Basic—Alimentary TractColitis and Intestinal Inflammation in IL10−/− Mice Results From IL-13Rα2–Mediated Attenuation of IL-13 Activity
Section snippets
Animals
Female C57BL/6, BALB/c, BALB/c il13rα2−/−, il13rα1−/−, il10−/−, and il10−/−il13rα2−/− 6- to 8-week-old mice were obtained from Taconic (Hudson, NY). Animals were housed under specific pathogen-free conditions at the National Institutes of Health in an American Association for the Accreditation of Laboratory Animal Care–approved facility. The National Institute of Allergy and Infectious Diseases Animal Care and Use Committee approved all experimental procedures. A minimum of 5 mice per group was
IL-17A and IFN-γ–Associated Colitis Is Reduced in the Absence of IL-13Rα2
IL-10 is a critical immunoregulatory cytokine that maintains intestinal homeostasis and symbiosis with enteric microflora. Germline deletion of IL-10 in mice results in spontaneous colitis after 3 to 4 months, driven by dysregulated immune responses to colonic flora.16 The onset of colitis can be accelerated and synchronized by feeding mice piroxicam, a nonsteroidal anti-inflammatory drug.23 It has been shown that piroxicam-induced colitis in il10−/− mice is attenuated following intestinal
Discussion
Following piroxicam treatment or infection with T muris, IFN-γ– and IL-17A–driven intestinal inflammation correlated with elevated IL-13Rα2 levels. Deletion of IL-13Rα2 abrogated IFN-γ and IL-17A and significantly attenuated the degree of inflammation in both models. These data suggest that IL-13Rα2 is directly responsible for the development of inflammation, as suggested in a different model of colitis.25 Alternatively, these observations suggest that IL-13Rα2 was blocking IL-1322, 24 and that
Acknowledgments
Dr Wilson's current affiliation is: National Institutes for Medical Research, Medical Research Council, London, England.
The authors thank Nicole Mahoney, Joy McFarlane, Jose Encarnacion, Lauren Donato, and SoBran staff for meticulous care of all animals; Mary Collins and Marion Kasaian at Wyeth LLC for providing IL-13Rα2–deficient mice; Sandra D. White, Robert W. Thompson, and National Institutes of Health Clinical Center staff for additional animal care, technical assistance, and complete
References (52)
- et al.
The intestinal epithelium: sensors to effectors in nematode infection
Mucosal Immunol
(2008) - et al.
Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells
Immunity
(2002) - et al.
Negative regulation of Th17 responses
Semin Immunol
(2007) - et al.
Interleukin-10-deficient mice develop chronic enterocolitis
Cell
(1993) - et al.
Th1/Th17 immune response is induced by mesenteric lymph node dendritic cells in Crohn's disease
Gastroenterology
(2009) - et al.
Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease
Immunity
(2008) - et al.
The Trichuris muris system: a paradigm of resistance and susceptibility to intestinal nematode infection
Adv Parasitol
(2004) The role of IL-13 and its receptor in allergy and inflammatory responses
J Allergy Clin Immunol
(1998)- et al.
The role of IL-13 and NK T cells in experimental and human ulcerative colitis
Mucosal Immunol
(2008) - et al.
IL-13 activates STAT6 and inhibits liver injury induced by ischemia/reperfusion
Am J Pathol
(1999)
Innate and adaptive mechanisms to control [corrected] pathological intestinal inflammation
J Pathol
Regulatory lymphocytes and intestinal inflammation
Annu Rev Immunol
Cause of death in patients with inflammatory bowel disease
Inflamm Bowel Dis
Critical role of IL-17 receptor signaling in acute TNBS-induced colitis
Inflamm Bowel Dis
Diminution of Circulating CD4+CD25 high T cells in naive Crohn's disease
Dig Dis Sci
Role of cytokines in inflammatory bowel disease
World J Gastroenterol
The role of IL-10 in inflammatory bowel disease: “of mice and men”
Toxicol Pathol
Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility
Nat Genet
Inflammatory bowel disease and mutations affecting the interleukin-10 receptor
N Engl J Med
Defective IL-10 production in severe phenotypes of Crohn's disease
J Leukoc Biol
Decreased mucosal interleukin-4 (IL-4) production in gut inflammation
J Clin Pathol
Role of helminths in regulating mucosal inflammation
Springer Semin Immunopathol
Piroxicam treatment of IL-10-deficient mice enhances colonic epithelial apoptosis and mucosal exposure to intestinal bacteria
Inflamm Bowel Dis
Unique functions of the type II interleukin 4 receptor identified in mice lacking the interleukin 13 receptor alpha1 chain
Nat Immunol
A functional IL-13 receptor is expressed on polarized murine CD4+ Th17 cells and IL-13 signaling attenuates Th17 cytokine production
J Immunol
RELMbeta/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract
Proc Natl Acad Sci U S A
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Conflicts of interest The authors disclose no conflicts.
Funding Supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. David Artis is funded by National Institutes of Health grant nos. AI61570 and Crohn's and Colitis Foundation of America's William and Shelby Modell Family Foundation Research Award.