title: Inhibitory effect of 5,6-dihydroergosteol-glucoside on atopic dermatitis-like skin lesions via suppression of NF-κB and STAT activation.
abstract: BACKGROUND
  Atopic dermatitis (AD) is a Th2-type disease. Keratinocytes, a major type in the skin, produce Th2 chemokines such as thymus and activation-regulated chemokine (TARC)/CCL17 and macrophage-derived chemokine (MDC)/CCL22, which play pivotal roles in the development of Th2-dominant inflammatory skin diseases. Recently, it was reported that 5,6-dihydroergosterol-glucoside (DHE-Glc) was synthesized and exhibited strong anti-inflammatory activity.
  
  
  OBJECTIVE
  We aimed to investigate the effects of DHE-Glc, a synthetic molecule derived from ergosterol, on AD-like skin lesions induced by 2,4-dinitrochlorobenzene (DNCB) in mice and to elucidate the effects of DHE-Glc on TNF-α/IFN-γ-induced production of CCL17 and CCL22 in human keratinocytes (HaCaTs) and DNCB induced skin inflammation mice model.
  
  
  METHODS
  Mice were sensitized and challenged on the skin of their backs with DNCB. At 30-60 days after sensitization, mice were treated with cutaneous administration of DHE-Glc by skin smear. HaCaT cells were used to evaluate the effects of DHE-Glc on production of CCL17 and CCL22 and investigate mechanisms of action by RT-PCR, ELISA, Western blot, and reporter assays.
  
  
  RESULTS
  Topical administration of DHE-Glc attenuated AD-like skin inflammatory symptoms. DHE-Glc decreased infiltration of epidermal eosinophils and mast cells, and reduced levels of IgE, histamine, and mRNA expression and protein levels of CCL17/CCL22 in the plasma of DNCB-treated animals. In addition, DHE-Glc suppressed TNF-α/IFN-γ-induced expression of the Th2 chemokines CCL17 and CCL22 by inhibiting NF-κB and STAT activation in TNF-α/IFN-γ-induced HaCaT cells.
  
  
  CONCLUSIONS
  DHE-Glc improved AD-like skin inflammatory symptoms on the backs of DNCB-induced mice, partly by suppressing production of Th2 chemokines, CCL17 and CCL22 in inflamed skin. Therefore, DHE-Glc is a potential therapeutic agent for skin inflammatory diseases such as AD.
authors.affiliation: Graduate School of Biotechnology and College of Life Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea.
authors.forename: Mira
authors.initials: M
authors.lastname: Jung
authors.affiliation: Graduate School of Biotechnology and College of Life Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea; Graduate School of East-West Medical Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea.
authors.forename: Tae Hoon
authors.initials: TH
authors.lastname: Lee
authors.affiliation: Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea.
authors.forename: Hyun Jeoung
authors.initials: HJ
authors.lastname: Oh
authors.affiliation: Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea.
authors.forename: Hakwon
authors.initials: H
authors.lastname: Kim
authors.affiliation: Graduate School of Biotechnology and College of Life Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea.
authors.forename: Youngsook
authors.initials: Y
authors.lastname: Son
authors.affiliation: Graduate School of East-West Medical Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea.
authors.forename: Eunjoo H
authors.initials: EH
authors.lastname: Lee
authors.affiliation: Graduate School of Biotechnology and College of Life Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea. Electronic address: jkim@khu.ac.kr.
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Kim
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D054414:Chemokine CCL17 / Q000235:genetics / Q000378:metabolism*; D054422:Chemokine CCL22 / Q000235:genetics / Q000378:metabolism*; D003876:Dermatitis, Atopic / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology*; D004137:Dinitrochlorobenzene; D004804:Eosinophils; D004817:Epidermis / Q000276:immunology; D004875:Ergosterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005960:Glucosides / Q000494:pharmacology*; D006632:Histamine / Q000097:blood; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007371:Interferon-gamma / Q000494:pharmacology; D015603:Keratinocytes; D008297:Male; D008407:Mast Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000097:blood; D050794:STAT1 Transcription Factor / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C000609874:5,6-dihydroergosterol-glucoside; D000893:Anti-Inflammatory Agents; C106230:CCL17 protein, human; C515482:CCL22 protein, human; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D004137:Dinitrochlorobenzene; D005960:Glucosides; D016328:NF-kappa B; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014409:Tumor Necrosis Factor-alpha; D007073:Immunoglobulin E; D006632:Histamine; D007371:Interferon-gamma; D004875:Ergosterol
keywords: 5,6-Dihydroergosterol-glucoside; Atopic dermatitis; Macrophage-derived chemokine; NF-κB; STAT; Thymus and activation-regulated; chemokine