Reduced small-intestinal injury induced by indomethacin in interleukin-17A-deficient mice.
OBJECTIVE
The pathogenesis of enteropathy induced by non-steroidal anti-inflammatory drugs (NSAIDs) is still unclear, and there are no established treatments. Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that has been associated with the development of chronic inflammatory diseases, including autoimmune diseases. To define the role of IL-17A in small intestinal injury and inflammation, we studied the effects of indomethacin administration in mice with targeted deletions of the IL-17A gene.


METHODS
Male C57BL/6 (wild-type) and homozygous IL-17A(-/-) C57BL/6 mice were subjected to this study. Indomethacin (10 mg/kg) was subcutaneously administered to induce small-intestinal damage. Indomethacin-induced lesions in the small intestine were evaluated by measuring the injured area and by histopathology. Also assessed were myeloperoxidase (MPO) activity, as an index of neutrophil accumulation, and intestinal mRNA expression for inflammatory cytokines.


RESULTS
The area of macroscopic ulcerative lesions, the MPO activity and the mRNA expression of inflammatory-associated chemokines, such as keratinocyte chemoattractant (KC), monocyte chemotactic protein-1 (MCP-1), and granulocyte-colony stimulating factor (G-CSF), were significantly increased in indomethacin-treated groups compared with the sham groups. The development of intestinal lesions by indomethacin was inhibited in IL-17A(-/-) mice compared with wild-type mice, together with significant suppression of the increased levels of MPO activities and KC, MCP-1, and G-CSF levels.


CONCLUSIONS
These findings demonstrate that IL-17A contributes to the development of indomethacin-induced small intestinal injury through upregulation of G-CSF, KC, and MCP-1. IL-17A might be a promising new therapeutic target to treat NSAID-induced enteritis.
Department of Molecular Gastroenterology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan.
Shinya
S
Yamada
Yuji
Y
Naito
Tomohisa
T
Takagi
Katsura
K
Mizushima
Yasuko
Y
Hirai
Ryusuke
R
Horie
Kohei
K
Fukumoto
Ken
K
Inoue
Akihito
A
Harusato
Naohisa
N
Yoshida
Kazuhiko
K
Uchiyama
Osamu
O
Handa
Takeshi
T
Ishikawa
Hideyuki
H
Konishi
Naoki
N
Wakabayashi
Nobuaki
N
Yagi
Satoshi
S
Kokura
Masakazu
M
Kita
Toshikazu
T
Yoshikawa
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018932:Chemokine CCL2 / Q000235:genetics; D054360:Chemokine CXCL1 / Q000235:genetics; D004195:Disease Models, Animal; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics; D007082:Ileum / Q000276:immunology* / Q000473:pathology; D007213:Indomethacin; D018836:Inflammation Mediators / Q000378:metabolism; D020381:Interleukin-17 / Q000172:deficiency* / Q000235:genetics; D007583:Jejunum / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology; D010437:Peptic Ulcer / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; C098680:Il17a protein, mouse; D018836:Inflammation Mediators; D020381:Interleukin-17; D012333:RNA, Messenger; D016179:Granulocyte Colony-Stimulating Factor; D009195:Peroxidase; D007213:Indomethacin