Induction of corticosteroid insensitivity in human PBMCs by microbial superantigens

Microbial superantigens have been described to contribute to the pathogenesis of chronic inflammatory diseases often complicated by insensitivity to glucocorticoid therapy. In bronchial asthma glucocorticoid insensitivity has been associated with increased expression of glucocorticoid receptor beta, an endogenous inhibitor of the classic glucocorticoid receptor alpha.

To study a potential mechanism by which superantigens could contribute to poor disease control, we examined their capacity to alter steroid sensitivity and expression of glucocorticoid receptor beta.

The capacity of dexamethasone to inhibit stimulation of PBMCs from 7 healthy subjects with the prototypic superantigens, staphylococcal enterotoxin (SE) B, toxic shock syndrome toxin (TSST)-1 and SEE, versus PHA, was tested. The expression of glucocorticoid receptor beta in normal PBMCs after stimulation with SEB, versus PHA, was assessed by immunocytochemistry.

Dexamethasone 10(-6) mol/L caused a 99% inhibition of PHA-induced PBMC proliferation but only a 19% inhibition of the SEB-induced, 26% inhibition of the TSST-1, and 29% inhibition of the SEE-induced PBMC proliferation (P <.01 for all superantigens versus PHA) demonstrating that superantigens can induce steroid insensitivity. Stimulation of normal PBMCs with SEB induced a significant increase of glucocorticoid receptor beta compared with PHA and unstimulated cells (P <.01).

We have demonstrated the capacity of microbial superantigens to induce glucocorticoid insensitivity, which should be considered in the diagnosis and treatment of patients with superantigen-triggered diseases. These data suggest that superantigens may contribute to glucocorticoid insensitivity through induction of glucocorticoid receptor beta.