Anti-inflammatory effect of chlorogenic acid on the IL-8 production in Caco-2 cells and the dextran sulphate sodium-induced colitis symptoms in C57BL/6 mice
Introduction
Chlorogenic acid (CHA) is a common polyphenol and is contained in various foods and beverages. Coffee, one of the most widely consumed beverages in the world, is a major source of CHA in the diet, with a daily intake of approximately 1 g in coffee drinkers. Other dietary sources of CHA include fruits, such as apples, pears, and berries (Clifford, 1999). It has been reported that CHA has potent antioxidative and free radical-scavenging activities in vitro (Kono et al., 1997). CHA also increases the resistance of LDL to lipid peroxidation (Laranjinha, Vierira, Almeida, & Madeira, 1996) and inhibits DNA damage (Shibata, Sakamoto, Oka, & Kono, 1999). Furthermore, CHA inhibits lipopolysaccharide-induced cyclooxygenase-2 expression in RAW264.7 cells (Shan et al., 2009). These antioxidative and anti-inflammatory effects suggest that CHA could aid in the prevention of cardiovascular diseases. Administration of dietary CHA was found to decrease the incidence of chemical carcinogenesis in the colon, liver, and tongue of animal models of cancer (Mori et al., 1986, Tanaka et al., 1990, Tanaka et al., 1993). CHA also shows suppressive effects on skin tumour promotion induced by chemical carcinogens in mice (Huang, Smart, Wong, & Conney, 1988). These protective effects of CHA against chemical carcinogenesis may be ascribed to its antioxidative and anti-inflammatory properties.
The intestinal epithelium is a tissue responsible for the absorption of dietary components, and intestinal epithelial cells are always exposed to high concentrations of dietary polyphenolic compounds, including CHA, when foods, such as coffee and fruits, are frequently consumed. CHA is absorbed, not only in its intact form, but also in its hydrolysed form, caffeic acid (CA) and quinic acid (QA), by mucosal and/or microbial esterase in the intestinal tract. Intestinal epithelial cells have a defence function in which cytokines and chemokines are produced in response to external stimuli, such as oxidative stress and tumour necrosis factor alpha (TNFα) (Molmenti et al., 1993, Stadnyk, 1994). Oxidative stress directly induces cell damage by modifying target molecules, including proteins, lipids, and DNA (Chandra et al., 2000, Hampton and Orrenius, 1997, Slater, 1984). In addition, oxidative stress promotes the production of several cytokines and chemokines, including IL-8 (Yamamoto, Kushima, Kisaki, Fujiyama, & Okabe, 2003). Additionally, TNFα is known to directly induce apoptosis in target cells (Satsu et al., 2006) and indirectly produce several cytokines and chemokines (Lang et al., 2004). Among several cytokines, IL-8 principally induces inflammation as a proinflammatory cytokine in intestinal epithelial cells. Previously, we found that IL-8 production was increased by H2O2 and/or TNFα in intestinal epithelial Caco-2 cells (Shin, Zhao, Satsu, Totsuka & Shimizu, 2011). In particular, the co-treatment with H2O2 and TNFα caused a synergistic effect on the IL-8 production. In the intestines, intestinal epithelial cells will be exposed to more than one stimulant, the cells being simultaneously stimulated by both oxidative stress and inflammatory cytokines, resulting in severer inflammatory diseases.
The dextran sulphate sodium (DSS)-experimental model displays many symptoms similar to those observed in human ulcerative colitis (UC), namely diarrhea, bloody feces, body weight loss, and shortening of the colon (Okayasu et al., 1990). Recently, the anti-inflammatory effects of certain diets have been receiving increased attention for the treatment of IBD. For example, dietary rutin has been reported to prevent DSS-induced colitis and, possibly, colorectal carcinogenesis, by suppressing a proinflammatory cytokine, IL-1β (Kwon, Murakami, Tanaka, & Ohigashi, 2005). In addition, dietary factors such as glutamine (Vicario, Amat, Rivero, Moretó, & Pelegrí, 2007), histidine (Andou et al., 2009), taurine (Zhao et al., 2007), and curcumin (Ung et al., 2009) were reported to have anti-inflammatory effects in experimental IBD models. Furthermore, caffeic acid phenethyl ester, which is one of the active components of propolis, decreased colonic NF-κB activity and prevented colitis in peptidoglycan-polysaccharide-treated rats (Fitzpatrick, Wang, & Le, 2001). This result showed that dietary phenolic acids and their derivatives might present an alternative way to improve intestinal inflammation, such as IBD.
In the present study, we investigated the effects of CHA on IL-8 production induced by H2O2 and TNFα in Caco-2 cells, as an in vitro study, and the colitis symptoms induced by DSS, as an in vivo study.
Section snippets
Materials
CHA, CA, and QA were purchased from Sigma (St. Louis, MO). The Caco-2 cell lines were obtained from the American Type Culture Collection (Rockville, MD, USA). DMEM was purchased from Wako Pure Chemicals Inc., Ltd. (Osaka, Japan). Fetal bovine serum (FBS), penicillin–streptomycin, and non-essential amino acids (NEAA) were purchased from Gibco (Gaithersburg, MD, USA). The monoclonal anti-human IL-8 antibody and biotinylated anti-human IL-8 antibody were purchased from Genzyme Techne (Minneapolis,
Inhibitory effects of CHA and CA on the TNFα- and H2O2-induced IL-8 production in Caco-2 cells
We used an in vitro experimental IBD model induced by H2O2 and TNFα to investigate the effects of CHA and its metabolites, CA and QA, on IL-8 secretion in Caco-2 cells. As a result, CHA and CA significantly inhibited TNFα- and H2O2-induced IL-8 secretion in a dose-dependent manner [p value; TNFα + H2O2 vs CHA 0.5 (p = 0.1182), 1 (p = 0.0261), and 2 (p = 0.0069) mmol/l], [p value; TNFα + H2O2 vs CA 0.5 (p = 0.0485), 1 (p = 0.0289), and 2 (p = 0.0022) mmol/l], and [p value; TNFα + H2O2 vs QA 0.5 (p = 0.7159), 1 (p =
Discussion
Intestinal epithelial-like cells, such as Caco-2 and HT-29, are often used to study inflammatory responses or regulatory factors in the intestine. In particular, Caco-2 cells are suitable for studying factors that control chemokine secretion because these cells have a high secretion level of the inflammatory chemokine IL-8, which triggers inflammatory responses. Using this experimental system, we previously found that various food factors, such as histidine, taurine, and isoflavone, inhibited
Conflict of interest statement
The authors have declared no conflict of interest.
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