Triptolide ameliorates Crohn's colitis is associated with inhibition of TLRs/NF-κB signaling pathway.

Growing evidence suggests that TLRs/NF-κB signaling pathway plays a critical role in the pathogenesis of Crohn's disease (CD). We have reported that triptolide, an active component from Tripterygium wilfordii Hook, showed therapeutic activity in IL-10-deficeint (IL-10-/- mice, a murine CD model. However the full mechanisms of action of this agent in CD remain largely unknown. We hypothesized that triptolide would ameliorate the experimental colitis by inhibiting TLRs/NF-κB signaling pathway. We found TLR2 and TLR4 were upregulated in IL-10-)/- mice, triptolide inhibited the TLRs/NF-κB signaling pathway in vivo. In addition, triptolide in vitro was able to downregulate the TLRs/NF-κB pathway in cultured colonic explants from CD patients. Our results confirm the therapeutic effect of triptolide in experimental colitis, and suggest it as a promising compound for CD treatment. These findings also support the possibility that targeted inhibition of TLR signaling pathway is an approach deserving further investigation as a therapeutic strategy for CD.

[1]  G. Rogler,et al.  Toll-like receptors 2 and 4 are up-regulated during intestinal inflammation. , 2001, Gastroenterology.

[2]  D. Haller,et al.  Bacteria‐ and host‐derived mechanisms to control intestinal epithelial cell homeostasis: Implications for chronic inflammation , 2007, Inflammatory bowel diseases.

[3]  P. Pothier,et al.  Biologic effects of epidermal growth factor in human fetal jejunum. , 1988, Gastroenterology.

[4]  M. Kamm,et al.  Characteristics of intestinal dendritic cells in inflammatory bowel diseases. , 2005, Gastroenterology.

[5]  J. Rodríguez-Sánchez,et al.  TNFα production to TLR2 ligands in active IBD patients , 2006 .

[6]  Benny J Chen,et al.  Triptolide, A Novel Immunosuppressive and Anti-Inflammatory Agent Purified from a Chinese Herb Tripterygium Wilfordii Hook F , 2001, Leukemia & lymphoma.

[7]  L. Andresen,et al.  Expression and function of toll-like receptor 8 and Tollip in colonic epithelial cells from patients with inflammatory bowel disease , 2009, Scandinavian journal of gastroenterology.

[8]  Ruslan Medzhitov,et al.  Role of toll-like receptors in spontaneous commensal-dependent colitis. , 2006, Immunity.

[9]  M. Leach,et al.  Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. , 1996, The Journal of clinical investigation.

[10]  I. Raskin,et al.  MyD88-dependent and independent pathways of Toll-Like Receptors are engaged in biological activity of Triptolide in ligand-stimulated macrophages , 2010, BMC chemical biology.

[11]  Liu Yu-lan,et al.  Therapeutic effects of mucosal tolerance on experimental colitis in rats , 2009, European journal of gastroenterology & hepatology.

[12]  D. Zhang,et al.  Tetrandrine ameliorates dextran-sulfate-sodium-induced colitis in mice through inhibition of nuclear factor -κB activation , 2008, International Journal of Colorectal Disease.

[13]  G. Veres,et al.  Increased expression of Toll‐like receptor (TLR) 2 and TLR4 in the colonic mucosa of children with inflammatory bowel disease , 2007, Clinical and experimental immunology.

[14]  P. Kao,et al.  Immunosuppressive and Anti-Inflammatory Mechanisms of Triptolide, the Principal Active Diterpenoid from the Chinese Medicinal Herb Tripterygium wilfordii Hook. f. , 2003, Drugs in R&D.

[15]  Weiming Zhu,et al.  Therapeutic effects of triptolide on interleukin-10 gene-deficient mice with colitis. , 2008, International immunopharmacology.

[16]  E. Bloemena,et al.  Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines , 1998, Clinical and experimental immunology.

[17]  F. Zhang,et al.  Oxymatrine attenuates intestinal ischemia/reperfusion injury in rats , 2008, Surgery Today.

[18]  Jie-shou Li,et al.  Triptolide ameliorates IL-10-deficient mice colitis by mechanisms involving suppression of IL-6/STAT3 signaling pathway and down-regulation of IL-17. , 2010, Molecular immunology.

[19]  Jie-shou Li,et al.  Efficacy of T2 in Active Crohn’s Disease: A Prospective Study Report , 2007, Digestive Diseases and Sciences.

[20]  T. Ohkusa,et al.  The role of bacterial infection in the pathogenesis of inflammatory bowel disease. , 2004, Internal medicine.

[21]  Z. Liu,et al.  Triptolide: a potent inhibitor of NF-kappa B in T-lymphocytes. , 2000, Acta pharmacologica Sinica.

[22]  N. Davidson,et al.  Studies with IL‐10‐/‐ mice: an overview , 1997, Journal of leukocyte biology.

[23]  Ruslan Medzhitov,et al.  Recognition of Commensal Microflora by Toll-Like Receptors Is Required for Intestinal Homeostasis , 2004, Cell.

[24]  H. Vetter,et al.  The anti-inflammatory activity of L-menthol compared to mint oil in human monocytes in vitro: a novel perspective for its therapeutic use in inflammatory diseases. , 1998, European journal of medical research.

[25]  D. Besselsen,et al.  Effects of Boswellia serrata in mouse models of chemically induced colitis. , 2005, American journal of physiology. Gastrointestinal and liver physiology.

[26]  M. Oriowo,et al.  Curcumin attenuates inflammation through inhibition of TLR-4 receptor in experimental colitis , 2009, Molecular and Cellular Biochemistry.

[27]  K. Ewe,et al.  Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD) , 1995, Clinical and experimental immunology.

[28]  J. Ko,et al.  The protective action of radix Astragalus membranaceus against hapten-induced colitis through modulation of cytokines. , 2009, Cytokine.

[29]  P. Lipsky,et al.  The Chinese anti-inflammatory and immunosuppressive herbal remedy Tripterygium wilfordii Hook F. , 2000, Rheumatic diseases clinics of North America.

[30]  S. Akira,et al.  Toll-like receptors control activation of adaptive immune responses , 2001, Nature Immunology.

[31]  J. Rodríguez-Sánchez,et al.  TNF alpha production to TLR2 ligands in active IBD patients. , 2006, Clinical immunology.

[32]  B. Wiedenmann,et al.  Escherichia coli Strain Nissle 1917 Ameliorates Experimental Colitis via Toll-Like Receptor 2- and Toll-Like Receptor 4-Dependent Pathways , 2006, Infection and Immunity.

[33]  R. Sartor.  Mechanisms of Disease: pathogenesis of Crohn's disease and ulcerative colitis , 2006, Nature Clinical Practice Gastroenterology &Hepatology.