TNF-like weak inducer of apoptosis (TWEAK) and TNF-α cooperate in the induction of keratinocyte apoptosis

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• 作者：Maya Zimmermann PhD^a ; ^{maya.zimmermann@siaf.uzh.ch} ; Andrea Koreck MD^b ; Norbert Meyer MD^a ; Tomasz Basinski PhD^a ; ^g ; Flurina Meiler PhD^a ; Burgler Simone PhD^a ; Stefan Woehrl MD^d ; Katharina Moritz MD^d ; Thomas Eiwegger MD^a ; ^e ; Peter Schmid-Grendelmeier MD^f ; Lajos Kemeny MD^b ; ^c ; Cezmi A. Akdis MD^a ; ^{akdisac@siaf.uzh.ch}
• 关键词：Human primary keratinocytes ; eczema formation ; atopic dermatitis ; psoriasis ; TNF-α ; TNF-like weak inducer of apoptosis ; TNF receptors ; Fn14 ; apoptosis
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2011
• 出版时间：January 2011
• 年：2011
• 卷：127
• 期：1
• 页码：200-207.e10
• 全文大小：2153 K

文摘

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.

Conclusion

The high expression of TWEAK in lesional AD skin contributes to the difference in keratinocyte apoptosis and lesional formation between AD and psoriasis.