Glucocorticoids Suppress Activation of Mast Cells through induction of Inhibitory Regulators of Signaling Pathways (94.13)

Abstract

Abstract Glucocorticoids suppress production of inflammatory cytokines via the glucocorticoid receptor (GR) by inhibiting activity of relevant transcription factors, a process known as transrepression. Here we provide evidence that dexamethasone and other glucocorticoids also suppress activation of mast cells through induction of synthesis of inhibitory regulators of signaling pathways by a process referred to as transactivation. The glucocorticoid-inducible regulators identified so far include Src-like adaptor protein (SLAP), downstream of tyrosine kinase (Dok)-1, MAP kinase phosphatase-1 (MPK-1) (Mol. Pharmacol. 67:598, 2005; J. Immunology 177:2047, 2006),. Suppressor of cytokine signaling 1 (Socs1), and cytokine inducible SH2-containing protein (Cish) (unpublished data). We have found that the induction of these inhibitory regulators account for the inhibition of key antigen-mediated signaling events such as the activation of the tyrosine kinase Syk, MAP kinase pathways, and downstream transcription factors. The effects of overexpressed wild type GR, and a dimerization-negative mutant GR with minimal transactivation activity, further suggest that the inhibitory actions of glucocorticoids are dependent on gene transactivation as well as cytokine-gene transrepression. These findings have important implications in the design and use of glucocorticoids that exhibit selectivity towards transrepression.