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. Copyright

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Journal Journal of Immunology
Verhaar, A.P, Wildenberg, M.E, Duijvestein, M, Vos, A.C.W, Peppelenbosch, M.P, Löwenberg, M, … van den Brink, G.R. (2013). Superantigen-induced steroid resistance depends on activation of phospholipase Cβ2. Journal of Immunology, 190(12), 6589–6595. doi:10.4049/jimmunol.1202898