Simvastatin Promotes Th2-Type Responses through the Induction of the Chitinase Family Member Ym1 in Dendritic Cells

Statins, best known for their lipid-lowering actions, also possess immunomodulatory properties. Recent studies have shown a Th2biasing effect of statins, although the underlying mechanism has not been identified. In this study, we investigated whether simvastatin can exercise a Th2-promoting effect through modulation of function of dendritic cells (DCs) without direct interaction with CD4+ T cells. Exposure of DCs to simvastatin induced the differentiation of a distinct subset of DCs characterized by a high expression of B220. These simvastatin-conditioned DCs up-regulated GATA-3 expression and down-regulated T-bet expression in cocultured CD4⁺ T cells in the absence of additional simvastatin added to the coculture. The Th2-biased transcription factor profile induced by simvastatin-treated DCs also was accompanied by increased Th2 (IL-4, IL-5, and IL-13) and decreased Thl (IFN-γ) cytokine secretion from the T cells. The Th2-promoting effect of simvastatin was found to depend on the chitinase family member Yml, known to be a lectin. Anti-Yml antibody abolished the Th2-promoting effect of simvastatin-treated DCs. Also, simvastatin was unable to augment Yml expression in DCs developed from STAT6⁻/⁻ or IL-4Rα⁻/⁻ mice. Thus, modulation of Yml production by DCs identifies a previously undescribed mechanism of Th2 polarization by statin.