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Conference Article| June 01 1988 Effect of interleukin-1 on free arachidonic acid levels in human synovial cells L. A. J. O'NEILL; L. A. J. O'NEILL 1Department of Pharmacology, Royal College of Surgeons, Lincolns Inn Fields, London WC2A 3PN, U.K. Search for other works by this author on: This Site PubMed Google Scholar G. P. LEWIS G. P. LEWIS 1Department of Pharmacology, Royal College of Surgeons, Lincolns Inn Fields, London WC2A 3PN, U.K. Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1988) 16 (3): 286. https://doi.org/10.1042/bst0160286 Article history Received: November 24 1987 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation L. A. J. O'NEILL, G. P. LEWIS; Effect of interleukin-1 on free arachidonic acid levels in human synovial cells. Biochem Soc Trans 1 June 1988; 16 (3): 286. doi: https://doi.org/10.1042/bst0160286 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search Keywords: IL-1, interleukin 1, PGE2, prostaglandin E2, AA, arachidonic acid, PC, phosphatidylcholine, PI, phosphatidylinositol, PS, phosphatidylserine, PE, phosphatidylethanolamine This content is only available as a PDF. © 1988 Biochemical Society1988 Article PDF first page preview Close Modal You do not currently have access to this content.
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Macrophage activation is a key event in the inflammatory process, since these cells produce a range of pro-inflammatory molecules, including ROS (reactive oxygen species), prostaglandins, cytokines and nitric oxide. These factors promote inflammation by causing vasodilation and recruitment of neutrophils, monocytes and lymphocytes, which ultimately clear infection and repair damaged tissue. One of the most potent macrophage activators is the Gram-negative-derived bacterial cell wall component LPS (lipopolysaccharide). LPS is sensed by TLR4 (Toll-like receptor 4) and triggers highly complex signalling pathways that culminate in activation of transcription factors such as NF-κB (nuclear factor κB), which in turn increases transcription of genes encoding proteins such as COX2 (cyclo-oxygenase 2, a key enzyme in prostaglandin biosynthesis), nitric oxide synthase and cytokines such as TNF (tumour necrosis factor). Recently, a role for metabolic pathways in the regulation of LPS signalling has become a focus of research in inflammation. A notable example is LPS promoting the so-called Warburg effect - aerobic glycolysis. This allows for an up-regulation in ATP production, and also for the production of biosynthetic intermediates to meet the demands of the activated macrophages. In this issue of the Biochemical Journal, Infantino et al. add a new finding to the role of metabolism in LPS action. They demonstrate a requirement for the mitochondrial citrate carrier in the induction of ROS, nitric oxide and prostaglandins by LPS. The knockdown of the carrier with siRNA (small interfering RNA), or the use of an inhibitor BTA (benzene-1,2,3-tricarboxylate), abolishes these responses. Although no mechanism is provided, the authors speculate that acetyl-CoA is synthesized from citrate in the cytosol. The acetyl-CoA generated could be required for phospholipid biosynthesis, the phospholipids being the source of arachidonic acid for prostaglandin production. Another product of citrate metabolism, oxaloacetate, will indirectly generate nitric oxide and ROS. This finding places citrate, transported from the mitochondria, as a key player in LPS signalling, at least for ROS, nitric oxide and prostaglandin production. This somewhat unexpected role for citrate in LPS action adds to a growing literature on the role for metabolism in the regulation of signalling in inflammation.
The NLRP3 inflammasome regulates the maturation of the pro-inflammatory cytokines IL-1 β and IL-18, which are important mediators in inflammatory disorders such as atherosclerosis, Type 2 diabetes and Alzheimer’s disease. Given its role as an inflammatory gatekeeper, NLRP3 expression is tightly controlled. It is transcriptionally regulated by NF- κ B as well as post-translationally by S-nitrosylation and ubiquitination. We decided to test whether NLRP3 is also regulated at the post-transcriptional level. We found that the NLRP3 3’ untranslated region (UTR) contains an evolutionarily conserved target site for miRNA-223 and we confirmed miR-223 as a direct negative regulator of NLRP3 using a luciferase reporter assay. Furthermore, overexpressing the miRNA reduces NLRP3 levels and IL-1 β production following activation with NLRP3 agonists. Since miR-223 is differentially expressed during myeloid differentiation, it could alter the threshold for inflammasome activation in different cell types. We have now generated a transgenic mouse deficient in the miR-223 target site in the NLRP3 3’UTR, which will allow us for the first time to study the importance of miRNA regulation of NLRP3 in vivo and in the context of inflammatory disease models. Interestingly, the human NLRP3 3’UTR can be alternatively polyadenlyated, giving rise to a truncated form of the transcript that lacks regulatory elements. While mRNA stability was not affected, a luciferase reporter assay showed that LPS stimulation could enhance expression of both 3’UTR isoforms. Using an RNA pulldown approach we identified potential RNA binding proteins that could mediate this effect. Ultimately, understanding the post-transcriptional control of NLRP3 expression will help to explain cell type-specific expression of NLRP3 and could potentially provide new opportunities to interfere with inflammasome activation in diseases such as Type 2 diabetes.
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