Lipoxin A(4) reduces lipopolysaccharide-induced inflammation in macrophages and intestinal epithelial cells through inhibition of nuclear factor-kappaB activation.
Lipoxins, which are bioactive lipids derived from omega-6 polyunsaturated fatty acids, play important roles in various biological functions. In this study, the anti-inflammatory effects of lipoxin A(4) (LXA4; 5S,6R,15S-trihydroxy-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)-alpha. LXA4 also reduced the LPS-induced nuclear translocation of nuclear factor-kappaB (NF-kappaB). In an LPS-induced acute inflammation mouse model, the injection of LXA4 at 5 microg/kg b.wt. led to down-regulation of the TNF-alpha level in serum and the TNF-alpha mRNA expression level in intestinal epithelial cells. Moreover, LXA4 reduced the LPS-caused phosphorylation of IkappaB kinases, IkappaB, and NF-kappaB, the degradation of IkappaB, and the nuclear translocation of NF-kappaB 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-alpha 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-kappaB activation, and, therefore, LXA4 may be useful as a therapeutic strategy against intestinal mucosa inflammation.
Division of Gastroenterology, Department of Internal Medicine, Graduate School of Medicine, Kobe University, Kobe, Hyogo 650-0017, Japan.
Izumi
I
Kure
Shin
S
Nishiumi
Yosuke
Y
Nishitani
Takeshi
T
Tanoue
Tsukasa
T
Ishida
Masashi
M
Mizuno
Tsuyoshi
T
Fujita
Hiromu
H
Kutsumi
Makoto
M
Arita
Takeshi
T
Azuma
Masaru
M
Yoshida
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018938:Caco-2 Cells; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides; D044045:Lipoxins / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D008070:Lipopolysaccharides; D044045:Lipoxins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C040527:lipoxin A4