Inhibition of the uric acid efflux transporter ABCG2 enhances stimulating effect of soluble uric acid on IL-1β production in murine macrophage-like J774.1 cells.

Autor: Notsu T; Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University, Yonago, Japan., Kurata Y; Department of Physiology II, Kanazawa Medical University, Uchinada, 920-0293, Japan. yasu@kanazawa-med.ac.jp., Ninomiya H; Department of Biological Regulation, Tottori University Faculty of Medicine, Yonago, Japan., Taufiq F; Department of Cardiology, Faculty of Medicine, Brawijaya University, Kota Malang, Jawa Timur, Indonesia., Komatsu K; Department of Psychiatry disease, Tottori University, Yonago, Japan., Miake J; Division of Pharmacology, Department of Pathophysiological and Therapeutic Science, Faculty of Medicine, Tottori University, Yonago, Japan., Sawano T; Division of Pharmacology, Department of Pathophysiological and Therapeutic Science, Faculty of Medicine, Tottori University, Yonago, Japan., Tsuneto M; Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University, Yonago, Japan., Shirayoshi Y; Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University, Yonago, Japan., Hisatome I; Department of Cardiology, National Hospital Organization Yonago Medical Center, Yonago, Japan.
Jazyk: angličtina
Zdroj: Hypertension research : official journal of the Japanese Society of Hypertension [Hypertens Res] 2023 Oct; Vol. 46 (10), pp. 2368-2377. Date of Electronic Publication: 2023 Aug 17.
DOI: 10.1038/s41440-023-01391-y
Abstrakt: Soluble uric acid (UA) absorbed by cells through UA transporters (UATs) accumulates intracellularly, activates the NLRP3 inflammasome and thereby increases IL-1β secretion. ABCG2 transporter excludes intracellular UA. However, it remains unknown whether ABCG2 inhibition leads to intracellular accumulation of UA and increases IL-1β production. In this study, we examined whether genetic and pharmacological inhibition of ABCG2 could increase IL-1β production in mouse macrophage-like J774.1 cells especially under hyperuricemic conditions. We determined mRNA and protein levels of pro-IL-1β, mature IL-1β, caspase-1 and several UATs in culture supernatants and lysates of J774.1 cells with or without soluble UA pretreatment. Knockdown experiments using an shRNA against ABCG2 and pharmacological experiments with an ABCG2 inhibitor were conducted. Extracellularly applied soluble UA increased protein levels of pro-IL-1β, mature IL-1β and caspase-1 in the culture supernatant from lipopolysaccharide (LPS)-primed and monosodium urate crystal (MSU)-stimulated J774.1 cells. J774.1 cells expressed UATs of ABCG2, GLUT9 and MRP4, and shRNA knockdown of ABCG2 increased protein levels of pro-IL-1β and mature IL-1β in the culture supernatant. Soluble UA increased mRNA and protein levels of ABCG2 in J774.1 cells without either LPS or MSU treatment. An ABCG2 inhibitor, febuxostat, but not a urate reabsorption inhibitor, dotinurad, enhanced IL-1β production in cells pretreated with soluble UA. In conclusion, genetic and pharmacological inhibition of ABCG2 enhanced IL-1β production especially under hyperuricemic conditions by increasing intracellularly accumulated soluble UA that activates the NLRP3 inflammasome and pro-IL-1β transcription in macrophage-like J774.1 cells.
(© 2023. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)
Databáze: MEDLINE
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