3,3'-diindolylmethane suppresses 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and tumor promotion in mouse skin via the downregulation of inflammatory mediators.
3,3'-Diindolylmethane (DIM) is a major acid-condensation product of indole-3-carbinol and is present in cruciferous vegetables. In this study, we evaluated the effects of DIM on antiinflammatory and antitumor promotion activity in mouse skin and explored the relevant mechanisms. When 12-O-tetradecanoylphorbol-13-acetate (TPA) was applied topically to the mouse ear to induce inflammation, DIM pretreatment effectively inhibited TPA-induced ear edema formation. To evaluate the mechanisms underlying DIM's antiinflammatory effects, DIM was topically treated to the shaved backs of mice 30 min before TPA treatment. DIM inhibited the TPA-induced increases in the expression of cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), chemokine (C-X-C motif) ligand (CXCL) 5, and interleukin (IL)-6 in mouse skin. DIM also inhibited nuclear factor-kappa B (NF-kappaB)'s DNA binding activity, the nuclear translocation of p65, and the degradation of inhibitor of kappaB (IkappaB) alpha in TPA-stimulated mouse skin. Furthermore, DIM reduced TPA-induced increases in the activity of extracellular signal regulated protein kinase (ERK)-1/2 and IkappaB kinase (IKK). When mouse skin papillomas were initiated via the topical application of 7,12-dimethylbenz[alpha]anthracene (DMBA) and promoted with repeated topical applications of TPA, repeated topical applications of DIM prior to each TPA treatment significantly suppressed the incidence and multiplicity of the papillomas. DIM also reduced the expression of COX-2 and iNOS, ERK phosphorylation, and the nuclear translocation of p65 in papillomas. Collectively, these results show that DIM exerts antiinflammatory and chemopreventive effects in mouse skin via the downregulation of COX-2, iNOS, CXCL5, and IL-6 expression, which may be mediated by reductions in NF-kappaB activation.
Kim
Eun Ji
EJ
Center for Efficacy Assessment and Development of Functional Foods and Drugs, Hallym University, Chuncheon, Korea.
Park
Heesook
H
Kim
Jongdai
J
Park
Jung Han Yoon
JH
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D054365:Chemokine CXCL5 / Q000235:genetics / Q000276:immunology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology; D004423:Ear / Q000473:pathology; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology; D007211:Indoles / Q000627:therapeutic use*; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000276:immunology*; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology; D010212:Papilloma / Q000517:prevention & control*; D012878:Skin Neoplasms / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate
D000893:Anti-Inflammatory Agents; D016588:Anticarcinogenic Agents; D054365:Chemokine CXCL5; C094739:Cxcl5 protein, mouse; D007211:Indoles; D018836:Inflammation Mediators; D015850:Interleukin-6; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D051550:I-kappa B Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D013755:Tetradecanoylphorbol Acetate; C016392:3,3'-diindolylmethane