Inhibitory effect of chroman carboxamide on interleukin-6 expression in response to lipopolysaccharide by preventing nuclear factor-kappaB activation in macrophages

Abstract

6-Hydroxy-7-methoxychroman-2-carboxylic acid (3-nitrophenyl)amide (CP-1158) is a synthetic chroman carboxamide with trolox-like chemical structure. In the present study, CP-1158 was found to inhibit interleukin (IL)-6 production in lipopolysaccharide (LPS)-stimulated macrophages RAW 264.7. The CP-1158 attenuated LPS-induced synthesis of IL-6 transcript but also inhibited LPS-induced IL-6 promoter activity. Further, CP-1158 attenuated LPS-induced syntheses of tumor necrosis factor (TNF)-alpha, IL-1beta, interferon-inducible protein (IP)-10 and macrophage inflammatory protein (MIP)-1beta transcripts. Nuclear factor (NF)-kappaB has been evidenced to play a major mechanism in LPS-induced expression of IL-6 or other inflammatory cytokines. CP-1158 prevented LPS-induced nuclear translocation of NF-kappaB complex and subsequently inhibited DNA binding activity of NF-kappaB complex as well as NF-kappaB transcriptional activity in macrophages RAW 264.7. However, CP-1158 did not affect LPS-induced phosphorylation and degradation of inhibitory kappaB (IkappaB). In another experiment, CP-1158 inhibited IL-6 promoter activity elicited by expression vectors encoding NF-kappaB p50 or p65 subunit. Taken together, CP-1158 inhibited LPS-induced expression of inflammatory cytokines including IL-6, targeting NF-kappaB activating pathway downstream IkappaB degradation, and thus could provide an anti-inflammatory potential of chroman carboxamide.