3,3′-diindolylmethane suppresses the inflammatory response to lipopolysaccharide in murine macrophages

3,3'-Diindolylmethane (DIM), a major acid-condensation product of indole-3-carbinol, has been shown to have multiple anticancer effects in experimental models. Because recurrent or chronic inflammation has been implicated in the development of a variety of human cancers, this study examined the antiinflammatory effects of DIM and the underlying mechanisms using lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophages. DIM significantly decreased the release of nitric oxide (NO), prostaglandin (PG)E-2, tumor necrosis factor a, interleukin (IL)-6, and IL-1/3 by RAW264.7 cells treated with LPS. DIM inhibited LIPS-induced increases in protein levels of inducible NO synthase (NOS), which were accompanied by decreased iNOS mRNA levels and transcriptional activity. The mRNA levels of phospholipase A(2) decreased, whereas neither cyclooxygenases-2 protein nor transcript was altered by DIM. In addition, DIM suppressed LPS-induced nuclear factor-kappa B (NF-kappa B) transcriptional activity, NF-kappa B DNA-binding activity, translocation of p65 (RelA) to the nucleus, and degradation of inhibitor of kappa B alpha. Furthermore, DIM decreased LPS-induced transcriptional activity of activator protein (AP)-1, AP-1 DNA-binding activity, and phosphorylation of stress-activated protein kinase/Jun-N-terminal kinase and c-Jun. We demonstrate that DIM inhibits LPS-induced release of proinflammatory mediators in murine macrophages. Downregulation of NF-kappa B and AP-1 signaling may be one of the mechanisms by which DIM inhibits inflammatory responses.