Hospital for Joint Diseases, New York, NY 10003, USA; Department of Biological Sciences, College of Science, Virginia Tech Blacksburg, VA 24060, USA; Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; RheuMatrix Inc., Blacksburg, VA 24060, USA. Electronic address: ashokamin2004@yahoo.com.
authors.forename: Ashok R
authors.initials: AR
authors.lastname: Amin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D023281:Genomics; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000494:pharmacology; D055432:Metabolomics; D051379:Mice; D018345:Mice, Knockout; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D054467:Phospholipases A2 / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D060066:Protein Interaction Maps; D020033:Protein Isoforms / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
chemical_list: D015777:Eicosanoids; D053583:Interleukin-1beta; D011453:Prostaglandins; D020033:Protein Isoforms; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D013482:Superoxide Dismutase; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D005982:Glutathione Transferase; D054467:Phospholipases A2
keywords: Genomics; Inflammation; Lung fibroblasts; Metabolomics; Prostaglandins