Monotropein isolated from the roots of Morinda officinalis ameliorates proinflammatory mediators in RAW 264.7 macrophages and dextran sulfate sodium (DSS)-induced colitis via NF-jB inactivation Ji-Sun Shin a,b,c,1 , Kyung-Jin Yun a,1 , Kyung-Sook Chung a,g , Kyeong-Hwa Seo e , Hee-Juhn Park d , Young-Wuk Cho b,c , Nam-In Baek e , DaeSik Jang f , Kyung-Tae Lee a,g,⇑ a Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea b Reactive Oxygen Species Medical Research Center, School of Medicine, Kyung Hee University, Seoul, Republic of Korea c Department of Physiology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea d Department of Pharmaceutical Engineering, Sangji University, Wonju, Republic of Korea e Graduate School of Biotechnology & Plant Metabolism Research Center, Kyung Hee University, Suwon, Republic of Korea f Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea g Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea article info Article history: Received 14 September 2012 Accepted 8 December 2012 Available online 20 December 2012 Keywords: Monotropein Morinda officinalis Nuclear factor-jB Ulcerative colitis abstract We previously demonstrated that monotropein isolated from the roots of Morinda officinalis (Rubiaceae) has anti-inflammatory effects in vivo. In the present study, we investigated the molecular mechanisms underlying the anti-inflammatory effects of monotropein in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and dextran sulfate sodium (DSS)-induced colitis mouse model. Monotropein was found to inhibit the expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-a (TNF-a), and interleukin-1b (IL-1b) mRNA in LPS-induced RAW 264.7 macro- phages. Treatment with monotropein decreased the DNA binding activity of nuclear factor-jB (NF-jB). Consistent with these findings, monotropein also suppressed phosphorylation and degradation of inhib- itory jB-a (IjB-a), and consequently the translocations of NF-jB. In the DSS-induced colitis model, monotropein reduced disease activity index (DAI), myeloperoxidase (MPO) activity, and inflammation- related protein expressions by suppressing NF-jB activation in colon mucosa. Taken together, these find- ings suggest that the anti-inflammatory effects of monotropein are mainly related to the inhibition of the expressions of inflammatory mediators via NF-jB inactivation, and support its possible therapeutic role in colitis. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction Deregulated or exacerbated inflammation is a hallmark of many human diseases, including arteriosclerosis, inflammatory bowel dis- ease (IBD), arthritis, infectious diseases, and cancer (Yamamoto and Gaynor, 2004). The IBDs, such as, ulcerative colitis (UC) and Crohn’s disease, are characterized by aberrant responses to luminal bacteria in genetically susceptible subjects and by a chronic inflammatory disorder of the digestive tract (Owczarek et al., 2009; Peyrin-Biroulet et al., 2008). The medical treatment of IBD relies mainly on tradi- tional drugs, such as 5-aminosalicylates (5-ASA), corticosteroids, and immunosuppressants like azathioprine and 6-mercaptopurine. Furthermore, although antibiotics are becoming increasingly impor- tant in the settings of steroid resistant disease and steroid-depen- dent patients (Hanauer, 1996), their side effects and systemic actions are so severe that they disturb quality of life, particularly when are long-term administered (Xu et al., 2004). Thus, it is impor- tant to develop an optimal therapy for IBD. Although the etiology of IBD has not been established, evidence indicates that the involvement of damaged epithelia and activated immune cells with excessive produc- tion of pro-inflammatory mediators in inflamed mucosa play an important role (Onizawa et al., 2009). The intestinal epithelium serves as a barrier between luminal triggers and the host, and an impaired barrier function could lead to increased uptake of luminal antigens that promote mucosal inflammation. In this sense, the regulation of resident intestinal macrophages by the recognition of conserved pathogen-associated molecular patterns, such as, Toll-like receptors (TLRs) and nucleotide-binding oligomerization domains, is critical for the understanding of the homeostasis of gut-associated immunity. Furthermore, deciphering the pathways involved in the 0278-6915/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.fct.2012.12.013 ⇑ Corresponding author Address: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Dongdaemun-Ku, Hoegi-Dong 130-701, Seoul, Republic of Korea. Tel.: +82 2 9610860; fax: +82 2 9663885. E-mail address: ktlee@khu.ac.kr (K.-T. Lee). 1 These authors contributed equally to this work. Food and Chemical Toxicology 53 (2013) 263–271 Contents lists available at SciVerse ScienceDirect Food and Chemical Toxicology journal homepage: www.elsevier.com/locate/foodchemtox