407 Glucocorticoids suppress TLR2/1-induced inflammation while maintaining host defense responses in human macrophages

Abstract

Glucocorticoids, widely used to treat inflammatory conditions in medicine, critically regulate human host defense. In contrast to well-described anti-inflammatory and immune suppressive effects on acquired immunity, recent evidence suggests that glucocorticoids ready innate host defense. In this regard, glucocorticoids were shown to enhance expression of TLR2 on various human cell types. Given a central role of TLR2 in activating macrophage host defense against intracellular pathogens, we studied the effect of glucocorticoids on TLR2 expression and function in primary human macrophages. We found that glucocorticoids upregulated TLR2 mRNA expression, as well as cell surface expression, yet suppressed central components of the TLR signaling cascade. Moreover, glucocorticoids had a much stronger suppressive effect on the TLR2/1 induction of pro-inflammatory cytokines TNF-a and IL-12p40 than on anti-inflammatory IL-10, thereby shifting the macrophage cytokine production towards an anti-inflammatory pattern. At the same time, glucocorticoids did not affect TLR2/1-induced lysosome acidification and antimicrobial activity against intracellular mycobacteria in human macrophages. In summary, our data suggest that glucocorticoids suppress TLR2/1-induced inflammatory macrophage responses, while preserving TLR2-induced macrophage-mediated host defense programs against intracellular infection.