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

Meenakshi Arora; Li Chen; Melissa Paglia; Iain Gallagher; Judith E Allen; Yatin M Vyas; Anuradha Ray; Prabir Ray

doi:10.1073/pnas.0508492103

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

Meenakshi Arora, Li Chen, Melissa Paglia, Iain Gallagher, Judith E Allen, Yatin M Vyas, Anuradha Ray, Prabir Ray

Research output: Contribution to journal › Article › peer-review

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-gamma) 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-4R alpha-/- mice. Thus, modulation of Ym1 production by DCs identifies a previously undescribed mechanism of Th2 polarization by statin.

Original language	English
Pages (from-to)	7777-82
Number of pages	6
Journal	Proceedings of the National Academy of Sciences (PNAS)
Volume	103
Issue number	20
DOIs	https://doi.org/10.1073/pnas.0508492103
Publication status	Published - 2006

Keywords / Materials (for Non-textual outputs)

Animals
Antigens, CD45
Bone Marrow Cells
Cell Shape
Cells, Cultured
Coculture Techniques
Dendritic Cells
GATA3 Transcription Factor
Humans
Hypolipidemic Agents
Interferon-gamma
Lectins
Lymphocyte Subsets
Male
Mice
Mice, Inbred BALB C
Mice, Knockout
Phenotype
Receptors, Cell Surface
STAT6 Transcription Factor
Simvastatin
Th1 Cells
Th2 Cells
beta-N-Acetylhexosaminidases

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10.1073/pnas.0508492103

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

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-gamma) 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-4R alpha-/- mice. Thus, modulation of Ym1 production by DCs identifies a previously undescribed mechanism of Th2 polarization by statin.",

keywords = "Animals, Antigens, CD45, Bone Marrow Cells, Cell Shape, Cells, Cultured, Coculture Techniques, Dendritic Cells, GATA3 Transcription Factor, Humans, Hypolipidemic Agents, Interferon-gamma, Lectins, Lymphocyte Subsets, Male, Mice, Mice, Inbred BALB C, Mice, Knockout, Phenotype, Receptors, Cell Surface, STAT6 Transcription Factor, Simvastatin, Th1 Cells, Th2 Cells, beta-N-Acetylhexosaminidases",

author = "Meenakshi Arora and Li Chen and Melissa Paglia and Iain Gallagher and Allen, \{Judith E\} and Vyas, \{Yatin M\} and Anuradha Ray and Prabir Ray",

year = "2006",

doi = "10.1073/pnas.0508492103",

language = "English",

volume = "103",

pages = "7777--82",

journal = "Proceedings of the National Academy of Sciences (PNAS)",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "20",

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TY - JOUR

T1 - Simvastatin promotes Th2-type responses through the induction of the chitinase family member Ym1 in dendritic cells

AU - Arora, Meenakshi

AU - Chen, Li

AU - Paglia, Melissa

AU - Gallagher, Iain

AU - Allen, Judith E

AU - Vyas, Yatin M

AU - Ray, Anuradha

AU - Ray, Prabir

PY - 2006

Y1 - 2006

N2 - 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-gamma) 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-4R alpha-/- mice. Thus, modulation of Ym1 production by DCs identifies a previously undescribed mechanism of Th2 polarization by statin.

AB - 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-gamma) 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-4R alpha-/- mice. Thus, modulation of Ym1 production by DCs identifies a previously undescribed mechanism of Th2 polarization by statin.

KW - Animals

KW - Antigens, CD45

KW - Bone Marrow Cells

KW - Cell Shape

KW - Cells, Cultured

KW - Coculture Techniques

KW - Dendritic Cells

KW - GATA3 Transcription Factor

KW - Humans

KW - Hypolipidemic Agents

KW - Interferon-gamma

KW - Lectins

KW - Lymphocyte Subsets

KW - Male

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Knockout

KW - Phenotype

KW - Receptors, Cell Surface

KW - STAT6 Transcription Factor

KW - Simvastatin

KW - Th1 Cells

KW - Th2 Cells

KW - beta-N-Acetylhexosaminidases

U2 - 10.1073/pnas.0508492103

DO - 10.1073/pnas.0508492103

M3 - Article

C2 - 16682645

SN - 0027-8424

VL - 103

SP - 7777

EP - 7782

JO - Proceedings of the National Academy of Sciences (PNAS)

JF - Proceedings of the National Academy of Sciences (PNAS)

IS - 20

ER -

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

Abstract

Keywords / Materials (for Non-textual outputs)

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