Genetic deletion of IL-25 (IL-17E) confers resistance to dextran sulfate sodium-induced colitis in mice.
BACKGROUND
IL-25 is emerging as a key regulator of inflammation in the intestinal mucosa because of its ability to promote type 2 while suppressing Th1 and Th17 responses. Several previous studies reported inconsistent results on the role of exogenous IL-25 in development of colonic inflammation and none were performed in animals with a genetic deletion of IL-25. We investigated the contribution of endogenous IL-25 to DSS-induced colitis using mice deficient in IL-25.


RESULTS
Mice were exposed to DSS in drinking water ad libitum either for seven days (acute) or for three cycles of seven days with DSS followed by 14 days without DSS (chronic) to induce colitis, respectively. The loss of body weight, appearance of diarrhea and bloody stools, and shortening of colon length were significantly less pronounced in IL-25(-/-) mice compared to WT mice after exposure to acute DSS. Histological examination showed that DSS-treated IL-25(-/-) mice had only mild inflammation in the colon, while severe inflammation developed in DSS-treated WT mice. A significant up-regulation of IL-33 was observed in acute DSS-treated WT but not in the IL-25(-/-) mice. There was significantly lower expression of pro-inflammatory cytokines in the colon of acute DSS-treated IL-25(-/-) compared to WT mice. IL-25(-/-) mice were also partially protected from chronic DSS challenge especially during the first 2 cycles of DSS exposure. In contrast to IL-25(-/-) mice, IL-13(-/-) mice were more susceptible to DSS-induced colitis. Finally, stimulation of T84 colonic epithelial cells with IL-25 up-regulated the expression of IL-33 and several pro-inflammatory cytokines.


CONCLUSIONS
These data indicate that endogenous IL-25 acts as a pro-inflammatory factor in DSS-induced colitis, which is unlikely to be mediated by IL-13 but possibly the induction of IL-33 and other pro-inflammatory mediators from colonic epithelial cells. The present study suggests that IL-25 may contribute to the pathogenesis of inflammatory bowel disease in at least a subgroup of patients.
Departments of Radiation Oncology and Medicine, University of Maryland School of Medicine, 10 S. Pine Street, MSTF, Room 7-00D, Baltimore, MD 21201 USA ; Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006 China.
An-Jiang
AJ
Wang
U.S. Department of Agriculture, Beltsville Human Nutrition Research Center, Agricultural Research Service, Diet, Genomics, and Immunology Laboratory, Beltsville, MD 20705 USA.
Allen
A
Smith
Departments of Radiation Oncology and Medicine, University of Maryland School of Medicine, 10 S. Pine Street, MSTF, Room 7-00D, Baltimore, MD 21201 USA.
Yanfei
Y
Li
U.S. Department of Agriculture, Beltsville Human Nutrition Research Center, Agricultural Research Service, Diet, Genomics, and Immunology Laboratory, Beltsville, MD 20705 USA.
Joseph F
JF
Urban
Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 USA.
Thirumalai R
TR
Ramalingam
Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 USA.
Thomas A
TA
Wynn
Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006 China.
Nonghua
N
Lu
Departments of Radiation Oncology and Medicine, University of Maryland School of Medicine, 10 S. Pine Street, MSTF, Room 7-00D, Baltimore, MD 21201 USA.
Terez
T
Shea-Donohue
Departments of Radiation Oncology and Medicine, University of Maryland School of Medicine, 10 S. Pine Street, MSTF, Room 7-00D, Baltimore, MD 21201 USA ; Department of Biochemistry, Zhongshan Medical School, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080 China.
Zhonghan
Z
Yang
Departments of Radiation Oncology and Medicine, University of Maryland School of Medicine, 10 S. Pine Street, MSTF, Room 7-00D, Baltimore, MD 21201 USA.
Aiping
A
Zhao
Colitis; DSS; IL-13; IL-25; IL-33; Mice