Dysregulation of innate and adaptive intestinal immune responses to bacterial microbiota is supposed to be involved in pathogenetic mechanisms of inflammatory bowel diseases (IBDs). We investigated expression of Toll-like receptor 2 (TLR2), TLR4, and their transmembrane coreceptor CD14 in biopsy samples from patients with IBD and in non-inflamed gut mucosa from controls. Small intestine and colon samples were obtained by colonoscopy from patients with Crohn's disease (CD), ulcerative colitis (UC), and controls. Immunohistochemical analysis of cryostat sections using polyclonal and monoclonal antibodies specific for TLR2, TLR4, and CD14 showed a significant increase in TLR2 expression in the terminal ileum of patients with inactive and active UC against controls. Significant upregulation of TLR4 expression relative to controls was found in the terminal ileum and rectum of UC patients in remission and in the terminal ileum of CD patients with active disease. CD14 expression was upregulated in the terminal ileum of CD patients in remission and with active disease, in the cecum of UC patients in remission and with active disease, and in rectum of UC patients with active disease. Hence, dysregulation of TLR2, TLR4, and CD14 expression in different parts of the intestinal mucosa may be crucial in IBD pathogenesis.

Department of Immunology and Gnotobiology Institute of Microbiology Academy of Sciences of the Czech Republic Prague Czech Republic

Expert Rev Gastroenterol Hepatol. 2008 Apr;2(2):193-6. doi: 10.1586/17474124.2.2.193. PubMed

See more in PubMed

Abreu MT, Arnold ET, Thomas LS, Gonsky R, Zhou Y, Hu B, Arditi M (2002) TLR4 and MD-2 expression is regulated by immune-mediated signals in human intestinal epithelial cells. J Biol Chem 227:20431–20437 PubMed

Aderem A, Ulevitch RJ (2000) Toll-like receptors in the induction of the innate immune response. Nature 406:782–787 PubMed

Akira S, Hemmi H (2003) Recognition of pathogen-associated molecular patterns by TLR family. Immunol Lett 85:85–95 PubMed

Autschbach F, Giese T, Gassler N, Sido B, Heuschen G, Heuschen U, Zuna I, et al. (2002) Cytokine/chemokine messenger-RNA expression profiles in ulcerative colitis and Crohn's disease. Virchows Arch 441:500–513 PubMed

Best WR (2006) Predicting the Crohn's disease activity index from the Harvey-Bradshaw Index. Inflamm Bowel Dis 12:304–310 PubMed

Brandtzaeg P (2001) Inflammatory bowel disease: clinics and pathology. Do inflammatory bowel disease and periodontal disease have similar immunopathogeneses? Acta Odontol Scand 59:235–243 PubMed

Cario E, Brown D, McKee M, Lynch-Devaney K, Gerken G, Podolsky DK (2002) Commensal- associated molecular patterns induce selective Toll-like receptor-trafficking from apical membrane to cytoplasmic compartments in polarized intestinal epithelium. Am J Pathol 160:165–173 PubMed PMC

Cario E, Podolsky D (2000) Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun 68:7010–7017 PubMed PMC

Danese S, Sans M, Fiocchi C (2004) Inflammatory bowel disease: the role of environmental factors. Autoimmun Rev 3:394–400 PubMed

Duchmann R, Kaiser I, Hermann E, Mayet W, Ewe K, Meyer zum Buschenfelde KH (1995) Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD). Clin Exp Immunol 102:448–455 PubMed PMC

Duchmann R, May E, Heike M, Knolle P, Neurath M, Meyer zum Buschenfelde KH (1999) T cell specificity and cross reactivity towards enterobacteria, bacteroides, bifidobacterium, and antigens from resident intestinal flora in humans. Gut 44:812–818 PubMed PMC

Elson CO, Cong Y, McCracken VJ, Dimmitt RA, Lorenz RG, Weaver CT (2005) Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota. Immunol Rev 206:260–276 PubMed

Fellermann K, Wehkamp J, Herrlinger KR, Stange EF (2003) Crohn's disease: a defensin deficiency syndrome? Eur J Gastroenterol Hepatol 15:627–634 PubMed

Furrie E, Macfarlane S, Thomson G, Macfarlane GT; Microbiology & Gut Biology Group; Tayside Tissue & Tumour Bank (2005) Toll-like receptors-2, -3 and -4 expression patterns on human colon and their regulation by mucosal-associated bacteria. Immunology 115:565–574 PubMed PMC

Fusunyan RD, Nanthakumar NN, Baldeon ME, Walker WA (2001) Evidence for an innate immune response in the immature human intestine: toll-like receptors on fetal enterocytes. Pediatr Res 49:589–593 PubMed

Grimm MC, Pavli P, Van de Pol E, Doe WF (1995) Evidence for a CD14+ population of monocytes in inflammatory bowel disease mucosa—implications for pathogenesis. Clin Exp Immunol 100:291–297 PubMed PMC

Hanauer SB (2006) Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities. Inflamm Bowel Dis 12(suppl 1):S3–9 PubMed

Hausmann M, Kiessling S, Mestermann S, Webb G, Spottl T, Andus T, Scholmerich J (2002) Toll-like receptors 2 and 4 are upregulated during intestinal inflammation. Gastroenterology 122:1987–2000 PubMed

Hudcovic T, Stepankova R, Cebra J, Tlaskalova-Hogenova H (2001) The role of microflora in the development of intestinal inflammation: acute and chronic colitis induced by dextran sulfate in germ-free and conventionally reared immunocompetent and immunodeficient mice. Folia Microbiol (Praha) 46:565–572 PubMed

Kawai T, Akira S (2006) TLR signaling. Cell Death Differ 13:816–825 PubMed

Lange S, Delbro DS, Jennische E, Mattsby-Baltzer I (1996) The role of Lps gene in experimental ulcerative colitis in mice. APMIS 104:823–833 PubMed

Maul J, Loddenkemper C, Mundt P, Berg E, Giese T, Stallmach A, Zeitz M, et al. (2005) Peripheral and intestinal regulatory CD4+ CD25high T cells in inflammatory bowel disease. Gastroenterology 128:1868–1878 PubMed

Medvedev AE, Lentschat A, Wahl LM, Golenbock DT, Vogel SN (2002) Dysregulation of LPS-induced Toll-like receptor 4-MyD88 complex formation and IL-1 receptor-associated kinase 1 activation in endotoxin-tolerant cells. J Immunol 169:5209–5216 PubMed

Melmed G, Thomas LS, Lee N, Tesfay SY, Lukasek K, Michelsen KS, Zhou Y, et al. (2003) Human intestinal epithelial cells are broadly unresponsive to Toll-like receptor 2-dependent bacterial ligands: implications for host-microbial interactions in the gut. J Immunol 170:1406–1415 PubMed

Nomura F, Akashi S, Sakao Y, Sato S, Kawai T, Matsumoto M, Nakanishi K, et al. (2000) Cutting edge: endotoxin tolerance in mouse peritoneal macrophages correlates with downregulation of surface toll-like receptor 4 expression. J Immunol 164:3476–3479 PubMed

Pugin J, Schurer-Maly CC, Leturcq D, Moriarty A, Ulevitch RJ, Tobias PS (1993) Lipopolysaccharide activation of human endothelial and epithelial cells is mediated by lipopolysaccharide-binding protein and soluble CD14. Proc Natl Acad Sci USA 90:2744–2748 PubMed PMC

Rogler G, Andus T, Aschenbrenner E, Vogl D, Falk W, Scholmerich J, Gross V (1997) Alterations of the phenotype of colonic macrophages in inflammatory bowel disease. Eur J Gastroenterol Hepatol 9:893–899 PubMed

Rugtveit J, Brandtzaeg P, Halstensen TS, Fausa O, Scott H (1994) Increased macrophage subset in inflammatory bowel disease: apparent recruitment from peripheral blood monocytes. Gut 35:669–674 PubMed PMC

Savage DC (1999) Mucosal microbiota. In Ogra PL, Mestecky J, Lamm ME, Strober W, Bienenstock J, McGhee J, eds. Mucosal Immunology. New York, Academic Press, 19–30

Schumann RR, Rietschel ET, Loppnow H (1994) The role of CD14 and lipopolysaccharide-binding protein (LBP) in the activation of different cell types by endotoxin. Med Microbiol Immunol (Berl) 183:279–297 PubMed

Singh B, Read S, Asseman C, Malmstrom V, Mottet C, Stephens LA, Stepankova R, et al. (2001) Control of intestinal inflammation by regulatory T cells. Immunol Rev 182:190–200 PubMed

Smith PD, Ochsenbauer-Jambor C, Smythies LE (2005) Intestinal macrophages: unique effector cells of the innate immune system. Immunol Rev 206:149–159 PubMed

Swidsinski A, Weber J, Loening-Baucke V, Hale LP, Lochs H (2005) Spatial organization and composition of the mucosal flora in patients with inflammatory bowel disease. J Clin Microbiol 43:3380–3389 PubMed PMC

Tlaskalova-Hogenova H, Stepankova R, Hudcovic T, Tuckova L, Cukrowska B, Lodinova-Zadnikova R, Kozakova H, et al. (2004) Commensal bacteria (normal microflora), mucosal immunity and chronic inflammatory and autoimmune diseases. Immunol Lett 93:97–108 PubMed

Tlaskalova-Hogenova H, Tuckova L, Lodinova-Zadnikova R, Stepankova R, Cukrowska B, Funda DP, Striz I, et al. (2002) Mucosal immunity: its role in defense and allergy. Int Arch Allergy Immunol 128:77–89 PubMed

Tlaskalova-Hogenova H, Tuckova L, Stepankova R, Hudcovic T, Palova-Jelinkova L, Kozakova H, Rossmann P, et al. (2005) Involvement of innate immunity in the development of inflammatory and autoimmune diseases. Ann NY Acad Sci 1051:787–798 PubMed

Toiyama Y, Akari T, Yoshiyama S, Hiro J, Miki C, Kusunoki M (2006) The expression patterns of Toll-like receptors in the ileal pouch mucosa of postoperative ulcerative colitis patients. Surg Today 36:287–290 PubMed

Wang JH, Doyle M, Manning BJ, Di Wu Q, Blankson S, Redmond HP (2002) Induction of bacterial lipoprotein tolerance is associated with suppression of toll-like receptor 2 expression. J Biol Chem 277:36068–36075 PubMed

Zarember KA, Godowski PJ (2002) Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol 168:554–561 PubMed

Serotonin attenuates tumor necrosis factor-induced intestinal inflammation by interacting with human mucosal tissue

Protective effect of Clostridium tyrobutyricum in acute dextran sodium sulphate-induced colitis: differential regulation of tumour necrosis factor-α and interleukin-18 in BALB/c and severe combined immunodeficiency mice

Spontaneous in vitro IL-6 production in various intestinal segments in patients with inflammatory bowel disease