title: Expression of thymus and activation-regulated chemokine (TARC) by human dermal cells, but not epidermal keratinocytes.
abstract: BACKGROUND
  Serum levels of thymus and activation-regulated chemokine (TARC/CCL17) have served as a reliable biomarker of disease progression of atopic dermatitis (AD). However, it remains to be scientifically explained why serum TARC levels correlate well with the degree of AD progression.
  
  
  OBJECTIVE
  We hypothesized that dermal cells, but not epidermal keratinocytes, are major cellular sources of TARC and thus responsible for subclinical skin inflammation. This study aimed to identify the skin cells that can produce TARC protein.
  
  
  METHODS
  Primary normal human epidermal keratinocytes (NHEK), dermal microvascular endothelial cells (HMVEC-dBl) and dermal fibroblasts (NHDF) were stimulated with TNF-α and IL-4, alone and in combination. TARC mRNA and protein levels were quantified by qPCR and ELISA, respectively. We also investigated the effects of such immunosuppressants as a corticosteroid (dexamethasone) and tacrolimus (FK506) on TARC production, and used various signaling inhibitors to evaluate the signaling pathways involved in TARC expression.
  
  
  RESULTS
  Although neither TNF-α nor IL-4 alone induced TARC production by any of the tested cell types, together they induced expression of TARC mRNA and appreciable amounts of TARC protein by HMVEC-dBl and NHDF, but not by NHEK. TARC production by those dermal cells was not inhibited by dexamethasone or FK506. TARC production by HMVEC-dBl was completely inhibited by NF-κB and p38 MAPK inhibitors, but not by an ERK inhibitor.
  
  
  CONCLUSIONS
  Dermal cells, but not epidermal keratinocytes, may be important cellular sources of TARC in AD skin. Therefore, even if epidermal eczematous lesions seem to be improved, complete inhibition of inflammation in the dermis is thought to be particularly important for suppressing both the TARC blood level and progression of AD. However, immunosuppressants did not directly inhibit TARC production by the dermal cells. Anti-inflammatory therapy may decrease TARC blood levels in AD patients indirectly, via its inhibitory effects on TNF-α- and/or IL-4-producing cells in the dermis.
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo 157-8535, Japan; Department of Health and Psychosocial Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan. Electronic address: shoda-t@ncchd.go.jp.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shoda
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo 157-8535, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Futamura
authors.affiliation: Department of Health and Psychosocial Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Kobayashi
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo 157-8535, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Saito
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo 157-8535, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo 157-8535, Japan. Electronic address: matsuda-a@ncchd.go.jp.
authors.forename: Akio
authors.initials: A
authors.lastname: Matsuda
mesh_terms: D002478:Cells, Cultured; D054414:Chemokine CCL17 / Q000096:biosynthesis* / Q000097:blood; D003876:Dermatitis, Atopic / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D015603:Keratinocytes / Q000378:metabolism*; D016328:NF-kappa B / Q000502:physiology; D012867:Skin / Q000166:cytology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: C106230:CCL17 protein, human; D054414:Chemokine CCL17; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Atopic dermatitis; Corticosteroid; Dermal cells; IL-4; TARC; TNF-α