title: Superantigen-induced steroid resistance depends on activation of phospholipase Cβ2.
abstract: The glucocorticoid receptor is present in a TCR-associated complex, which includes the Src family tyrosine kinase Lck. Glucocorticoids rapidly dissociate this complex, resulting in the inhibition of canonical Lck-phospholipase C (PLC)γ-dependent TCR signaling. The relative importance of this nongenomic role for the glucocorticoid receptor compared with its direct transcriptional effects is not known. Superantigens induce a state of steroid resistance in activated T cells. It was reported that, in addition to canonical Lck-PLCγ signaling, superantigens can activate a noncanonical G protein-PLCβ-dependent signaling pathway. In this study, we show that staphylococcal enterotoxin B activates a Gαq and PLCβ2-dependent pathway in human T cells. We find that this pathway bypasses the need for canonical Lck-PLCγ signaling in T cell activation and renders superantigen-stimulated T cells insensitive to glucocorticoids in vitro. We show that the PLCβ inhibitor U-73122 sensitizes staphylococcal enterotoxin B-treated mice to dexamethasone in vivo. In conclusion, we find that effects of glucocorticoids on TCR-induced T cell proliferation are mainly nongenomic and can be bypassed by the activation of an Lck-independent signaling pathway.
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2300RC Leiden, The Netherlands.
authors.forename: Auke P
authors.initials: AP
authors.lastname: Verhaar
authors.forename: Manon E
authors.initials: ME
authors.lastname: Wildenberg
authors.forename: Marjolijn
authors.initials: M
authors.lastname: Duijvestein
authors.forename: Anne Christine W
authors.initials: AC
authors.lastname: Vos
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.forename: Mark
authors.initials: M
authors.lastname: Löwenberg
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Hommes
authors.forename: Gijs R
authors.initials: GR
authors.lastname: van den Brink
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D054799:Phospholipase C beta / Q000276:immunology / Q000378:metabolism*; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D018089:Superantigens / Q000276:immunology*; D014162:Transfection
chemical_list: D005938:Glucocorticoids; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D018089:Superantigens; D003907:Dexamethasone; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D054799:Phospholipase C beta