Constitutive Activation of Epithelial TLR4 Augments Inflammatory Responses to Mucosal Injury and Drives Colitis-associated Tumorigenesis

被引:157
作者
Fukata, Masayuki [1 ]
Shang, Limin [2 ]
Santaolalla, Rebeca [1 ]
Sotolongo, John [1 ]
Pastorini, Cristhine [1 ]
Espana, Cecilia [1 ]
Ungaro, Ryan [3 ]
Harpaz, Noam [4 ]
Cooper, Harry S. [5 ]
Elson, Greg [6 ]
Kosco-Vilbois, Marie [6 ]
Zaias, Julia [7 ]
Perez, Maria T. [8 ]
Mayer, Lloyd [2 ]
Vamadevan, Arunan S. [1 ]
Lira, Sergio A. [2 ]
Abreu, Maria T. [1 ]
机构
[1] Univ Miami, Div Gastroenterol, Dept Med, Miller Sch Med, Miami, FL 33101 USA
[2] Mt Sinai Sch Med, Inst Immunol, New York, NY USA
[3] Mt Sinai Sch Med, Dept Med, Div Gastroenterol, New York, NY USA
[4] Mt Sinai Sch Med, Dept Pathol, New York, NY USA
[5] Fox Chase Canc Ctr, Dept Pathol, Philadelphia, PA 19111 USA
[6] Novimmune SA, Geneva, Switzerland
[7] Univ Miami, Dept Vet Resources, Miller Sch Med, Miami, FL 33101 USA
[8] Univ Miami, Dept Pathol, Miller Sch Med, Miami, FL 33101 USA
关键词
Toll-like receptor; cancer; innate immunity; ulcerative colitis; villin; TOLL-LIKE RECEPTOR-4; COLORECTAL NEOPLASIA; BOWEL-DISEASE; RECOGNITION; PROMOTES; CANCER; MODEL;
D O I
10.1002/ibd.21527
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background: Chronic intestinal inflammation culminates in cancer and a link to Toll-like receptor-4 (TLR4) has been suggested by our observation that TLR4 deficiency prevents colitis-associated neoplasia. In the current study we address the effect of the aberrant activation of epithelial TLR4 on induction of colitis and colitis-associated tumor development. We take a translational approach to address the consequences of increased TLR signaling in the intestinal mucosa. Methods: Mice transgenic for a constitutively active TLR4 under the intestine-specific villin promoter (villin-TLR4 mice) were treated with dextran sodium sulfate (DSS) for acute colitis and azoxymethane (AOM)-DSS TLR4 expression was analyzed by immunohistochemistry in colonic tissue from patients with ulcerative colitis (UC) and UC-associated cancer. The effect of an antagonist TLR4 antibody (Ab) was tested in prevention of colitis-associated neoplasia in the AOM-DSS model. Results: Villin-TLR4 mice were highly susceptible to both acute colitis and colitis-associated neoplasia. Villin-TLR4 mice had increased epithelial expression of COX-2 and mucosal PGE(2) production at baseline. Increased severity of colitis in villin-TLR4 mice was characterized by enhanced expression of inflammatory mediators and increased neutrophilic infiltration. In human UC samples, TLR4 expression was upregulated in almost all colitis-associated cancer and progressively increased with grade of dysplasia. As a proof of principle, a TLR4/MD-2 antagonist antibody inhibited colitis-associated neoplasia in the mouse model. Conclusions: Our results show that regulation of TLRs can affect the outcome of both acute colitis and its consequences, cancer. Targeting TLR4 and other TLRs may ultimately play a role in prevention or treatment of colitis-associated cancer.
引用
收藏
页码:1464 / 1473
页数:10
相关论文
共 25 条
[1]   The interleukin-23 axis in intestinal inflammation [J].
Ahern, Philip P. ;
Izcue, Ana ;
Maloy, Kevin J. ;
Powrie, Fiona .
IMMUNOLOGICAL REVIEWS, 2008, 226 :147-159
[2]  
Annese Vito, 2007, Expert Rev Clin Immunol, V3, P287, DOI 10.1586/1744666X.3.3.287
[3]   Modelling dysplasia detection in ulcerative colitis: clinical implications of surveillance intensity [J].
Awais, D. ;
Siegel, C. A. ;
Higgins, P. D. R. .
GUT, 2009, 58 (11) :1498-1503
[4]   Dysplasia and cancer in the dextran sulfate sodium mouse colitis model. Relevance to colitis-associated neoplasia in the human: a study of histopathology, B-catenin and p53 expression and the role of inflammation [J].
Cooper, HS ;
Murthy, S ;
Kido, K ;
Yoshitake, H ;
Flanigan, A .
CARCINOGENESIS, 2000, 21 (04) :757-768
[5]   TLR4/MD-2 monoclonal antibody therapy affords protection in experimental models of septic shock [J].
Daubeuf, Bruno ;
Mathison, John ;
Spiller, Stephan ;
Hugues, Stephanie ;
Herren, Suzanne ;
Ferlin, Walter ;
Kosco-Vilbois, Marie ;
Wagner, Hermann ;
Kirschning, Carsten J. ;
Ulevitch, Richard ;
Elson, Greg .
JOURNAL OF IMMUNOLOGY, 2007, 179 (09) :6107-6114
[6]   Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis [J].
Fukata, M ;
Michelsen, KS ;
Eri, R ;
Thomas, LS ;
Hu, B ;
Lukasek, K ;
Nast, CC ;
Lechago, J ;
Xu, RL ;
Naiki, Y ;
Soliman, A ;
Arditi, M ;
Abreu, MT .
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2005, 288 (05) :G1055-G1065
[7]   Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors [J].
Fukata, Masayuki ;
Chen, Anli ;
Vamadevan, Arunan S. ;
Cohen, Jason ;
Breglio, Keith ;
Krishnareddy, Suneeta ;
Hsu, David ;
Xu, Ruiliang ;
Harpaz, Noam ;
Dannenberg, Andrew J. ;
Subbaramaiah, Kotha ;
Cooper, Harry S. ;
Itzkowitz, Steven H. ;
Abreu, Maria T. .
GASTROENTEROLOGY, 2007, 133 (06) :1869-1881
[8]   Cox-2 is regulated by Toll-like receptor-4 (TLR4) signaling: Role in proliferation and apoptosis in the intestine [J].
Fukata, Masayuki ;
Chen, Anli ;
Klepper, Arielle ;
Krishnareddy, Suneeta ;
Vamadevan, Arunan S. ;
Thomas, Lisa S. ;
Xu, Ruliang ;
Inoue, Hiroyasu ;
Arditi, Moshe ;
Dannenberg, Andrew J. ;
Abreu, Maria T. .
GASTROENTEROLOGY, 2006, 131 (03) :862-877
[9]   Innate Immune Signaling by Toll-like Receptor-4 (TLR4) Shapes the Inflammatory Microenvironment in Colitis-Associated Tumors [J].
Fukata, Masayuki ;
Hernandez, Yasmin ;
Conduah, Daisy ;
Cohen, Joson ;
Chen, Anli ;
Breglio, Keith ;
Goo, Tyralee ;
Hsu, David ;
Xu, Ruliang ;
Abreu, Maria T. .
INFLAMMATORY BOWEL DISEASES, 2009, 15 (07) :997-1006
[10]   Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: A cohort study [J].
Gupta, Roopali Bansal ;
Harpaz, Noam ;
Itzkowitz, Steven ;
Hossain, Sabera ;
Matula, Sierra ;
Kornbluth, Asher ;
Bodian, Carol ;
Ullman, Thomas .
GASTROENTEROLOGY, 2007, 133 (04) :1099-1105