title: Mutual upregulation of endothelin-1 and IL-25 in atopic dermatitis.
abstract: BACKGROUND
  Endothelin-1 (ET-1) has been reported to evoke histamine-independent pruritus in mammals. However, its association with pruritus or inflammation of atopic dermatitis (AD) has not been clarified. We sought to investigate the role of ET-1 in the skin inflammation of AD.
  
  
  METHODS
  To examine the role of ET-1 in AD, we investigated the expression of ET-1 and IL-25 in the skin of an AD mouse model and patients with AD and examined the mutual regulatory relationship between ET-1 and IL-25, one of the important cytokines in AD, using the human HaCaT keratinocyte cell line.
  
  
  RESULTS
  We immunohistochemically confirmed the upregulation of ET-1 and IL-25 expression in the epidermis of both the AD mouse model and patients with AD. In vitro, IL-25 upregulated ET-1 mRNA and protein expression in a concentration- and time-dependent fashion in HaCaT cells. This IL-25-induced ET-1 expression was inhibited by ERK1/2 or JNK inhibitor. In a reciprocal manner, ET-1 also induced IL-25 upregulation. The enhancing effect of ET-1 on IL-25 was inhibited by an endothelin A receptor antagonist, ERK1/2 inhibitor, or p38 inhibitor, but not by an endothelin B receptor antagonist or JNK inhibitor.
  
  
  CONCLUSIONS
  These findings suggest that mutual upregulation of ET-1 and IL-25 takes place in the epidermis of AD, which may be a future target for antipruritic agents.
authors.affiliation: Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: M K
authors.initials: MK
authors.lastname: Aktar
authors.affiliation: Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kido-Nakahara
authors.affiliation: Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.|Division of Skin Surface Sensing, Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Furue
authors.affiliation: Division of Skin Surface Sensing, Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nakahara
mesh_terms: D000818:Animals; D003876:Dermatitis, Atopic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D019332:Endothelin-1; C486701:IL25 protein, human; D020381:Interleukin-17; D012333:RNA, Messenger; D044022:Receptor, Endothelin A
keywords: IL-25; MAPK; atopic dermatitis; endothelin-1; keratinocyte