title: Monosodium urate crystals trigger Nrf2- and heme oxygenase-1-dependent inflammation in THP-1 cells.
abstract: Gouty arthritis is an inflammatory disease that is caused by an accumulation of monosodium urate (MSU) crystals in the joints. MSU is capable of activating the nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome, leading to interleukin-1β (IL-1β) secretion. Reactive oxygen species (ROS) are major mediators of the NLRP3/IL-1β interaction. Although nuclear factor E2-related factor 2 (Nrf2) is recognized as a transcription factor that is involved in the response to oxidative stress, the effect of MSU on Nrf2 and on Nrf2-mediated antioxidant enzymes remains unclear. The treatment of THP-1 monocytes using phorbol 12-myristate 13-acetate (PMA) was shown to initiate inflammatory responses. Here, we showed that THP-1 cells, following treatment with MSU crystals, significantly increased IL-1β release, NLRP3 inflammasome activation and ROS production. MSU also promoted the nuclear translocation of Nrf2 and activated lysosomal destabilization. Moreover, the levels of heme oxygenase-1 (HO-1) in gene and protein expressions were upregulated by MSU. MSU-induced IL-1β secretion and NLRP3 inflammasome activation were inhibited by the knockdown of Nrf2 and via the HO-1 inhibitor zinc (II) protoporphyrin IX (ZnPP). In addition, HO-1 inhibition increased the level of superoxide anion production and the consumption of glutathione. These findings suggest that Nrf2 and HO-1 mediate redox homeostasis and interact with pro-inflammatory factors in MSU-challenged THP-1 cells, thereby providing new insight into how MSU-induced gouty inflammation is mediated by specific mechanisms that are involved in the Nrf2/Ho-1 antioxidant signaling pathway.Cellular & Molecular Immunology advance online publication, 11 August 2014; doi:10.1038/cmi.2014.65.
authors.affiliation: Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan, China.
authors.forename: Jhih-Jia
authors.initials: JJ
authors.lastname: Jhang
authors.affiliation: Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan, China.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Cheng
authors.affiliation: Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan, China.
authors.forename: Cheng-Ying
authors.initials: CY
authors.lastname: Ho
authors.affiliation: 1] Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan, China [2] Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan, China.
authors.forename: Gow-Chin
authors.initials: GC
authors.lastname: Yen
mesh_terms: D002352:Carrier Proteins / Q000276:immunology; D045744:Cell Line, Tumor; D006073:Gout / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D051547:Heme Oxygenase-1 / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D053583:Interleukin-1beta / Q000276:immunology; D008247:Lysosomes / Q000276:immunology; D051267:NF-E2-Related Factor 2 / Q000276:immunology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010084:Oxidation-Reduction / Q000187:drug effects; D011524:Protoporphyrins / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D014527:Uric Acid / Q000633:toxicity*
chemical_list: D002352:Carrier Proteins; C508585:IL1B protein, human; D053583:Interleukin-1beta; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D011524:Protoporphyrins; D017382:Reactive Oxygen Species; C017803:zinc protoporphyrin; D014527:Uric Acid; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D013755:Tetradecanoylphorbol Acetate
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