Planta Med 2013; 79(02): 102-109
DOI: 10.1055/s-0032-1328057
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Curcumin Improves TNBS-Induced Colitis in Rats by Inhibiting IL-27 Expression via the TLR4/NF-κB Signaling Pathway

Zhaojing Zeng
1   Department of Gastroenterology, The Western Hospital, First Affiliated Hospital of Guangxi Medical University, Nanning,Guangxi, China
,
Lingling Zhan
2   Department of Clinical Experimental Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
,
Hui Liao
1   Department of Gastroenterology, The Western Hospital, First Affiliated Hospital of Guangxi Medical University, Nanning,Guangxi, China
,
Lan Chen
1   Department of Gastroenterology, The Western Hospital, First Affiliated Hospital of Guangxi Medical University, Nanning,Guangxi, China
,
Xiaoping Lv
1   Department of Gastroenterology, The Western Hospital, First Affiliated Hospital of Guangxi Medical University, Nanning,Guangxi, China
› Author Affiliations
Further Information

Publication History

received 24 August 2012
revised 28 October 2012

accepted 10 November 2012

Publication Date:
18 December 2012 (online)

Abstract

Curcumin is a widely used spice with anti-inflammatory and anticancer properties. It has been reported to have beneficial effects in experimental colitis. This study explored whether curcumin improves colonic inflammation in a rat colitis model through inhibition of the TLR4/NF-κB signaling pathway and IL-27 expression. After induction of colitis with 2,4,6-trinitrobenzene sulfonic acid, rats were intragastrically administered with curcumin or sulfasalazine daily for one week. Rat intestinal mucosa was collected for evaluation of the disease activity index, colonic mucosa damage index, and histological score. Myeloperoxidase activity was detected by immunohistochemistry, and mRNA and protein expression levels of TLR4, NF-κB, and IL-27 in colonic mucosa were detected by RT-PCR and Western blot. Compared with the untreated colitis group, the curcumin-treated group showed significant decreases in the disease activity index, colonic mucosa damage index, histological score, myeloperoxidase activity, and expressions of NF-κB mRNA, IL-27 mRNA, TLR4 protein, NF-κB p65 protein, and IL-27 p28 protein (p < 0.05). TLR4 mRNA expression did not differ between groups. Disease activity index decreased more rapidly in the curcumin-treated group than in the sulfasalazine-treated group (p < 0.05). There was no significant difference in TLR4, NF-κB, and IL-27 mRNA and proteins between curcumin-treated and sulfasalazine-treated groups. Curcumin shows significant therapeutic effects on 2,4,6-trinitrobenzene sulfonic acid-induced colitis that are comparable to sulfasalazine. The anti-inflammatory actions of curcumin on colitis may involve inhibition of the TLR4/NF-κB signaling pathway and of IL-27 expression.

 
  • References

  • 1 Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, Benchimol EI, Panaccione R, Ghosh S, Barkema HW, Kaplan GG. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012; 142: 46-54 , e42
  • 2 Gismera CS, Aladren BS. Inflammatory bowel diseases: a disease (s) of modern times? Is incidence still increasing?. World J Gastroenterol 2008; 14: 5491-5498
  • 3 Schreiber S, Raedler A, Stenson WF, MacDermott RP. The role of the mucosal immune system in inflammatory bowel disease. Gastroenterol Clin North Am 1992; 21: 451-502
  • 4 Li MC, He SH. IL-10 and its related cytokines for treatment of inflammatory bowel disease. World J Gastroenterol 2004; 10: 620-625
  • 5 Liu Y, Zhang Z, Wang L, Li J, Dong L, Yue W, Chen J, Sun X, Zhong L, Sun D. TLR4 monoclonal antibody blockade suppresses dextran-sulfate-sodium-induced colitis in mice. J Gastroenterol Hepatol 2010; 25: 209-214
  • 6 Nielsen OH, Kirman I, Rudiger N, Hendel J, Vainer B. Upregulation of interleukin-12 and -17 in active inflammatory bowel disease. Scand J Gastroenterol 2003; 38: 180-185
  • 7 Liu J, Guan X, Ma X. Regulation of IL-27 p 28 gene expression in macrophages through MyD88- and interferon-gamma-mediated pathways. J Exp Med 2007; 204: 141-152
  • 8 Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A, Dassopoulos T, Bitton A, Yang H, Targan S, Datta LW, Kistner EO, Schumm LP, Lee AT, Gregersen PK, Barmada MM, Rotter JI, Nicolae DL, Cho JH. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006; 314: 1461-1463
  • 9 Schmidt C, Giese T, Ludwig B, Mueller-Molaian I, Marth T, Zeuzem S, Meuer SC, Stallmach A. Expression of interleukin-12-related cytokine transcripts in inflammatory bowel disease: elevated interleukin-23p19 and interleukin-27p28 in Crohnʼs disease but not in ulcerative colitis. Inflamm Bowel Dis 2005; 11: 16-23
  • 10 Deguchi Y, Andoh A, Inatomi O, Yagi Y, Bamba S, Araki Y, Hata K, Tsujikawa T, Fujiyama Y. Curcumin prevents the development of dextran sulfate Sodium (DSS)-induced experimental colitis. Dig Dis Sci 2007; 52: 2993-2998
  • 11 Xia J, Deng C, Zhang M, Zun Z, Kiang H. Effects of curcumin on NF-κB and TNF-α expression in the intestinal mucosa of mice with dextran-sulfate-sodium-induced ulcerative colitis. World Chin J Digestol 2005; 13: 255-257
  • 12 Kumar A, Dhawan S, Hardegen NJ, Aggarwal BB. Curcumin (Diferuloylmethane) inhibition of tumor necrosis factor (TNF)-mediated adhesion of monocytes to endothelial cells by suppression of cell surface expression of adhesion molecules and of nuclear factor-kappaB activation. Biochem Pharmacol 1998; 55: 775-783
  • 13 Morris GP, Beck PL, Herridge MS, Depew WT, Szewczuk MR, Wallace JL. Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology 1989; 96: 795-803
  • 14 Luk HH, Ko JK, Fung HS, Cho CH. Delineation of the protective action of zinc sulfate on ulcerative colitis in rats. Eur J Pharmacol 2002; 443: 197-204
  • 15 Klebanoff SJ, Coombs RW. Viricidal effect of polymorphonuclear leukocytes on human immunodeficiency virus-1. Role of the myeloperoxidase system. J Clin Invest 1992; 89: 2014-2017
  • 16 Song W, Zhang Z, Xiao B. Effects of curcumin on MPO and SOD of methotrexate-induced small intestinal damage in rats. Mod Digest Interv 2008; 13: 14-17
  • 17 Chadwick VS, Schlup MM, Ferry DM, Chang AR, Butt TJ. Measurements of unsaturated vitamin B12-binding capacity and myeloperoxidase as indices of severity of acute inflammation in serial colonoscopy biopsy specimens from patients with inflammatory bowel disease. Scand J Gastroenterol 1990; 25: 1196-1204
  • 18 Poltorak A, Smirnova I, He X, Liu MY, Van Huffel C, McNally O, Birdwell D, Alejos E, Silva M, Du X, Thompson P, Chan EK, Ledesma J, Roe B, Clifton S, Vogel SN, Beutler B. Genetic and physical mapping of the Lps locus: identification of the toll-4 receptor as a candidate gene in the critical region. Blood Cells Mol Dis 1998; 24: 340-355
  • 19 Liu Y, Wang L, Zhang Z. Protective effects of toll like receptor 4 monoclonal antibodies on gut mucosal nuclear factor kappa B signaling pathway in mice with dextran-sulfate-sodium-induced acute ulcerative colitis. Shanghai Med J 2009; 32: 702-705
  • 20 Lubbad A, Oriowo MA, Khan I. Curcumin attenuates inflammation through inhibition of TLR-4 receptor in experimental colitis. Mol Cell Biochem 2009; 322: 127-135
  • 21 Siddique I, Khan I. Mechanism of regulation of Na-H exchanger in inflammatory bowel disease: role of TLR-4 signaling mechanism. Dig Dis Sci 2011; 56: 1656-1662
  • 22 Schmid RM, Adler G. NF-kappaB/rel/IkappaB: implications in gastrointestinal diseases. Gastroenterology 2000; 118: 1208-1228
  • 23 Gan H, Ouyang Q, Jia D, Xia Q. [Activation of nuclear factor-kappaB and its relationship with cytokine gene expression in colonic mucosa of ulcerative colitis patients]. Zhonghua Nei Ke Za Zhi 2002; 41: 252-255
  • 24 Blackwell TS, Christman JW. The role of nuclear factor-kappa B in cytokine gene regulation. Am J Respir Cell Mol Biol 1997; 17: 3-9
  • 25 Neurath MF, Fuss I, Schurmann G, Pettersson S, Arnold K, Muller-Lobeck H, Strober W, Herfarth C, Buschenfelde KH. Cytokine gene transcription by NF-kappa B family members in patients with inflammatory bowel disease. Ann N Y Acad Sci 1998; 859: 149-159
  • 26 Moynagh PN. The NF-kappaB pathway. J Cell Sci 2005; 118: 4589-4592
  • 27 Li JH, Yu JP, Yu HG, Xu XM, Yu LL, Liu J, Luo HS. Melatonin reduces inflammatory injury through inhibiting NF-kappaB activation in rats with colitis. Mediators Inflamm 2005; 2005: 185-193
  • 28 Xia B, Crusius J, Meuwissen S, Pena A. Inflammatory bowel disease: definition, epidemiology, etiologic aspects, and immunogenetic studies. World J Gastroenterol 1998; 4: 446-458
  • 29 Pflanz S, Timans JC, Cheung J, Rosales R, Kanzler H, Gilbert J, Hibbert L, Churakova T, Travis M, Vaisberg E, Blumenschein WM, Mattson JD, Wagner JL, To W, Zurawski S, McClanahan TK, Gorman DM, Bazan JF, de Waal Malefyt R, Rennick D, Kastelein RA. IL-27, a heterodimeric cytokine composed of EBI3 and p 28 protein, induces proliferation of naive CD4(+) T cells. Immunity 2002; 16: 779-790
  • 30 Yoshida H. [Immune regulation by IL-27 for therapeutic usage]. Nihon Rinsho Meneki Gakkai Kaishi 2009; 32: 202-213
  • 31 Yoshimura T, Takeda A, Hamano S, Miyazaki Y, Kinjyo I, Ishibashi T, Yoshimura A, Yoshida H. Two-sided roles of IL-27: induction of Th1 differentiation on naive CD4+ T cells versus suppression of proinflammatory cytokine production including IL-23-induced IL-17 on activated CD4+ T cells partially through STAT3-dependent mechanism. J Immunol 2006; 177: 5377-5385
  • 32 Takeda A, Hamano S, Yamanaka A, Hanada T, Ishibashi T, Mak TW, Yoshimura A, Yoshida H. Cutting edge: role of IL-27/WSX-1 signaling for induction of T-bet through activation of STAT1 during initial Th1 commitment. J Immunol 2003; 170: 4886-4890
  • 33 Owaki T, Asakawa M, Fukai F, Mizuguchi J, Yoshimoto T. IL-27 induces Th1 differentiation via p 38 MAPK/T-bet- and intercellular adhesion molecule-1/LFA-1/ERK1/2-dependent pathways. J Immunol 2006; 177: 7579-7587
  • 34 Castoldi A, Braga TT, Correa-Costa M, Aguiar CF, Bassi EJ, Correa-Silva R, Elias RM, Salvador F, Moraes-Vieira PM, Cenedeze MA, Reis MA, Hiyane MI, Pacheco-Silva A, Goncalves GM, Saraiva Camara NO. TLR2, TLR4 and the MYD88 signaling pathway are crucial for neutrophil migration in acute kidney injury induced by sepsis. PLoS One 2012; 7: e37584
  • 35 Stumhofer JS, Laurence A, Wilson EH, Huang E, Tato CM, Johnson LM, Villarino AV, Huang Q, Yoshimura A, Sehy D, Saris CJ, OʼShea JJ, Hennighausen L, Ernst M, Hunter CA. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol 2006; 7: 937-945
  • 36 Sasaoka T, Ito M, Yamashita J, Nakajima K, Tanaka I, Narita M, Hara Y, Hada K, Takahashi M, Ohno Y, Matsuo T, Kaneshiro Y, Tanaka H, Kaneko K. Treatment with IL-27 attenuates experimental colitis through the suppression of the development of IL-17-producing T helper cells. Am J Physiol Gastrointest Liver Physiol 2011; 300: G568-G576
  • 37 Cui Y, Liu Z, Zhao Z. Significance of IL-27 expression in the intestinal mucosa of patients with inflammatory bowel disease. World Chin J Digestol 2010; 18: 39-43
  • 38 Wirtz S, Becker C, Fantini MC, Nieuwenhuis EE, Tubbe I, Galle PR, Schild HJ, Birkenbach M, Blumberg RS, Neurath MF. EBV-induced gene 3 transcription is induced by TLR signaling in primary dendritic cells via NF-kappa B activation. J Immunol 2005; 174: 2814-2824
  • 39 Sugimoto K, Hanai H, Tozawa K, Aoshi T, Uchijima M, Nagata T, Koide Y. Curcumin prevents and ameliorates trinitrobenzene sulfonic acid-induced colitis in mice. Gastroenterology 2002; 123: 1912-1922
  • 40 Jobin C, Bradham CA, Russo MP, Juma B, Narula AS, Brenner DA, Sartor RB. Curcumin blocks cytokine-mediated NF-kappa B activation and proinflammatory gene expression by inhibiting inhibitory factor I-kappa B kinase activity. J Immunol 1999; 163: 3474-3483
  • 41 Rao CV, Kawamori T, Hamid R, Reddy BS. Chemoprevention of colonic aberrant crypt foci by an inducible nitric oxide synthase-selective inhibitor. Carcinogenesis 1999; 20: 641-644
  • 42 Chen A, Xu J, Johnson AC. Curcumin inhibits human colon cancer cell growth by suppressing gene expression of epidermal growth factor receptor through reducing the activity of the transcription factor Egr-1. Oncogene 2006; 25: 278-287
  • 43 Lee YK, Park SY, Kim YM, Park OJ. Regulatory effect of the AMPK-COX-2 signaling pathway in curcumin-induced apoptosis in HT-29 colon cancer cells. Ann N Y Acad Sci 2009; 1171: 489-494
  • 44 Prasad CP, Rath G, Mathur S, Bhatnagar D, Ralhan R. Potent growth suppressive activity of curcumin in human breast cancer cells: Modulation of Wnt/beta-catenin signaling. Chem Biol Interact 2009; 181: 263-271
  • 45 Ak T, Gulcin I. Antioxidant and radical scavenging properties of curcumin. Chem Biol Interact 2008; 174: 27-37