Combined defects in epithelial and immunoregulatory factors exacerbate the pathogenesis of inflammation: mucin 2-interleukin 10-deficient mice.
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.
van der Sluis
Maria
M
Division of Neonatology, Department of Pediatrics, Erasmus MC and Sophia Children's Hospital, Rotterdam, The Netherlands.
Bouma
Janneke
J
Vincent
Audrey
A
Velcich
Anna
A
Carraway
Kermit L
KL
Büller
Hans A
HA
Einerhand
Alexandra W C
AW
van Goudoever
Johannes B
JB
Van Seuningen
Isabelle
I
Renes
Ingrid B
IB
D000818:Animals; D003092:Colitis / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D004848:Epithelium / Q000276:immunology* / Q000473:pathology; D006579:Heterozygote; D007150:Immunohistochemistry; D007155:Immunologic Factors / Q000378:metabolism*; D007249:Inflammation / Q000209:etiology* / Q000473:pathology; D016753:Interleukin-10 / Q000172:deficiency* / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D055262:Mucin-2; D009077:Mucins / Q000172:deficiency* / Q000235:genetics
D016207:Cytokines; D007155:Immunologic Factors; C524626:Muc2 protein, mouse; D055262:Mucin-2; D009077:Mucins; D016753:Interleukin-10