期刊
CELLULAR & MOLECULAR IMMUNOLOGY
卷 12, 期 4, 页码 424-434出版社
CHIN SOCIETY IMMUNOLOGY
DOI: 10.1038/cmi.2014.65
关键词
HO-1; monosodium urate; NLRP3 inflammasome; Nrf2; THP-1 cells
类别
资金
- National Science Council, Taiwan [NSC102-2313-B-005-006-MY3]
- Ministry of Education, Taiwan, under the ATU
Gouty arthritis is an inflammatory disease that is caused by an accumulation of monosodium urate (MSU) crystals in the joints. MSUis capable of activating the nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome, leading to interleukin-1 beta (IL-1 beta) secretion. Reactive oxygen species (ROS) are major mediators of the NLRP3/IL-1 beta 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-1 beta 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-1 beta 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.
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