title: TNF-like weak inducer of apoptosis (TWEAK) and TNF-α cooperate in the induction of keratinocyte apoptosis.
abstract: BACKGROUND
  Activation of skin keratinocytes followed by their apoptotic death leads to eczema and spongiosis formations in patients with atopic dermatitis (AD). TNF-like weak inducer of apoptosis (TWEAK) binds to its receptor, fibroblast growth factor-inducible 14 (Fn14), and controls many cellular activities, including proliferation, migration, differentiation, apoptosis, angiogenesis, and inflammation.
  
  
  OBJECTIVE
  The aim of the study was to investigate the role of TWEAK and Fn14 in the formation of eczema in patients with AD.
  
  
  METHODS
  Primary keratinocytes were isolated from nonlesional skin from patients with AD and psoriasis and from normal skin of healthy donors. Apoptosis analysis was performed by using annexin V/7-aminoactinomycin D and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining. The expression and regulation of TWEAK, TNF-α, Fn14, TNF receptor (TNFR) 1, and TNFR2 were measured by means of RT-PCR, flow cytometric analysis, and ELISA. TWEAK and Fn14 expression of lesional AD and psoriatic skin and normal control skin was analyzed by using immunohistochemistry and immunofluorescence.
  
  
  RESULTS
  TWEAK and TNF-α cooperate in the induction of apoptosis in primary keratinocytes obtained from patients with AD, patients with psoriasis, and healthy subjects and in artificial skin equivalents. TNFR1 and Fn14 were the main receptors involved. TWEAK upregulates TNF-α expression in primary keratinocytes, whereas TNF-α did not affect the expression of TWEAK and its receptors. High TWEAK expression was observed in AD lesions but not in psoriatic lesions or normal skin. Fn14 was highly expressed in the lesional skin of patients with AD and patients with psoriasis and in healthy control skin.
  
  
  CONCLUSIONS
  The high expression of TWEAK in lesional AD skin contributes to the difference in keratinocyte apoptosis and lesional formation between AD and psoriasis.
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.
authors.forename: Maya
authors.initials: M
authors.lastname: Zimmermann
authors.forename: Andrea
authors.initials: A
authors.lastname: Koreck
authors.forename: Norbert
authors.initials: N
authors.lastname: Meyer
authors.forename: Tomasz
authors.initials: T
authors.lastname: Basinski
authors.forename: Flurina
authors.initials: F
authors.lastname: Meiler
authors.forename: Burgler
authors.initials: B
authors.lastname: Simone
authors.forename: Stefan
authors.initials: S
authors.lastname: Woehrl
authors.forename: Katharina
authors.initials: K
authors.lastname: Moritz
authors.forename: Thomas
authors.initials: T
authors.lastname: Eiwegger
authors.forename: Peter
authors.initials: P
authors.lastname: Schmid-Grendelmeier
authors.forename: Lajos
authors.initials: L
authors.lastname: Kemeny
authors.forename: Cezmi A
authors.initials: CA
authors.lastname: Akdis
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D002469:Cell Separation; D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D003876:Dermatitis, Atopic / Q000150:complications / Q000378:metabolism / Q000473:pathology; D004485:Eczema / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000378:metabolism*
chemical_list: D000074049:Cytokine TWEAK; C109743:TNFSF12 protein, human; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors