Fluoxetine inhibits lipopolysaccharide-induced NF-κB signaling in bone marrow-derived dendritic cells, and ameliorates intestinal inflammation in IL-10 knockout mice

Abstract

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.