Colitis development during the suckling-weaning transition in mucin Muc2-deficient mice.

The mucin Muc2 is the structural component of the colonic mucus layer. Adult Muc2 knockout (Muc2(-/-)) mice suffer from severe colitis. We hypothesized that Muc2 deficiency induces inflammation before weaning of mother's milk [postnatal day (P) 14] with aggravation of colitis after weaning (P28). Muc2(-/-) and wild-type mice were killed at embryonic day 18.5 and P1.5, P7.5, P14, P21, and P28. Colonic morphology, influx of T cells, and goblet cell-specific protein expression was investigated by (immuno)histochemistry. Cytokine and Toll-like receptor (TLR) profiles in the colon were analyzed by quantitative RT-PCR. Muc2(-/-) mice showed an increased and persistent influx of Cd3ε-positive T cells in the colonic mucosa as of P1.5. This was accompanied by mucosal damage at P28 in the distal colon but not in the proximal colon. At P14, the proinflammatory immune response [i.e., increased interleukin (IL)-12 p35, IL-12 p40, and tumor necrosis factor-α, expression] in the distal colon of Muc2(-/-) mice presented with an immune suppressive response [i.e., increased Foxp3, transforming growth factor (TGF)-β1, IL-10, and Ebi3 expression]. In contrast, at P28, a proinflammatory response remained in the distal colon, whereas the immune suppressive response (i.e., Foxp3 and TGF-β1 expression) declined. The proximal colon of Muc2(-/-) mice did not show morphological damage and was dominated by an immune suppressive response at P14 and P28. Interestingly, changes in expression of TLRs and TLR-related molecules were observed in the distal colon at P14 and P28 and in the proximal colon only at P28. Colitis in Muc2(-/-) mice is limited before weaning by immune suppressive responses and exacerbates in the distal colon after weaning because of the decline in the immune suppressive response.

[1]  D. Tibboel,et al.  Epithelial Functions of the Residual Bowel After Surgery for Necrotising Enterocolitis in Human Infants , 2009, Journal of pediatric gastroenterology and nutrition.

[2]  R. Xu,et al.  A novel Toll-like receptor 4 antagonist antibody ameliorates inflammation but impairs mucosal healing in murine colitis. , 2009, American journal of physiology. Gastrointestinal and liver physiology.

[3]  J. Ozolek,et al.  Reciprocal Expression and Signaling of TLR4 and TLR9 in the Pathogenesis and Treatment of Necrotizing Enterocolitis1 , 2009, The Journal of Immunology.

[4]  D. Vignali,et al.  Interleukin‐35: odd one out or part of the family? , 2008, Immunological reviews.

[5]  Sung-Moo Park,et al.  MyD88 Signaling Is Not Essential for Induction of Antigen-Specific B Cell Responses but Is Indispensable for Protection against Streptococcus pneumoniae Infection following Oral Vaccination with Attenuated Salmonella Expressing PspA Antigen1 , 2008, The Journal of Immunology.

[6]  S. Peiró,et al.  IL-6 induces MUC4 expression through gp130/STAT3 pathway in gastric cancer cell lines. , 2008, Biochimica et biophysica acta.

[7]  A. Velcich,et al.  The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria , 2008, Proceedings of the National Academy of Sciences.

[8]  S. Akira,et al.  MyD88-Dependent Pathway in T Cells Directly Modulates the Expansion of Colitogenic CD4+ T Cells in Chronic Colitis1 , 2008, The Journal of Immunology.

[9]  T. van der Poll,et al.  TLR2-Dependent MyD88 Signaling Contributes to Early Host Defense in Murine Enterococcus faecium Peritonitis , 2008, The Journal of Immunology.

[10]  P. Rossmann,et al.  Expression of Toll-like Receptor 2 (TLR2), TLR4, and CD14 in Biopsy Samples of Patients With Inflammatory Bowel Diseases: Upregulated Expression of TLR2 in Terminal Ileum of Patients With Ulcerative Colitis , 2008, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[11]  Y. Aigrain,et al.  Expression of TLR-2, TLR-4, NOD2 and pNF-κB in a Neonatal Rat Model of Necrotizing Enterocolitis , 2007, PloS one.

[12]  D. Hackam,et al.  A Critical Role for TLR4 in the Pathogenesis of Necrotizing Enterocolitis by Modulating Intestinal Injury and Repair1 , 2007, The Journal of Immunology.

[13]  G Gerken,et al.  Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. , 2007, Gastroenterology.

[14]  R. Thomson,,et al.  The Roles of Bacteria and TLR4 in Rat and Murine Models of Necrotizing Enterocolitis1 , 2006, The Journal of Immunology.

[15]  S. Danese,et al.  Etiopathogenesis of inflammatory bowel diseases. , 2006, World journal of gastroenterology.

[16]  J. Meijerink,et al.  Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. , 2006, Gastroenterology.

[17]  J. Holst,et al.  Diet- and colonization-dependent intestinal dysfunction predisposes to necrotizing enterocolitis in preterm pigs. , 2006, Gastroenterology.

[18]  M. Hornef,et al.  Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells , 2006, The Journal of experimental medicine.

[19]  S. Batra,et al.  Regulation of mucin expression: mechanistic aspects and implications for cancer and inflammatory diseases. , 2006, Biochimica et biophysica acta.

[20]  L. Thim,et al.  Structure of mammalian trefoil factors and functional insights. , 2005, Cellular and molecular life sciences : CMLS.

[21]  W. Hoffmann.  Trefoil factors , 2005, Cellular and Molecular Life Sciences CMLS.

[22]  M. Hornef,et al.  Myeloid differentiation factor 88‐dependent signalling controls bacterial growth during colonization and systemic pneumococcal disease in mice , 2005, Cellular microbiology.

[23]  K. Ushida,et al.  Development of intestinal microbiota in mice and its possible interaction with the evolution of luminal IgA in the intestine. , 2005, Experimental animals.

[24]  C. Hofmann,et al.  CpG motifs of bacterial DNA essentially contribute to the perpetuation of chronic intestinal inflammation. , 2005, Gastroenterology.

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

[26]  N. Blin,et al.  IL-4 and IL-13 Up-Regulate Intestinal Trefoil Factor Expression: Requirement for STAT6 and De Novo Protein Synthesis1 , 2004, The Journal of Immunology.

[27]  N. Lelyveld,et al.  Microbiological factors associated with neonatal necrotizing enterocolitis: protective effect of early antibiotic treatment , 2003, Acta paediatrica.

[28]  D. Taupin,et al.  Trefoil factors: initiators of mucosal healing , 2003, Nature Reviews Molecular Cell Biology.

[29]  T. Abe,et al.  mRNA of MUC2 is stimulated by IL‐4, IL‐13 or TNF‐α through a mitogen‐activated protein kinase pathway in human colon cancer cells , 2003, Immunology and cell biology.

[30]  Judy H. Cho,et al.  The genetics of inflammatory bowel disease. , 2003, Gastroenterology.

[31]  M. Caplan,et al.  Neonatal Necrotizing Enterocolitis: Clinical Considerations and Pathogenetic Concepts , 2002, Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society.

[32]  A. Cummins,et al.  Effect of breast milk and weaning on epithelial growth of the small intestine in humans , 2002, Gut.

[33]  Kan Yang,et al.  Colorectal Cancer in Mice Genetically Deficient in the Mucin Muc2 , 2002, Science.

[34]  J. Raemaekers,et al.  A novel method to compensate for different amplification efficiencies between patient DNA samples in quantitative real-time PCR. , 2001, The Journal of molecular diagnostics : JMD.

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

[36]  D. Podolsky,et al.  Differential Alteration in Intestinal Epithelial Cell Expression of Toll-Like Receptor 3 (TLR3) and TLR4 in Inflammatory Bowel Disease , 2000, Infection and Immunity.

[37]  J. Dekker,et al.  Selective sparing of goblet cells and paneth cells in the intestine of methotrexate-treated rats. , 2000, American journal of physiology. Gastrointestinal and liver physiology.

[38]  S. Akira,et al.  Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. , 1999, Immunity.

[39]  R. Mackie,et al.  Developmental microbial ecology of the neonatal gastrointestinal tract. , 1999, The American journal of clinical nutrition.

[40]  R. Sartor,et al.  Resident Enteric Bacteria Are Necessary for Development of Spontaneous Colitis and Immune System Activation in Interleukin-10-Deficient Mice , 1998, Infection and Immunity.

[41]  M. Fishman,et al.  Impaired Defense of Intestinal Mucosa in Mice Lacking Intestinal Trefoil Factor , 1996, Science.

[42]  H. Hedrich,et al.  Response of germfree rat colonic mucous cells to peroral endotoxin application. , 1996, European journal of cell biology.

[43]  J. Dekker,et al.  Quantitative analysis of MUC2 synthesis in ulcerative colitis. , 1996, Biochemical and biophysical research communications.

[44]  R. Newcombe,et al.  Thickness of adherent mucus gel on colonic mucosa in humans and its relevance to colitis. , 1994, Gut.

[45]  D. Podolsky,et al.  Identification and characterization of rat intestinal trefoil factor: tissue- and cell-specific member of the trefoil protein family. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[46]  D. Savage,et al.  Microbial Colonization of the Intestinal Epithelium in Suckling Mice , 1973, Infection and immunity.

[47]  Shizuo Akira,et al.  MyD88-deficient mice develop severe intestinal inflammation in dextran sodium sulfate colitis , 2004, Journal of Gastroenterology.

[48]  L. R. Jacobs,et al.  Regional distribution and alterations of lectin binding to colorectal mucin in mucosal biopsies from controls and subjects with inflammatory bowel diseases. , 1985, The Journal of clinical investigation.