Simvastatin promotes Th2-type responses through the induction of the chitinase family member Ym1 in dendritic cells

doi:10.1073/pnas.0508492103

Simvastatin promotes Th2-type responses through the induction of the chitinase family member Ym1 in dendritic cells

Departments of *Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine and
^§Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;
^†Institute of Immunology & Infection Research, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom; and
^‡Department of Pediatrics, Division of Hematology and Oncology, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15213

Edited by William E. Paul, National Institutes of Health, Bethesda, MD, and approved March 31, 2006 (received for review September 28, 2005)

Abstract

Statins, best known for their lipid-lowering actions, also possess immunomodulatory properties. Recent studies have shown a Th2-biasing 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 Th1 (IFN-γ) cytokine secretion from the T cells. The Th2-promoting effect of simvastatin was found to depend on the chitinase family member Ym1, known to be a lectin. Anti-Ym1 antibody abolished the Th2-promoting effect of simvastatin-treated DCs. Also, simvastatin was unable to augment Ym1 expression in DCs developed from STAT6^−/− or IL-4Rα^−/− mice. Thus, modulation of Ym1 production by DCs identifies a previously undescribed mechanism of Th2 polarization by statin.

Footnotes

^¶To whom correspondence should be addressed. E-mail: rayp{at}pitt.edu
Author contributions: A.R. and P.R. designed research; M.A., L.C., M.P., I.G., and Y.M.V. performed research; I.G. and J.E.A. contributed new reagents/analytic tools; M.A., M.P., A.R., and P.R. analyzed data; and M.A., A.R., and P.R. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviation:

DC,

dendritic cell.