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Dexamethasone enhances interaction of endogenous Annexin 1 with L‐selectin and triggers shedding of L‐selectin in the monocytic cell line U‐937
Author(s) -
De Coupade Catherine,
Solito Egle,
Levine Jon D
Publication year - 2003
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705413
Subject(s) - annexin a1 , annexin a2 , annexin , jurkat cells , mediator , microbiology and biotechnology , endogeny , cell culture , biology , chemistry , endocrinology , flow cytometry , t cell , immunology , genetics , immune system
L‐selectin, constitutively expressed by leukocytes, is involved in the initial binding of leukocytes to activated endothelium. Anti‐inflammatory drugs like glucocorticoids can induce shedding of L‐selectin, but the mechanism is still unknown. Annexin 1, a protein whose synthesis and externalization/secretion are induced during the inflammatory response, has been proposed as a mediator of the anti‐inflammatory actions of glucocorticoids. The monocytic cell line U‐937 strongly expresses Annexin 1 after 24 h of phorbol 12‐myristate 13‐acetate (PMA, 1 n M ) treatment and externalizes/releases the protein after additional 16 h of dexamethasone (1 μ M ) treatment. This study investigated the possible regulation of cell surface L‐selectin shedding by endogenous Annexin 1, and its role in glucocorticoid‐induced L‐selectin shedding in the U‐937 cell line. PMA‐ and dexamethasone treatment‐induced L‐selectin shedding was potentially mediated by Annexin 1, since neutralizing antibodies against Annexin 1 reduced dexamethasone‐ and Annexin 1‐induced shedding. Immunoprecipitation and binding assays provided support for the suggestion that this effect could be mediated by an interaction between externalized Annexin 1 and L‐selectin. Such interaction involved the N‐terminal domain of Annexin 1 and was calcium‐dependent. Confocal microscopy studies demonstrated increased colocalization of Annexin 1 and L‐selectin on the cell surface. Overall, our study provides new insights into the potential role of endogenous ANXA1 as a mediator of dexamethasone‐induced L‐selectin shedding, which may contribute to the anti‐inflammatory activity of glucocorticoids.British Journal of Pharmacology (2003) 140 , 133–145. doi: 10.1038/sj.bjp.0705413