Contents lists available at ScienceDirect International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp Daphnoretin modulates differentiation and maturation of human dendritic cells through down-regulation of c-Jun N-terminal kinase Chien-An Chen a,b,c , Chien-Kuo Liu d,e , Ming-Ling Hsu f , Chih-Wen Chi f , Chun-Chuan Ko f , Jian-Syun Chen d , Cheng-Ta Lai d , Hen-Hong Chang g,h , Tzung-Yan Lee c , Yuen-Liang Lai i,j,k,⁎ , Yu-Jen Chen f,h,i,⁎ a Department of Radiation Oncology in Zhongxing Branch, Taipei City Hospital, Taipei, Taiwan b Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan c Graduate Institute of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan d Division of Colon and Rectal Surgery, Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan e Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan f Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan g School of Post-Baccalaureate Traditional Chinese Medicine, College of Chinese Medicine, and Research Center for Chinese Medicine and Acupuncture, China Medical University, Taichung, Taiwan h Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan i Department of Radiation Oncology, Mackay Memorial Hospital, Taipei, Taiwan j Hospice and Palliative Care Center, Mackay Memorial Hospital, Taipei, Taiwan k Mackay Medical College, New Taipei City, Taiwan ARTICLE INFO Keywords: Daphnoretin Dendritic cell Differentiation Maturation JNK ABSTRACT Daphnoretin, an active constituent of Wikstroemia indica C.A. Meys, has been shown possessing anti-cancer activity. In this study, we examined the effect of daphnoretin on differentiation and maturation of human myeloid dendritic cells (DCs). After treatment with daphnoretin (0, 1.1, 3.3, 10 and 30 μM) to initiate mono- cytes, the recovery rate of DCs was reduced in a dose-dependent manner. The mature DCs differentiated in the presence of daphnoretin had fewer and shorter dendrites. Daphnoretin modulated DCs differentiation and ma- turation in terms of lower expression of CD1a, CD40, CD83, DC-SIGN, and HLA-DR. Daphnoretin inhibited the allostimulatory activity of DCs on proliferation of naive CD4 + CD45 + RA + T cell. On the mitogen-activated protein kinase, daphnoretin down-regulated the lipopolysaccharide-augmented expression of phosphorylated c- Jun N-terminal kinase (pJNK), but not p38 and extracellular signal-regulated kinase 1/2 (ERK1/2). Activation of JNK by anisomycin reversed the effect of daphnoretin on daphnoretin-inhibited pJNK expression and dendrite formation of DCs. In disease model related to maturation of DCs, daphnoretin suppressed the acute rejection of skin allografts in mice. Our results suggest that daphnoretin modulated differentiation and maturation of DCs toward a state of atypical maturation with impaired allostimulatory function and this effect may go through down-regulation of phosphorylated JNK. 1. Introduction Dendritic cells (DCs) are highly specialized leukocytes, which pre- sent antigens to naive T cells and play a pivotal role in both cell- mediated and humoral immune responses [1].The ability of DCs to stimulate T cells is attributed to their ability to capture antigens, mi- grate into lymphoid organs, and express high levels of im- munostimulatory molecules, such as major histocompatibility complex (MHC) class II, co-stimulatory molecules and secretion of IL-12 [1]. While exposed to various microbial and inflammatory products, such as lipopolysaccharide (LPS), interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), DCs mature and migrate into lymphoid tissues to interact with T and B cells [2–5]. The function of DCs depends on the state of ma- turation and the immature DCs can suppress acute rejection of allo- grafts [6] after transplantation. Daphnoretin (7-hydroxyl-6-methoxy-3,7′-dicoumarylether) is a naturally occurring bicoumarin compound isolated from Wikstroemia indica C.A. Meys [7]. It has been reported to possess bioactivity in suppressing the expression of hepatitis B surface antigen and in acti- vating protein kinase C with translocation of PKC from the cytosol to http://dx.doi.org/10.1016/j.intimp.2017.07.021 Received 7 April 2017; Received in revised form 11 July 2017; Accepted 20 July 2017 ⁎ Corresponding authors at: Department of Radiation Oncology, Mackay Memorial Hospital, Taipei 10449, Taiwan. E-mail addresses: enochlai@mmh.org.tw (Y.-L. Lai), oncoman@mmh.org.tw (Y.-J. Chen). International Immunopharmacology 51 (2017) 25–30 1567-5769/ © 2017 Elsevier B.V. All rights reserved. MARK