Induction of GITRL expression in human keratinocytes by Th2 cytokines and TNF-α: Implications for atopic dermatitis

A. M. Byrne, E. Goleva, F. Chouiali, Mark Kaplan, Q. A. Hamid, Donald Y M Leung

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background: Glucocorticoid-induced TNF receptor-related protein ligand (GITRL), a ligand for the T cell co-stimulatory molecule GITR, is expressed by keratinocytes and involved in chemokine production. The expression of GITRL in skin inflammation remains unknown. Objectives: This study investigated cytokine regulation of keratinocyte GITRL expression. Methods: Glucocorticoid-induced TNF receptor expression was evaluated in cytokine-treated human epidermal keratinocytes (HEK)s, murine PAM 212 cell line, murine and human skin explants by real time PCR, flow cytometry and immunostaining. Functional responses to GITR fusion protein were examined by real time PCR and ELISA. GITRL expression in AD and psoriasis was studied by immunohistochemistry. Results: Skin biopsies from STAT6VT transgenic mice, which develop spontaneous atopic skin inflammation, were found by immunofluoresence, to have increased keratinocyte GITRL expression. Exposure to Th2 cytokines augmented GITRL mRNA expression in the murine PAM 212 keratinocytic cell line and murine skin explants. In contrast, GITRL mRNA and protein expression was only increased in HEKs and human skin explants in the presence of the combination of TNF-α and Th2 cytokines. A synergistic effect of Th2 cytokines and GITR fusion protein on production of CCL17, the Th2 chemokine, by murine keratinocytes was demonstrated. Immunohistochemical staining showed that acute AD lesions have increased expression of GITRL compared with normal skin, chronic AD lesions and psoriatic plaques. Conclusions and Clinical Relevance: Our studies demonstrate that GITRL expression is augmented by Th2 cytokines and TNF-α in keratinocytes. Increased GITRL expression in acute AD skin lesions is shown. This observation suggests a link between cytokine-regulated keratinocyte GITRL expression and its role in inflammatory responses in AD.

Original languageEnglish
Pages (from-to)550-559
Number of pages10
JournalClinical and Experimental Allergy
Volume42
Issue number4
DOIs
StatePublished - Apr 2012

Fingerprint

Tumor Necrosis Factor Receptors
Atopic Dermatitis
Keratinocytes
Glucocorticoids
Cytokines
Ligands
Proteins
Skin
Real-Time Polymerase Chain Reaction
Chemokine CCL17
Inflammation
Cell Line
Messenger RNA
Chemokines
Psoriasis
Transgenic Mice
Flow Cytometry

Keywords

  • Atopic dermatitis
  • Skin
  • Th2 cytokines

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Induction of GITRL expression in human keratinocytes by Th2 cytokines and TNF-α : Implications for atopic dermatitis. / Byrne, A. M.; Goleva, E.; Chouiali, F.; Kaplan, Mark; Hamid, Q. A.; Leung, Donald Y M.

In: Clinical and Experimental Allergy, Vol. 42, No. 4, 04.2012, p. 550-559.

Research output: Contribution to journalArticle

Byrne, A. M. ; Goleva, E. ; Chouiali, F. ; Kaplan, Mark ; Hamid, Q. A. ; Leung, Donald Y M. / Induction of GITRL expression in human keratinocytes by Th2 cytokines and TNF-α : Implications for atopic dermatitis. In: Clinical and Experimental Allergy. 2012 ; Vol. 42, No. 4. pp. 550-559.
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AB - Background: Glucocorticoid-induced TNF receptor-related protein ligand (GITRL), a ligand for the T cell co-stimulatory molecule GITR, is expressed by keratinocytes and involved in chemokine production. The expression of GITRL in skin inflammation remains unknown. Objectives: This study investigated cytokine regulation of keratinocyte GITRL expression. Methods: Glucocorticoid-induced TNF receptor expression was evaluated in cytokine-treated human epidermal keratinocytes (HEK)s, murine PAM 212 cell line, murine and human skin explants by real time PCR, flow cytometry and immunostaining. Functional responses to GITR fusion protein were examined by real time PCR and ELISA. GITRL expression in AD and psoriasis was studied by immunohistochemistry. Results: Skin biopsies from STAT6VT transgenic mice, which develop spontaneous atopic skin inflammation, were found by immunofluoresence, to have increased keratinocyte GITRL expression. Exposure to Th2 cytokines augmented GITRL mRNA expression in the murine PAM 212 keratinocytic cell line and murine skin explants. In contrast, GITRL mRNA and protein expression was only increased in HEKs and human skin explants in the presence of the combination of TNF-α and Th2 cytokines. A synergistic effect of Th2 cytokines and GITR fusion protein on production of CCL17, the Th2 chemokine, by murine keratinocytes was demonstrated. Immunohistochemical staining showed that acute AD lesions have increased expression of GITRL compared with normal skin, chronic AD lesions and psoriatic plaques. Conclusions and Clinical Relevance: Our studies demonstrate that GITRL expression is augmented by Th2 cytokines and TNF-α in keratinocytes. Increased GITRL expression in acute AD skin lesions is shown. This observation suggests a link between cytokine-regulated keratinocyte GITRL expression and its role in inflammatory responses in AD.

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