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Induction of GITRL expression in human keratinocytes by T h2 cytokines and TNF ‐α: implications for atopic dermatitis
Author(s) -
Byrne A. M.,
Goleva E.,
Chouiali F.,
Kaplan M. H.,
Hamid Q. A.,
Leung D. Y.M.
Publication year - 2012
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1111/j.1365-2222.2012.03956.x
Subject(s) - chemokine , cytokine , keratinocyte , proinflammatory cytokine , immunology , tumor necrosis factor alpha , fusion protein , medicine , flow cytometry , inflammation , microbiology and biotechnology , cell culture , chemistry , biology , recombinant dna , biochemistry , gene , genetics
Summary 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 STAT 6 VT transgenic mice, which develop spontaneous atopic skin inflammation, were found by immunofluoresence, to have increased keratinocyte GITRL expression. Exposure to T h2 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 HEK s and human skin explants in the presence of the combination of TNF ‐α and T h2 cytokines. A synergistic effect of T h2 cytokines and GITR fusion protein on production of CCL 17, the T h2 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 T h2 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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