Anti-inflammatory effect of resveratrol in old mice liver Bui Thanh Tung a,b,1 , Elisabeth Rodríguez-Bies a , Elena Talero b , Enrique Gamero-Estévez a , Virginia Motilva b , Plácido Navas a , Guillermo López-Lluch a, ⁎ a Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide CSIC, CIBERER-Instituto de Salud San Carlos III, Carretera de Utrera Km 1, 41013 Sevilla, Spain b Departmento de Farmacología, Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain abstract article info Article history: Received 18 January 2015 Accepted 9 February 2015 Available online 14 February 2015 Section Editor: B. Grubeck-Loebenstein Keywords: Aging Resveratrol Inflammation Cytokines Liver Inflammation is a hallmark of aging. Caloric restriction and resveratrol (RSV) have shown important effects on prevention of oxidative stress and inflammation. Here, we investigate the progression of proinflammatory markers in liver during aging and the effect of RSV on inflammation markers in the liver of old male C57BL/6J mice. Young (2 months), mature (12 months) and old (18 months) mice were fed during 6 months with RSV. Levels of IL-1β, IL-6, IL-10, IL-17 and TNF-α were evaluated by ELISA in mice liver. Levels of pro-inflammatory cytokines, IL-1β, IL-6, IL-17 and TNF-α and also their respective mRNA increased in the liver from old mice. How- ever, RSV decreased these levels in the case of IL-1β and TNF-α but only in old mice showing no effect on young and mature animals. This reduction was also found at the mRNA level. Levels of mRNA of the components of NALP-3 inflammasome, ASC, CASP-1, NALP-1 and NALP-3, also showed an age-dependent increase that was reversed by RSV. Furthermore, cyclooxygenase 2 levels, a marker of proinflammatory innate immune activity, were also upregulated in aged liver and reversed again by RSV. In conclusion, our study confirms that aging is accompanied by an increase in the proinflammatory pattern in the liver and that RSV reduces this pattern in old mice liver. © 2015 Elsevier Inc. All rights reserved. 1. Introduction According to the free radical theory of aging, free radicals are respon- sible for the declining function and efficiency of biological systems in aging (Harman, 1956). One of the main sources of systemic oxidative stress is inflammatory reactions (Chung et al., 2011) and strong evidences support that chronic low-grade systemic inflammation is a common manifestation of aging (Brüünsgaard and Pedersen, 2003). Higher levels of circulating pro-inflammatory cytokines such as IL-6 and TNF-α, and acute phase proteins such as C-reactive protein and serum amyloid A, are typical of aged people even in the absence of chronic disease (Brüünsgaard and Pedersen, 2003). In this systemic in- flammatory status, the liver has being indicated as playing a central role. This is because, the liver not only contains the greatest concentration of the body's resident tissue macrophages, the Kupffer cells, but hepato- cytes can also be a main source of a variety of proinflammatory cytokines (Glasgow et al., 2007). The key players in the inflammatory reaction are nuclear factor-κB (NF-κB), interleukin-1β (IL-1β), IL-6, IL-17 and IL-18, tumor necrosis factor-α (TNF-α), cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS). It has been demonstrated that expression of these pro-inflammatory factors is enhanced by redox-sensitive tran- scription factor NF-κB(Chung et al., 2006) indicating an important role of oxidative stress in chronic inflammation during aging (Jung et al., 2009). Among these factors, IL-6 is a cytokine with pleiotropic ef- fects and its increase is associated with chronic inflammations, autoim- mune diseases, and hematopoietic disorders (Wunderlich et al., 2010). TNF-α is also a pro-inflammatory multifunctional cytokine that also contributes to the production of IL-6 (Williams et al., 2008) and IL-1 (IL-1α and IL-1β) plays a critical role in acute and chronic inflammation (Di Iorio et al., 2003). A cytoplasmic multiprotein complex known as inflammasome par- ticipates in the production of proinflammatory cytokines (Agostini et al., 2004). The NALP-3 inflammasome is composed of the NALP-3 (NACHT, leucine-rich-repeat (LRR), and pyrin domain-containing pro- tein 3), apoptosis-associated speck-like protein (ASC) and caspase-1 (CASP-1) (Martinon et al., 2006; Schroder et al., 2010). CASP-1 is re- sponsible for the conversion of pro-IL-1β, pro-IL-18 and pro-IL-33 to their mature forms (Ye and Ting, 2008). In the liver, inflammasomes are expressed in both parenchymal and non-parenchymal cells and are involved in various forms of liver diseases (Szabo and Csak, 2012). Resveratrol (RSV) (3,5,4′-trihydoxy-trans-stilbene) is a polyphenol found in a large number of plant species such as mulberries, peanuts, and grapes, and is present in red wine (Rivera et al., 2009). This polyphenol has been reported to exert multiple biological activities against inflammation, oxidative stress, tumor initiation and progression, Experimental Gerontology 64 (2015) 1–7 ⁎ Corresponding author at: Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide, Carretera de Utrera Km. 1, 41013 Sevilla, Spain. E-mail address: glopllu@upo.es (G. López-Lluch). 1 Currently at the: School of Medicine and Pharmacy, Vietnam National University, Hanoi, 144 Xuan Thuy, Cau Giay, Hanoi, Viet Nam. http://dx.doi.org/10.1016/j.exger.2015.02.004 0531-5565/© 2015 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Experimental Gerontology journal homepage: www.elsevier.com/locate/expgero