Fluoxetine inhibits lipopolysaccharide-induced NF-κB signaling in bone marrow-derived dendritic cells, and ameliorates intestinal inflammation in IL-10 knockout mice
Fluoxetine의 골수 유도 수지상 세포에서 NF-κB 신호 전달 억제와 IL-10 유전자 제거 생쥐에서 장내 염증반응에 대한 효과
- 의과대학 의학과
- Issue Date
- 서울대학교 대학원
- fluoxetine; NF-κB; dendritic cell; inflammatory bowel disease; Interleukin-10 knockout mouse
- 학위논문 (박사)-- 서울대학교 대학원 : 의학과 내과학 전공, 2013. 2. 김주성.
- We previously demonstrated that fluoxetine inhibits NF-κB signaling in intestinal epithelial cells and reduces the severity of dextran sulfate sodium (DSS)-induced colitis. However, little is available regarding the effect of fluoxetine on dendritic cells and chronic colitis. Therefore, we investigated the effect of fluoxetine on lipopolysaccharide (LPS)-induced NF-κB in bone marrow derived dendritic cells (BMDCs) and Th-1 driven colitis in IL-10 knockout (IL-10-/-) mice.
BMDCs isolated from IL-10-/- and wild type mice were pretreated with fluoxetine and then stimulated with LPS. IL-12p40 and TNF-α gene expression were determined by real-time RT-PCR. IκB phosphorylation/degradation and DNA binding activity of NF-κB in BMDCs were evaluated by Western blot analysis and electrophoretic mobility shift assay, respectively. Specific pathogen free (SPF) 7 to 8-week-old IL-10-/- mice on a C57BL/6 background were used for this study. To induce colitis, piroxicam was fed to IL-10-/- mice for 10 days at a dose of 200 ppm in the diet. After the induction of colitis, IL-10-/- mice were administered daily either vehicle or two dosage of fluoxetine (1mg/kg or 5mg/kg) by oral gavage for the next 2 weeks. The severity of colitis was assessed by body weight, colon length, and histopathologic grade.
Fluoxetine inhibited IL-12p40 and TNF-α gene expression in BMDCs. Fluoxetine blocked IκB phosphorylation/degradation and DNA binding activity of NF-κB in BMDCs. The diet containing piroxicam induced significant colitis in IL-10-/- mice. Administration of fluoxetine attenuated the severity of intestinal inflammation. A significant improvement in body weight was observed in mice treated with 5 mg/kg of fluoxetine compared to those treated with vehicle. The shortening of colon length in mice was significantly attenuated by fluoxetine (1 mg/kg and 5 mg/kg). Administration of fluoxetine 5 mg/kg significantly reduced intestinal inflammation assessed by histopathologic grading in IL-10-/- mice.
Fluoxetine amelirates intestinal inflammation in IL-10-/- mice, which suggest that fluoxetine could be a potential therapeutic agent for inflammatory bowel disease.