Role of tumor necrosis factor-α in the pathogenesis of indomethacin-induced small intestinal injury in mice.
The pathogenesis of small intestinal damage caused by non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin is still unclear. For this reason, there is currently no therapeutic strategy for ameliorating such damage. On the other hand, molecular treatment strategies targeting tumor necrosis factor (TNF)-α exert beneficial effects on intestinal lesions in patients with inflammatory bowel disease (IBD). To clarify the participation of TNF-α in NSAID-induced small intestinal damage, we investigated the effects of indomethacin administration in mice with targeted deletion of the TNF-α gene. Indomethacin (10 mg/kg) was administered subcutaneously to male C57BL/6 (wild-type: WT) mice and TNF-α-deficient (TNF-α-/-) mice to induce small intestinal damage. The ulcer score, the tissue-associated myeloperoxidase (MPO) activity as an index of neutrophil infiltration, and the expression of keratinocyte chemoattractant (KC) mRNA in the small intestinal mucosa were measured. In addition, we performed a TUNEL assay to evaluate indomethacin-induced apoptosis of intestinal epithelial cells and measured the expression of caspase-3 protein and Bcl-2 mRNA. The ulcer score, MPO activity, and expression of KC mRNA were significantly increased after indomethacin administration. These increases were significantly inhibited in TNF-α-/- mice compared with WT mice. Apoptotic cells were observed by the TUNEL assay in the area of the ulcerative lesion, and they were significantly fewer in TNF-α-/- mice compared with WT mice. The expression of cleaved caspase-3 protein was induced by indomethacin administration, and significantly inhibited in TNF-α-/- mice compared with that of WT mice. The expression level of Bcl-2 mRNA in indomethacin-treated TNF-α-/- mice was significantly higher than that in WT mice. TNF-α plays an important role in the pathogenesis of indomethacin-induced small intestinal damage. These results suggest that TNF-α could become a new therapeutic target for NSAID-induced small intestinal damage.
Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.
Kohei
K
Fukumoto
Yuji
Y
Naito
Tomohisa
T
Takagi
Shinya
S
Yamada
Ryusuke
R
Horie
Ken
K
Inoue
Akihito
A
Harusato
Ikuhiro
I
Hirata
Tastushi
T
Omatsu
Katsura
K
Mizushima
Yasuko
Y
Hirai
Naohisa
N
Yoshida
Kazuhiko
K
Uchiyama
Takeshi
T
Ishikawa
Osamu
O
Handa
Hideyuki
H
Konishi
Naoki
N
Wakabayashi
Nobuaki
N
Yagi
Satoshi
S
Kokura
Hiroshi
H
Ichikawa
Masakazu
M
Kita
Toshikazu
T
Yoshikawa
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D053148:Caspase 3; D054360:Chemokine CXCL1 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D007213:Indomethacin / Q000009:adverse effects* / Q000494:pharmacology; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000276:immunology / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000276:immunology* / Q000293:injuries / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009195:Peroxidase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D007213:Indomethacin