Like Glucocorticoids (GCs), Mineralocorticoids (MCs) Inhibit Activation‐induced Apoptosis and Cytokine Production in Human Peripheral Blood T Lymphocytes

Abstract

Both lymphocyte apoptosis and cytokine production, somewhat paradoxically, have been linked to death from sepsis. Corticosteroids improve hypotension in septic shock, but have inconsistent effects on survival possibly due to adverse effects. Although better known for inducing thymocyte apoptosis, GC receptor (GR) agonists inhibit activation‐induced T‐cell death via repression of CD95 ligand. Closely related to GR, MC receptor (MR) is highly expressed in T‐cells and therefore may regulate T‐cell function. Dexamethasone (DEX), a GR agonist, and deoxycorticosterone (DOC), a MR agonist, were studied in human T‐cells. Both DEX and DOC dose‐dependently inhibited PHA‐induced T‐cell apoptosis as measured by caspase 3 and 9 activity and annexin V with propidium iodide flow cytometry. Preliminary experiments using staphylococcal enterotoxin B (a superantigen) to stimulate T cells showed similar results. DEX and DOC suppressed FasL and IL‐2, but not Fas mRNA and protein. Moreover, DEX and DOC inhibited NFκB‐ and AP1‐driven reporter assays in PHA/PMA‐stimulated Jurkat cells, consistent with a nuclear receptor trans‐repression mechanism. MR, like GR can inhibit apoptosis and inflammatory responses in activated human T‐cells. MR agonists and antagonists may be useful for modulating T‐cell apoptosis and function in sepsis and other states of immune hyperactivity. Research Support: intramural NIH