TY - JOUR
T1 - Combined defects in epithelial and immunoregulatory factors exacerbate the pathogenesis of inflammation
T2 - Mucin 2-interleukin 10-deficient mice
AU - Van Der Sluis, Maria
AU - Bouma, Janneke
AU - Vincent, Audrey
AU - Velcich, Anna
AU - Carraway, Kermit L.
AU - Büller, Hans A.
AU - Einerhand, Alexandra W.C.
AU - Van Goudoever, Johannes B.
AU - Van Seuningen, Isabelle
AU - Renes, Ingrid B.
N1 - Funding Information:
Sophia Foundation for Scientific Research, Rotterdam, The Netherlands Organization for Scientific Research, The Hague, The Foundation ‘De Drie Lichten’, all situated in the Netherlands, The Association Franc¸ois Aupetit, Paris, France and the National Institutes of Health, United States are gratefully acknowledged for their financial support. We would like to thank W Chung, IMA Louwers and LF de Ruiter for their excellent technical assistance.
PY - 2008/6/24
Y1 - 2008/6/24
N2 - 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-10DKO) 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-10DKO and Muc2-/- mice showed significant growth retardation and clinical signs of colitis at 4 and 5 weeks, respectively. Muc2/IL-10DKO 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-10DKO 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-10DKO mice. In conclusion, Muc2/IL-10DKO 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.
AB - 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-10DKO) 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-10DKO and Muc2-/- mice showed significant growth retardation and clinical signs of colitis at 4 and 5 weeks, respectively. Muc2/IL-10DKO 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-10DKO 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-10DKO mice. In conclusion, Muc2/IL-10DKO 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.
KW - Experimental colitis
KW - Goblet cell
KW - Inflammatory bowel diseases
KW - Intestine
KW - Mice
KW - Mucin
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U2 - 10.1038/labinvest.2008.28
DO - 10.1038/labinvest.2008.28
M3 - Article
C2 - 18427556
AN - SCOPUS:44349163907
VL - 88
SP - 634
EP - 642
JO - Laboratory Investigation
JF - Laboratory Investigation
SN - 0023-6837
IS - 6
ER -