PMID- 30761138 OWN - NLM STAT- MEDLINE DCOM- 20191231 LR - 20211214 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 10 DP - 2019 TI - Secretion of IL-1beta From Monocytes in Gout Is Redox Independent. PG - 70 LID - 10.3389/fimmu.2019.00070 [doi] LID - 70 AB - The pro-inflammatory cytokine interleukin-1beta (IL-1beta) plays important roles in immunity but is also implicated in autoimmune disease. The most well-established mechanism of IL-1beta secretion is via activation of the NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasome which requires an initial priming signal followed by an activating signal. However, the precise mechanism by which the inflammasome is activated remains unclear. The role of reactive oxygen species (ROS) in this process is contradictory, with some studies suggesting that ROS are crucial while others describe opposite effects. In this study, we evaluated the effects of oxidative stress on IL-1beta secretion. Gout is a disease driven solely by IL-1beta secretion in response to monosodium urate (MSU) crystals which form during periods of hyperuricemia and thus presents an opportunity to study factors contributing to IL-1beta secretion. Sera and monocytes were isolated from patients with gout to determine whether differences in antioxidant status could explain the susceptibility of these individuals to gout attacks. In addition, sera and monocytes were collected from patients with chronic kidney disease (CKD) for comparison as this condition is associated with high levels of oxidative stress and disturbances in serum uric acid levels. There were differences in some aspects of antioxidant defenses in gout patients and these were mainly due to higher serum uric acid. Monocytes from gout patients were more responsive to priming, but not activation, of the NLRP3 inflammasome. However, expression of the components of the NLRP3 inflammasome were unaffected by priming or activation of the inflammasome, nor were these expression levels differentially regulated in gout patients. Inhibition of ROS by N-Acetyl Cysteine inhibited TLR2-induced priming of the NLRP3 inflammasome, but had no effect on MSU-induced activation. Together these findings demonstrate that oxidative stress only affects priming of the NLRP3 inflammasome but does not influence activation. FAU - Alberts, Ben M AU - Alberts BM AD - Clinical and Experimental Medicine, Brighton and Sussex Medical School, Brighton, United Kingdom. FAU - Bruce, Connor AU - Bruce C AD - Clinical and Experimental Medicine, Brighton and Sussex Medical School, Brighton, United Kingdom. FAU - Basnayake, Kolitha AU - Basnayake K AD - Sussex Kidney Unit, Royal Sussex County Hospital, Brighton, United Kingdom. FAU - Ghezzi, Pietro AU - Ghezzi P AD - Clinical and Experimental Medicine, Brighton and Sussex Medical School, Brighton, United Kingdom. FAU - Davies, Kevin A AU - Davies KA AD - Clinical and Experimental Medicine, Brighton and Sussex Medical School, Brighton, United Kingdom. FAU - Mullen, Lisa M AU - Mullen LM AD - Clinical and Experimental Medicine, Brighton and Sussex Medical School, Brighton, United Kingdom. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190129 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Antioxidants) RN - 0 (Furans) RN - 0 (Heterocyclic Compounds, 4 or More Rings) RN - 0 (IL1B protein, human) RN - 0 (Indenes) RN - 0 (Inflammasomes) RN - 0 (Interleukin-1beta) RN - 0 (Lipopeptides) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (NLRP3 protein, human) RN - 0 (Pam(3)CSK(4) peptide) RN - 0 (Reactive Oxygen Species) RN - 0 (Sulfonamides) RN - 0 (Sulfones) RN - 0 (TLR2 protein, human) RN - 0 (Toll-Like Receptor 2) RN - 268B43MJ25 (Uric Acid) RN - 6RS86E2BWQ (N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide) RN - EC 1.15.1.1 (Superoxide Dismutase) RN - EC 1.15.1.1 (superoxide dismutase 2) RN - EC 1.8.1.9 (TXNRD1 protein, human) RN - EC 1.8.1.9 (Thioredoxin Reductase 1) RN - WYQ7N0BPYC (Acetylcysteine) SB - IM MH - Acetylcysteine/pharmacology MH - Antioxidants/analysis MH - Cell Survival/drug effects MH - Furans/pharmacology MH - Gene Expression MH - Gout/*blood MH - Heterocyclic Compounds, 4 or More Rings MH - Humans MH - Hyperuricemia MH - Indenes MH - Inflammasomes/metabolism MH - Interleukin-1beta/chemistry/*genetics/*metabolism MH - Lipopeptides/pharmacology MH - Monocytes/*metabolism MH - NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors/genetics/metabolism MH - Oxidation-Reduction MH - Oxidative Stress/drug effects MH - Reactive Oxygen Species/metabolism MH - Renal Insufficiency, Chronic/blood MH - Sulfonamides/pharmacology MH - Sulfones MH - Superoxide Dismutase/genetics MH - Thioredoxin Reductase 1/genetics MH - Toll-Like Receptor 2/agonists/metabolism MH - Uric Acid/blood/pharmacology PMC - PMC6361747 OTO - NOTNLM OT - IL-1beta OT - NLRP3 inflammasome OT - antioxidant capacity OT - chronic kidney disease OT - gout OT - reactive oxygen species OT - redox regulation EDAT- 2019/02/15 06:00 MHDA- 2020/01/01 06:00 PMCR- 2019/01/01 CRDT- 2019/02/15 06:00 PHST- 2018/11/01 00:00 [received] PHST- 2019/01/11 00:00 [accepted] PHST- 2019/02/15 06:00 [entrez] PHST- 2019/02/15 06:00 [pubmed] PHST- 2020/01/01 06:00 [medline] PHST- 2019/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2019.00070 [doi] PST - epublish SO - Front Immunol. 2019 Jan 29;10:70. doi: 10.3389/fimmu.2019.00070. eCollection 2019.