Skip to main content Accessibility help

Curcumin suppresses p38 mitogen-activated protein kinase activation, reduces IL-1β and matrix metalloproteinase-3 and enhances IL-10 in the mucosa of children and adults with inflammatory bowel disease

  • Jenny Epstein (a1), Guillermo Docena (a1), Thomas T. MacDonald (a1) and Ian R. Sanderson (a1)


Inflammatory bowel disease (IBD) is a major source of morbidity in children and adults. Its incidence is rising, particularly in young people. IBD carries a lifelong risk of cancer, which is proportional to disease duration. Drug and surgical treatments rarely offer cure and often carry a high side effect burden. Dietary therapy is highly effective in Crohn's disease. For these reasons, there is much interest in developing novel dietary treatments in IBD. Curcumin, a component of the spice turmeric, and an anti-inflammatory and anti-cancer agent, shows preclinical and clinical potential in IBD. Its mechanisms of action are unknown. Our aim was to assess the effect of curcumin on key disease mediators p38 mitogen-activated protein kinase (MAPK), IL-1β, IL-10 and matrix metalloproteinase-3 (MMP-3) in the gut of children and adults with IBD. Colonic mucosal biopsies and colonic myofibroblasts (CMF) from children and adults with active IBD were cultured ex vivo with curcumin. p38 MAPK, NF-κB and MMP-3 were measured by immunoblotting. IL-1β and IL-10 were measured by ELISA. We show reduced p38 MAPK activation in curcumin-treated mucosal biopsies, enhanced IL-10 and reduced IL-1β. We demonstrate dose-dependent suppression of MMP-3 in CMF with curcumin. We conclude that curcumin, a naturally occurring food substance with no known human toxicity, holds promise as a novel therapy in IBD.


Corresponding author

*Corresponding author: Jenny Epstein, fax +44 2078822187, email


Hide All
1Eaden, JA, Abrams, KR & Mayberry, JF (2001) The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 48, 526535.
2Friedman, S (2006) Cancer in Crohn's disease. Gastroenterol Clin North Am 35, 621639.
3Sawczenko, A & Sandhu, BK (2003) Presenting features of inflammatory bowel disease in Great Britain and Ireland. Arch Dis Child 88, 9951000.
4Logan, RFA (1998) Inflammatory bowel disease incidence: up, down or unchanged? Gut 42, 309311.
5Goh, K & Xiao, SD (2009) Inflammatory bowel disease: a survey of the epidemiology in Asia. J Dig Dis 10, 16.
6Montgomery, SM, Morris, DL, Pounder, RE, et al. (1999) Asian ethnic origin and the risk of inflammatory bowel disease. Eur J Gastroenterol Hepatol 11, 543546.
7Heuschkel, RB, Menache, CC, Megerian, JT, et al. (2000) Enteral nutrition and corticosteroids in the treatment of acute Crohn's disease in children. J Pediatr Gastroenterol Nutr 31, 815.
8Bannerjee, K, Camacho-Hubner, C, Babinska, K, et al. (2004) Anti-inflammatory and growth-stimulating effects precede nutritional restitution during enteral feeding in Crohn disease. J Pediatr Gastroenterol Nutr 38, 270275.
9Lionetti, P, Callegari, ML, Ferrari, S, et al. (2005) Enteral nutrition and microflora in pediatric Crohn's disease. JPEN 29 Suppl. 4, S173S178.
10Beattie, RM, Bentsen, BS & MacDonald, TT (1998) Childhood Crohn's disease and the efficacy of enteral diets. Nutrition 14, 345350.
11Aggarwal, S, Ichikawa, H, Takada, Y, et al. (2006) Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IkappaBalpha kinase and Akt activation. Molecular pharmacology 69, 195206.
12Singh, S & Aggarwal, BB (1995) Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane) [corrected]. J Biol Chem 270, 2499525000.
13Bharti, AC, Donato, N & Aggarwal, BB (2003) Curcumin (diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells. J Immunol 171, 38633871.
14Rao, CV (2007) Regulation of COX and LOX by curcumin. Adv Exp Med Biol 595, 213226.
15Goel, A, Kunnumakkara, AB & Aggarwal, BB (2008) Curcumin as ‘Curecumin’: from kitchen to clinic. Biochem Pharmacol 75, 787809.
16Xu, J, Fu, Y & Chen, A (2003) Activation of peroxisome proliferator-activated receptor-gamma contributes to the inhibitory effects of curcumin on rat hepatic stellate cell growth. Am J Physiol 285, G20G30.
17Camacho-Barquero, L, Villegas, I, Sanchez-Calvo, JM, et al. (2007) Curcumin, a Curcuma longa constituent, acts on MAPK p38 pathway modulating COX-2 and iNOS expression in chronic experimental colitis. Int Immunopharmacol 7, 333342.
18Cho, JW, Lee, KS & Kim, CW (2007) Curcumin attenuates the expression of IL-1beta, IL-6, and TNF-alpha as well as cyclin E in TNF-alpha-treated HaCaT cells; NF-kappaB and MAPKs as potential upstream targets. Int J Mol Med 19, 469474.
19Lee, CW, Lin, WN, Lin, CC, et al. (2006) Transcriptional regulation of VCAM-1 expression by tumor necrosis factor-alpha in human tracheal smooth muscle cells: involvement of MAPKs, NF-kappaB, p300, and histone acetylation. J Cell Physiol 207, 174186.
20Balasubramanyam, K, Varier, RA, Altaf, M, et al. (2004) Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription. J Biol Chem 279, 5116351171.
21Monteleone, G, Del Vecchio Blanco, G, Monteleone, I, et al. (2005) Post-transcriptional regulation of Smad7 in the gut of patients with inflammatory bowel disease. Gastroenterology 129, 14201429.
22Ongeri, EM, Verderame, MF & Hammond, JM (2005) Follicle-stimulating hormone induction of ovarian insulin-like growth factor-binding protein-3 transcription requires a TATA box-binding protein and the protein kinase A and phosphatidylinositol-3 kinase pathways. Mol Endocrinol 19, 18371848.
23White, NR, Mulligan, P, King, PJ, et al. (2006) Sodium butyrate-mediated Sp3 acetylation represses human insulin-like growth factor binding protein-3 expression in intestinal epithelial cells. J Pediatr Gastroenterol Nutr 42, 134141.
24Holt, PR, Katz, S & Kirshoff, R (2005) Curcumin therapy in inflammatory bowel disease: a pilot study. Dig Dis Sci 50, 21912193.
25Hanai, H, Iida, T, Takeuchi, K, et al. (2006) Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol 4, 15021506.
26Balasubramanyam, K, Swaminathan, V, Ranganathan, A, et al. (2003) Small molecule modulators of histone acetyltransferase p300. J Biol Chem 278, 1913419140.
27Yoshida, M, Kijima, M, Akita, M, et al. (1990) Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem 265, 1717417179.
28Ridley, SH, Sarsfield, SJ, Lee, JC, et al. (1997) Actions of IL-1 are selectively controlled by p38 mitogen-activated protein kinase: regulation of prostaglandin H synthase-2, metalloproteinases, and IL-6 at different levels. J Immunol 158, 31653173.
29Dean, JL, Brook, M, Clark, AR, et al. (1999) p38 Mitogen-activated protein kinase regulates cyclooxygenase-2 mRNA stability and transcription in lipopolysaccharide-treated human monocytes. J Biol Chem 274, 264269.
30Underwood, DC, Osborn, RR, Bochnowicz, S, et al. (2000) SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung. Am J Physiol Lung Cell Mol Physiol 279, L895L902.
31Waetzig, GH, Seegert, D, Rosenstiel, P, et al. (2002) p38 Mitogen-activated protein kinase is activated and linked to TNF-alpha signaling in inflammatory bowel disease. J Immunol 168, 53425351.
32Lee, JC, Kassis, S, Kumar, S, et al. (1999) p38 Mitogen-activated protein kinase inhibitors – mechanisms and therapeutic potentials. Pharmacol Ther 82, 389397.
33Reinecker, HC, Steffen, M, Witthoeft, T, et al. (1993) Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn's disease. Clin Exp Immunol 94, 174181.
34Kang, BY, Song, YJ, Kim, KM, et al. (1999) Curcumin inhibits Th1 cytokine profile in CD4+T cells by suppressing interleukin-12 production in macrophages. Br J Pharmacol 128, 380384.
35Jagetia, G & Aggarwal, B (2007) ‘Spicing up’ of the immune system by curcumin. J Clin Immunol 27, 1935.
36Zhang, M, Deng, CS, Zheng, JJ, et al. (2006) Curcumin regulated shift from Th1 to Th2 in trinitrobenzene sulphonic acid-induced chronic colitis. Acta Pharmacol Sin 27, 10711077.
37Jobin, C, Bradham, CA, Russo, MP, et al. (1999) Curcumin blocks cytokine-mediated NF-kappa B activation and proinflammatory gene expression by inhibiting inhibitory factor I-kappa B kinase activity. J Immunol 163, 34743483.
38Jurrmann, N, Brigelius-Flohe, R & Bol, G-F (2005) Curcumin blocks interleukin-1 (IL-1) signaling by inhibiting the recruitment of the IL-1 receptor-associated kinase IRAK in murine thymoma EL-4 cells. J Nutr 135, 18591864.
39Moore, KW, de Waal Malefyt, R, Coffman, RL, et al. (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19, 683765.
40de Waal Malefyt, R, Yssel, H, Roncarolo, MG, et al. (1992) Interleukin-10. Curr Opin Immunol 4, 314320.
41Fiorentino, DF, Zlotnik, A, Mosmann, TR, et al. (1991) IL-10 inhibits cytokine production by activated macrophages. J Immunol 147, 38153822.
42de Waal Malefyt, R, Haanen, J, Spits, H, et al. (1991) Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med 174, 915924.
43Chomarat, P, Vannier, E, Dechanet, J, et al. (1995) Balance of IL-1 receptor antagonist/IL-1 beta in rheumatoid synovium and its regulation by IL-4 and IL-10. J Immunol 154, 14321439.
44Schreiber, S, Heinig, T, Thiele, HG, et al. (1995) Immunoregulatory role of interleukin 10 in patients with inflammatory bowel disease. Gastroenterology 108, 14341444.
45de Waal Malefyt, R, Yssel, H & de Vries, JE (1993) Direct effects of IL-10 on subsets of human CD4+T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. J Immunol 150, 47544765.
46Asseman, C, Mauze, S, Leach, MW, et al. (1999) An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med 190, 9951004.
47Groux, H, O'Garra, A, Bigler, M, et al. (1997) A CD4+T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737742.
48Lindsay, JO & Hodgson, HJ (2001) Review Article: the immunoregulatory cytokine interleukin-10 – a therapy for Crohn's disease? Aliment Pharmacol Ther 15, 17091716.
49Pender, SL, Breese, EJ, Gunther, U, et al. (1998) Suppression of T cell-mediated injury in human gut by interleukin 10: role of matrix metalloproteinases. Gastroenterology 115, 573583.
50Kuhn, R, Lohler, J, Rennick, D, et al. (1993) Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263274.
51Rennick, DM & Fort, MM (2000) Lessons from genetically engineered animal models. XII. IL-10-deficient (IL-10( − / − ) mice and intestinal inflammation. Am J Physiol 278, G829G833.
52Fahey, AJ, Adrian Robins, R & Constantinescu, CS (2007) Curcumin modulation of IFN-beta and IL-12 signalling and cytokine induction in human T cells. J Cell Mol Med 11, 11291137.
53Méndez-Samperio, P, Trejo, A & Perez, A (2008) Mycobacterium bovis Bacillus Calmette-Guérin (BCG) stimulates IL-10 production via the PI3K/Akt and p38 MAPK pathways in human lung epithelial cells. Cell Immunol 251, 3742.
54Hickey, FB, Brereton, CF & Mills, KH (2008) Adenylate cycalse toxin of Bordetella pertussis inhibits TLR-induced IRF-1 and IRF-8 activation and IL-12 production and enhances IL-10 through MAPK activation in dendritic cells. J Leukoc Biol 84, 234243.
55Chanteux, H, Guisset, AC, Pilette, C, et al. (2007) LPS induces IL-10 production by human alveolar macrophages via MAPKinases- and Sp1-dependent mechanisms. Respir Res 8, 71.
56Tone, M, Powell, MJ, Tone, Y, et al. (2000) IL-10 gene expression is controlled by the transcription factors Sp1 and Sp3. J Immunol 165, 286291.
57Hoang, B, Trinh, A, Birnbaumer, L, et al. (2007) Decreased MAPK- and PGE2-dependent IL-11 production in Gialpha2 − / −  colonic myofibroblasts. Am J Physiol 292, G1511G1519.
58Pender, SL & MacDonald, TT (2004) Matrix metalloproteinases and the gut – new roles for old enzymes. Curr Opin Pharmacol 4, 546550.
59Kruidenier, L, MacDonald, TT, Collins, JE, et al. (2006) Myofibroblast matrix metalloproteinases activate the neutrophil chemoattractant CXCL7 from intestinal epithelial cells. Gastroenterology 130, 127136.
60Yodkeeree, S, Garbisa, S & Limtrakul, P (2008) Tetrahydrocurcumin inhibits HT1080 cell migration and invasion via downregulation of MMPs and uPA. Acta Pharmacol Sin 29, 853860.
61Saja, K, Babu, MS, Karunagaran, D, et al. (2007) Anti-inflammatory effect of curcumin involves downregulation of MMP-9 in blood mononuclear cells. Int Immunopharmacol 7, 16591667.
62Binion, DG, Heidemann, J, Li, MS, et al. (2009) Vascular cell adhesion molecule-1 expression in human intestinal microvascular endothelial cells is regulated by PI 3-kinase/Akt/MAPK/NF-kappaB: inhibitory role of curcumin. Am J Physiol 297, G259G268.
63Binion, DG, Otterson, MF & Rafiee, P (2008) Curcumin inhibits VEGF-mediated angiogenesis in human intestinal microvascular endothelial cells through COX-2 and MAPK inhibition. Gut 57, 15091517.
64Chen, YR & Tan, TH (1998) Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin. Oncogene 17, 173178.
65Collett, GP & Campbell, FC (2004) Curcumin induces c-jun N-terminal kinase-dependent apoptosis in HCT116 human colon cancer cells. Carcinogenesis 25, 21832189.
66Hu, M, Du, Q, Vancurova, I, et al. (2005) Proapoptotic effect of curcumin on human neutrophils: activation of the p38 mitogen-activated protein kinase pathway. Crit Care Med 33, 25712578.
67Wu, CY, Hsieh, HL, Sun, CC, et al. (2008) IL-1 beta induces proMMP-9 expression via c-Src-dependent PDGFR/PI3K/Akt/p300 cascade in rat brain astrocytes. J Neurochem 105, 14991512.
68Basu, S, Pathak, S, Pathak, SK, et al. (2007) Mycobacterium avium-induced matrix metalloproteinase-9 expression occurs in a cyclooxygenase-2-dependent manner and involves phosphorylation- and acetylation-dependent chromatin modification. Cell Microbiol 9, 28042816.
69Lee, CW, Lin, CC, Lin, WN, et al. (2007) TNF-alpha induces MMP-9 expression via activation of Src/EGFR, PDGFR/PI3K/Akt cascade and promotion of NF-kappaB/p300 binding in human tracheal smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 292, L799L812.
70Pender, SL, Quinn, JJ, Sanderson, IR, et al. (2000) Butyrate upregulates stromelysin-1 production by intestinal mesenchymal cells. Am J Physiol 279, G918G924.
71Lao, CD, Ruffin, MTt, Normolle, D, et al. (2006) Dose escalation of a curcuminoid formulation. BMC Complementary Altern Med 6, 10.
72Chainani-Wu, N (2003) Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa). J Altern Complement Med 9, 161168.
73Sood, A, Midha, V, Sood, N, et al. (2003) Incidence and prevalence of ulcerative colitis in Punjab, North India. Gut 52, 15871590.
74Thia, KT, Loftus, EV Jr, Sandborn, WJ, et al. (2008) An update on the epidemiology of inflammatory bowel disease in Asia. Am J Gastroenterol 103, 31673182.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

British Journal of Nutrition
  • ISSN: 0007-1145
  • EISSN: 1475-2662
  • URL: /core/journals/british-journal-of-nutrition
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed