Lipoxin A₄ reduces lipopolysaccharide-induced inflammation in macrophages and intestinal epithelial cells through inhibition of nuclear factor-κB activation

Lipoxins, which are bioactive lipids derived from ω-6 polyunsaturated fatty acids, play important roles in various biological functions. In this study, the anti-inflammatory effects of lipoxin A₄ (LXA4; 5S,6R,15Strihydroxy-7,9,13-trans-11-eicosatetraenoic acid) were investigated in in vitro cultured cell experiments and in vivo animal experiments. In mouse peritoneal macrophages and mouse macrophage cell line RAW264.7 cells, LXA4 reduced the lipopolysaccharide (LPS)-induced increase in the mRNA expression level of tumor necrosis factor (TNF)-α. LXA4 also reduced the LPS-induced nuclear translocation of nuclear factor-κB (NF-κB). In an LPS-induced acute inflammation mouse model, the injection of LXA4 at 5 μg/kg b.wt. led to down-regulation of the TNF-α level in serum and the TNF-α mRNA expression level in intestinal epithelial cells. Moreover, LXA4 reduced the LPS-caused phosphorylation of IκB kinases, IκB, and NF-κB, the degradation of IκB, and the nuclear translocation of NF-κB in intestinal epithelial cells. In a coculture system using RAW264.7 cells and human colon carcinoma cell line Caco-2 cells, treatment with LXA4 to Caco-2 cells led to reduction of LPS-evoked TNF-α production in RAW264.7 cells and interleukin-8 mRNA expression in Caco-2 cells. These results indicate that LXA4 exerts anti-inflammatory effects through inhibition of NF-κB activation, and, therefore, LXA4 may be useful as a therapeutic strategy against intestinal mucosa inflammation.