Tannic acid modulates NFjB signaling pathway and skin inflammation in NC/Nga mice through PPARc expression Vengadeshprabhu Karuppagounder a , Somasundaram Arumugam a , Rajarajan Amirthalingam Thandavarayan a,b , Vigneshwaran Pitchaimani a , Remya Sreedhar a , Rejina Afrin a , Meilei Harima a , Hiroshi Suzuki a , Mayumi Nomoto a , Shizuka Miyashita a , Kenji Suzuki c , Masahiko Nakamura d , Kazuyuki Ueno e , Kenichi Watanabe a,⇑ a Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan b Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030, USA c Department of Gastroenterology, Niigata University Graduate School of Medical and Dental Sciences, Niigata City 951-8510, Japan d Department of Cardiology, Yamanashi Prefectural Center Hospital, 1-1-1 Fujimi Kofu, Yamanashi 400-8506, Japan e Department of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan article info Article history: Received 13 February 2015 Received in revised form 12 May 2015 Accepted 14 May 2015 Available online xxxx Keywords: Tannic acid Nuclear factor kappa B Tumor necrosis factor Cytokine Peroxisome proliferator-activated receptor abstract Polyphenolic compound tannic acid, which is mainly found in grapes and green tea, is a potent antioxi- dant with anticarcinogenic activities. In this present study, we hypothesized that tannic acid could inhibit nuclear factor (NF)jB signaling and inflammation in atopic dermatitis (AD) NC/Nga mice. We have ana- lyzed the effects of tannic acid on dermatitis severity, histopathology and expression of inflammatory sig- naling proteins in house dust mite extract induced AD mouse skin. In addition, serum levels of T helper (Th) cytokines (interferon (IFN)c, interleukin (IL)-4) were measured by enzyme-linked immunosorbent assay. Treatment with tannic acid ameliorated the development of AD-like clinical symptoms and effec- tively inhibited hyperkeratosis, parakeratosis, acanthosis, mast cells and infiltration of inflammatory cells in the AD mouse skin. Serum levels of IFNc and IL-4 were significantly down-regulated by tannic acid. Furthermore, tannic acid treatment inhibited DfE induced tumor necrosis factor (TNF)a, high mobility group protein (HMG)B1, receptor for advanced glycation end products (RAGE), extracellular signal-regulated kinase (ERK)1/2, NFjB, cyclooxygenase (COX)2, IL-1b and increased the protein expres- sion of peroxisome proliferator-activated receptor (PPAR)c. Taken together, our results demonstrate that, DfE induced skin inflammation might be mediated through NFjB signaling and tannic acid may be a potential therapeutic agent for AD, which may possibly act via induction of PPARc protein. Ó 2015 Elsevier Ltd. All rights reserved. 1. Introduction Atopic dermatitis (AD) is an allergic inflammatory skin disease. Although the pathogenesis of AD is complicated, infiltration of immune cells such as mast cells, neutrophils, eosinophils, and lym- phocytes are elevated in disease state [1]. In addition, serum immunoglobulin E (IgE) levels are elevated in AD [2]. Dermatophagoides farinae (DfE) is one of the common house dust mite allergen, which is mainly associated with human AD and bronchial asthma [3]. AD patients are sensitive to DfE and upon exposure, macrophages are known to accumulate in acutely or chronically inflamed skin [4]. The high mobility group protein (HMG)B1, a nuclear protein secreted by immune cells, such as macrophages and dendritic cells, is released into extracellular space, triggering inflammatory immune response, tumor metasta- sis and autoimmune disease. Extracellular HMGB1 interacts with a multi ligand-receptor for advanced glycation end products (RAGE) leading to the activation of nuclear factor (NF)jB proinflammatory signaling, thereby triggering a variety of inflammatory cytokines such as interleukin (IL)-1b, tumor necrosis factor (TNF)a, IL-4, IL-6 and interferon (IFN)c [5]. Moreover, the elevated levels of cytokines can further induce NFjB activation and thereby worsen- ing the disease condition. The peroxisome proliferator-activated receptors (PPARs) were identified as the nuclear hormone receptor superfamily and their subtypes such as PPARa and c are mainly involved in insulin http://dx.doi.org/10.1016/j.cyto.2015.05.016 1043-4666/Ó 2015 Elsevier Ltd. All rights reserved. ⇑ Corresponding author at: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha Ku, Niigata 956-8603, Japan. Tel.: +81 250 25 5267; fax: +81 250 25 5021. E-mail address: watanabe@nupals.ac.jp (K. Watanabe). Cytokine xxx (2015) xxx–xxx Contents lists available at ScienceDirect Cytokine journal homepage: www.journals.elsevier.com/cytokine Please cite this article in press as: Karuppagounder V et al. Tannic acid modulates NFjB signaling pathway and skin inflammation in NC/Nga mice through PPARc expression. Cytokine (2015), http://dx.doi.org/10.1016/j.cyto.2015.05.016