151. Combined defects in epithelial and immunoregulatory factors exacerbate the pathogenesis of inflammation:mucin 2-interleukin 10-deficient mice
- Author
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Ingrid B. Renes, Alexandra W. C. Einerhand, Maria van der Sluis, Janneke Bouma, Johannes B. van Goudoever, Kermit L. Carraway, Isabelle Van Seuningen, Hans A. Büller, Anna Velcich, Audrey Vincent, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc], University of Miami Leonard M. Miller School of Medicine [UMMSM], Erasmus MC-Sophia Hospital [Rotterdam, Netherlands], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, University of Miami Leonard M. Miller School of Medicine (UMMSM), Pediatrics, General Paediatrics, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), and Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille
- Subjects
Heterozygote ,medicine.medical_specialty ,Pathology ,Colon ,[SDV]Life Sciences [q-bio] ,Mucin 2 ,digestive system ,Epithelium ,Pathology and Forensic Medicine ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Intestinal mucosa ,Internal medicine ,medicine ,Animals ,Immunologic Factors ,Intestinal Mucosa ,Colitis ,Molecular Biology ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Inflammation ,Mice, Knockout ,Mucin-2 ,0303 health sciences ,Goblet cell ,business.industry ,Mucin ,Mucins ,Interleukin ,Cell Biology ,respiratory system ,medicine.disease ,Immunohistochemistry ,Ulcerative colitis ,digestive system diseases ,Interleukin-10 ,3. Good health ,Disease Models, Animal ,Interleukin 10 ,medicine.anatomical_structure ,Endocrinology ,030220 oncology & carcinogenesis ,Cytokines ,business - Abstract
Expression of the mucin MUC2, the structural component of the colonic mucus layer, is lowered in ulcerative colitis. Furthermore, interleukin (IL)-10 knockout (IL-10-/-) mice develop colitis and have reduced Muc2 levels. Our aim was to obtain insight into the role of Muc2 and IL-10 in epithelial protection. Muc2-IL-10 double-knockout (Muc2/IL-10(DKO)) mice were characterized and compared to Muc2 knockout (Muc2-/-), IL-10-/- and wild-type (WT) mice. Clinical symptoms, intestinal morphology and differences in epithelial-specific protein levels were analyzed. In addition, levels of the pro-inflammatory cytokines in colonic tissue and serum were determined. IL-10-/- mice were indistinguishable from WT mice throughout this experiment and showed no clinical or histological signs of colitis. Muc2/IL-10(DKO) and Muc2-/- mice showed significant growth retardation and clinical signs of colitis at 4 and 5 weeks, respectively. Muc2/IL-10(DKO) mice had a high mortality rate (50% survival/5 weeks) compared to the other types of mice (100% survival). Microscopic analysis of the colon of Muc2/IL-10(DKO) mice showed mucosal thickening, increased proliferation, superficial erosions and a diminished Muc4 expression. Furthermore, pro-inflammatory cytokines were significantly upregulated, both in tissue (mRNA) and systemically in Muc2/IL-10(DKO) mice. In conclusion, Muc2/IL-10(DKO) mice develop colitis, which is more severe in every aspect compared to Muc2-/- and IL-10-/- mice. These data indicate that (i) in case of Muc2 deficiency, the anti-inflammatory cytokine IL-10 can control epithelial damage, though to a limited extent and (ii) the mucus layer is most likely a key factor determining colitis.
- Published
- 2008