title: Topical application of marine briarane-type diterpenes effectively inhibits 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and dermatitis in murine skin.
abstract: BACKGROUND
  Skin is the largest organ in the body, and is directly exposed to extrinsic assaults. As such, the skin plays a central role in host defense and the cutaneous immune system is able to elicit specific local inflammatory and systemic immune responses against harmful stimuli. 12-O-tetradecanoylphorbol-13-acetate (TPA) can stimulate acute and chronic inflammation and tumor promotion in skin. TPA-induced dermatitis is thus a useful in vivo pharmacological platform for drug discovery. In this study, the inhibitory effect of briarane-type diterpenes (BrDs) from marine coral Briareum excavatum on TPA-induced dermatitis and dendritic cell (DC) function was explored.
  
  
  METHODS
  Evans blue dye exudation was used to determine vascular permeability. H&E-stained skin section was used to determine the formation of edema in mouse abdominal skin. We also used immunohistochemistry staining and western blot assays to evaluate the activation of specific inflammation makers and key mediators of signaling pathway in the mouse skin. Furthermore, mouse bone marrow DCs were used to determine the relationship between the chemical structure of BrDs and their regulation of DC function.
  
  
  RESULTS
  BrD1 remarkably suppressed TPA-induced vascular permeability and edema in skin. At the biochemical level, BrD1 inhibited TPA-induced expression of cyclooxygenase-2, inducible nitric oxide synthase and matrix metalloproteinase-9, the key indicators of cutaneous inflammation. This inhibition was apparently mediated by interference with the Akt/NF-κB-mediated signaling network. BrD1 also inhibited TNF-α and IL-6 expression in LPS-stimulated BMDCs. The 8, 17-epoxide of BrDs played a crucial role in the inhibition of IL-6 expression, and replacement of the C-12 hydroxyl group with longer esters in BrDs gradually decreased this inhibitory activity.
  
  
  CONCLUSIONS
  Our results suggest that BrDs warrant further investigation as natural immunomodulatory agents for control of inflammatory skin diseases.
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taiwan.
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Wei
authors.forename: Sheng-Yen
authors.initials: SY
authors.lastname: Lin
authors.forename: Yi-Jyun
authors.initials: YJ
authors.lastname: Chen
authors.forename: Chih-Chun
authors.initials: CC
authors.lastname: Wen
authors.forename: Chiung-Yao
authors.initials: CY
authors.lastname: Huang
authors.forename: Arulselvan
authors.initials: A
authors.lastname: Palanisamy
authors.forename: Ning-Sun
authors.initials: NS
authors.lastname: Yang
authors.forename: Jyh-Horng
authors.initials: JH
authors.lastname: Sheu
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003877:Dermatitis, Contact / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D004224:Diterpenes / Q000008:administration & dosage* / Q000494:pharmacology; D004487:Edema / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate
chemical_list: D004224:Diterpenes; D015850:Interleukin-6; C574336:excavatolide B; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D013755:Tetradecanoylphorbol Acetate