title: Glucocorticoids downregulate Fyn and inhibit IP(3)-mediated calcium signaling to promote autophagy in T lymphocytes.
abstract: T cell receptor activation induces inositol 1,4,5 trisphosphate (IP(3))-mediated calcium signaling that is essential for cell metabolism and survival. Moreover, inhibitors of IP(3) or pharmacological agents that disrupt calcium homeostasis readily induce autophagy. Using a glucocorticoid-sensitive CD4/CD8 positive T cell line, we found that dexamethasone prevented both IP(3)-mediated and spontaneous calcium signals within a timeframe that correlated with the induction of autophagy. We determined that this loss in IP(3)-mediated calcium signaling was dependent upon the downregulation of the Src kinase Fyn at the mRNA and protein level. Because it has previously been shown that Fyn positively regulates IP(3)-mediated calcium release by phosphorylating Type I IP(3) receptors (IP(3)R1), we investigated the effect of glucocorticoids on IP(3)R1 phosphorylation at Tyr353. Accordingly, glucocorticoid-mediated downregulation of Fyn prevented IP(3)R1 phosphorylation at Tyr353. Moreover, selective knockdown of Fyn or treatment with a Src inhibitor also attenuated IP(3)-mediated calcium release and induced autophagy. Collectively, these data indicate that glucocorticoids promote autophagy by inhibiting IP(3)-dependent calcium signals. These findings carry important therapeutic implications given the widespread use of dexamethasone as both a chemotherapeutic and immunosuppressive agent.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Harr
authors.forename: Karen S
authors.initials: KS
authors.lastname: McColl
authors.forename: Fei
authors.initials: F
authors.lastname: Zhong
authors.forename: Jason K
authors.initials: JK
authors.lastname: Molitoris
authors.forename: Clark W
authors.initials: CW
authors.lastname: Distelhorst
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D020013:Calcium Signaling / Q000187:drug effects*; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology
chemical_list: D005938:Glucocorticoids; D053496:Inositol 1,4,5-Trisphosphate Receptors; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D003907:Dexamethasone; D015544:Inositol 1,4,5-Trisphosphate; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn
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