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Biochemical, Molecular, and Genetic Mechanisms

3,3'-Diindolylmethane Suppresses the Inflammatory Response to Lipopolysaccharide in Murine Macrophages^1–3,

⁴ Department of Food Science and Nutrition, ⁵ Center for Efficacy Assessment and Development of Functional Foods and Drugs, and ⁶ Department of Biochemistry, Hallym University, Chuncheon 200-702, South Korea; and ⁷ National Research Laboratory, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea

^* To whom correspondence should be addressed. E-mail: jyoon{at}hallym.ac.kr.

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)E₂, tumor necrosis factor , interleukin (IL)-6, and IL-1β by RAW264.7 cells treated with LPS. DIM inhibited LPS-induced increases in protein levels of inducible NO synthase (iNOS), which were accompanied by decreased iNOS mRNA levels and transcriptional activity. The mRNA levels of phospholipase A₂ decreased, whereas neither cyclooxygenases-2 protein nor transcript was altered by DIM. In addition, DIM suppressed LPS-induced nuclear factor-B (NF-B) transcriptional activity, NF-B DNA-binding activity, translocation of p65 (RelA) to the nucleus, and degradation of inhibitor of B. 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-B and AP-1 signaling may be one of the mechanisms by which DIM inhibits inflammatory responses.

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