title: Piperlongumine Suppresses Dendritic Cell Maturation by Reducing Production of Reactive Oxygen Species and Has Therapeutic Potential for Rheumatoid Arthritis.
abstract: Piperlongumine (PLM) is a natural product from the plant Piper longum that inhibits platelet aggregation, atherosclerosis plaque formation, and tumor cell growth. It has potential value in immunomodulation and the management of autoimmune diseases. In this study, we investigated the role of PLM in regulating the differentiation and maturation of dendritic cells (DCs), a critical regulator of immune tolerance, and evaluated its clinical effects in a rheumatoid arthritis mouse model. We found that PLM treatment reduced LPS-induced murine bone marrow-derived DC maturation, characterized by reduced expression of CD80/86, secretion of MCP-1, IL-12p70, IL-6, TNFα, IFN-γ, and IL-23, and reduced alloproliferation of T cells; however, PLM does not affect cell differentiation. Furthermore, PLM reduced intracellular reactive oxygen species (ROS) production by DCs and inhibited the activation of p38, JNK, NF-κB, and PI3K/Akt signaling pathways. Conversely, PLM increased the expression of GSTP1 and carbonyl reductase 1, two enzymes that counteract ROS effects. ROS inhibition by exogenous N-acetyl-l-cysteine suppressed DC maturation. PLM treatment improved the severity of arthritis and reduced in vivo splenic DC maturation, collagen-specific CD4(+) T cell responses, and ROS production in mice with collagen-induced arthritis. Taken together, these results suggest that PLM inhibits DC maturation by reducing intracellular ROS production and has potential as a therapeutic agent for rheumatoid arthritis.
authors.affiliation: Department of Rheumatology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Youjun
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Rheumatology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Maohua
authors.initials: M
authors.lastname: Shi
authors.affiliation: Department of Rheumatology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Qiu
authors.affiliation: Department of Rheumatology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Mingcheng
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Rheumatology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Zeng
authors.affiliation: Department of Rheumatology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Yaoyao
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Rheumatology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Zhan
authors.affiliation: Department of Rheumatology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Liuqin
authors.initials: L
authors.lastname: Liang
authors.affiliation: Department of Rheumatology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Xiuyan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Rheumatology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China xuhanshi@mail.sysu.edu.cn.
authors.forename: Hanshi
authors.initials: H
authors.lastname: Xu
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000429:Alcohol Oxidoreductases / Q000235:genetics; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D051940:B7-2 Antigen / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000008:administration & dosage; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology*; D004148:Dioxolanes / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D051549:Glutathione S-Transferase pi / Q000235:genetics; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D010881:Piperidones
chemical_list: D000111:Acetylcysteine; D000429:Alcohol Oxidoreductases; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D003094:Collagen; D016207:Cytokines; D004148:Dioxolanes; D051549:Glutathione S-Transferase pi; D007371:Interferon-gamma; D018664:Interleukin-12; D015850:Interleukin-6; D017382:Reactive Oxygen Species; C497965:Cd86 protein, mouse; C555915:carbonyl reductase 1, mouse; C496557:Gstp1 protein, mouse; C498077:piperlongumine; D010881:Piperidones