title: High-mobility group box 1 suppresses resolvin D1-induced phagocytosis via induction of resolvin D1-inactivating enzyme, 15-hydroxyprostaglandin dehydrogenase.
abstract: High-mobility group box 1 (HMGB1) enhances inflammatory reactions by potentiating the activity of pro-inflammatory mediators and suppressing the phagocytosis of apoptotic neutrophils. However, the effects of HMGB1 on phagocytosis induced by pro-resolving mediators, such as resolvins, have not been studied up until this point. In this study, we investigated the effects and underlying mechanism of HMGB1 on resolvin D1-induced phagocytosis of MDA-MB-231 cells, which were selected as a model system based on their phagocytic capability and ease of transfecting them with a plasmid or siRNA in several cancer cell lines. Then we confirmed effects of HMGB1 in THP-1 cells. Resolvin D1 (RvD1) enhanced phagocytosis in MDA-MB-231 and THP-1 cells. HMGB1 suppressed RvD1-induced phagocytosis in MDA-MB.231 and THP-1 cells. HMGB1 dose-dependently induced the expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the inactivating enzyme in pro-resolving lipid mediators such as RvE1 and RvD1. Involvement of 15-PGDH in-HMGB-1-induced suppression of phagocytosis was examined using siRNA of 15-PGDH or 15-PGDH inhibitor, TD23. Surprisingly, the silencing of 15-PGDH increased phagocytotic activity of MDA-MB-231 cells. TD23 also enhanced phagocytosis of MDA-MB-231 and THP-1 cells. In conclusion, the release of HMGB1 during the inflammatory phase induces 15-PGDH expression, which suppresses the phagocytotic activity of macrophages. These processes might be involved in the mechanism that blocks the resolution of inflammation, thereby allowing acute inflammation to progress to chronic inflammation.
authors.affiliation: BK21PLUS R-FIND team, College of Pharmacy, Dongguk University, Seoul 100-715, Republic of Korea.
authors.forename: Gyeoung-Jin
authors.initials: GJ
authors.lastname: Kang
authors.affiliation: BK21PLUS R-FIND team, College of Pharmacy, Dongguk University, Seoul 100-715, Republic of Korea.
authors.forename: Hye-Ja
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea.
authors.forename: Yun Pyo
authors.initials: YP
authors.lastname: Kang
authors.affiliation: BK21PLUS R-FIND team, College of Pharmacy, Dongguk University, Seoul 100-715, Republic of Korea.
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: BK21PLUS R-FIND team, College of Pharmacy, Dongguk University, Seoul 100-715, Republic of Korea.
authors.forename: Hyun Ji
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: BK21PLUS R-FIND team, College of Pharmacy, Dongguk University, Seoul 100-715, Republic of Korea.
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Byun
authors.affiliation: BK21PLUS R-FIND team, College of Pharmacy, Dongguk University, Seoul 100-715, Republic of Korea.
authors.forename: Mi Kyung
authors.initials: MK
authors.lastname: Park
authors.affiliation: Department of Polymer Science & Engineering, Chosun University, Gwangju 501-759, Republic of Korea.
authors.forename: Hoon
authors.initials: H
authors.lastname: Cho
authors.affiliation: College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea.
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Kwon
authors.affiliation: BK21PLUS R-FIND team, College of Pharmacy, Dongguk University, Seoul 100-715, Republic of Korea. Electronic address: uatheone@dongguk.edu.
authors.forename: Chang-Hoon
authors.initials: CH
authors.lastname: Lee
keywords: 15-PGDH; HMGB1; Phagocytosis; Resolution of inflammation; Resolvin D1