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Proc Natl Acad Sci U S A. May 16, 2006; 103(20): 7777–7782.
Published online May 8, 2006. doi:  10.1073/pnas.0508492103
PMCID: PMC1472521

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 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.

Keywords: statin, T cells, IL-4Rα, STAT6, GATA-3

Dendritic cells (DCs) are professional antigen-presenting cells that have the ability to stimulate naïve T cells and initiate a primary immune response. DCs also play a critical role in mediating the differentiation of CD4+ T cells into Th1- and Th2-polarized subsets (1). T cell differentiation along the Th1 lineage is regulated by specific transcription factors such as T-bet, which plays an essential role in IFN-γ production (2). The master regulator of Th2 differentiation is GATA-3 as we and others described in refs. 37.

Statins are the most potent cholesterol-lowering drugs that target the enzyme 3-hydroxy-3-methyl-gutaryl-CoA reductase (8). Recent in vitro findings indicate that statins also have potent immunoregulatory activity (9). These new effects of statins have been described as potential treatment options against autoimmune diseases (1012). Oral administration of atorvastatin prevented paralysis in mice via suppression of Th1 and augmentation of Th2 responses in a study of experimental autoimmune encephalomyelitis (11). There are likely to be several molecular mechanisms through which statins exert their immunomodulatory effects (13), but these mechanisms have yet to be elucidated. Recent studies have suggested that the Th2-biasing effects of statins may be induced via direct effects of statins on T cells (14) and antigen-presenting cells (11, 14, 15). However, whether statins can indeed promote Th2 differentiation via direct effects on antigen-presenting cells has not been shown. Because DCs are the key antigen-presenting cells that activate naïve T cells (16), we addressed the influence of simvastatin on the differentiation and function of DCs. We show that simvastatin has a direct effect on DC function, which instructs DCs to drive T cell differentiation toward the Th2 lineage. Treatment of DCs with simvastatin up-regulated expression of the molecule Ym1 on DCs. Ym1 is a member of a family of mammalian proteins that share homology to chitinases of lower organisms (17, 18). Chitinases have been recently associated with the development of allergic airways disease (19). Ym1 does not have enzyme activity but has been characterized as a lectin with specific binding affinity for heparin/heparan sulfate (18). Antibody-mediated neutralization of Ym1 abolishes the Th2-polarizing effect of simvastatin-treated DCs. Also, DCs generated from STAT6−/− mice or IL-4Rα−/− mice failed to up-regulate Ym1 production upon simvastatin treatment. Our studies show that simvastatin-induced augmentation of Th2 responses depends on Ym1 production by DCs, which requires the IL-4Rα/STAT6 signaling axis.

Results and Discussion

Simvastatin Induces High Expression of B220.

To determine the effect of simvastatin on DCs, bone marrow cells were cultured with granulocyte/macrophage colony-stimulating factor for 6 days, followed by purification of CD11c+ cells (>95% purity). Phenotypically, the CD11c+ cells were essentially B220 (Fig. 1A). The CD11c+ DCs then were grown in the presence or absence of 1 μM simvastatin for 2 days, and multicolor flow cytometric analysis was performed. Simvastatin treatment was found to induce the differentiation of a distinct subset of DCs characterized by high expression of B220 (Fig. 1A). The control DCs and simvastatin-treated DCs displayed typical DC-type morphology, as observed by light and electron microscopy (Fig. 1B). Although the control DCs adhered well to glass, the simvastatin-treated DCs adhered less well and were somewhat rounder. Overall, the morphology of the simvastatin-treated DCs was similar to the description of murine and human pDCs as we and others have described (ref. 20; Fig. 1B).

Fig. 1.
Phenotype and morphology of simvastatin-treated DCs. (A) Bone marrow progenitors were grown in the presence of granulocyte/macrophage colony-stimulating factor (10 ng/ml) for 6 days, and CD11c+ DCs were purified. CD11c+ DCs were cultured further in the ...

To further characterize the different DC subsets, the expression of additional cell surface molecules was examined. DCs generated in the presence or absence of simvastatin expressed high levels of CD11b and DEC-205 but no Gr1 or CD19 (Fig. 1C). Importantly, the B220+ DCs were not B cells because they lacked the lineage marker for B cells, CD19. These phenotypic characteristics clearly showed that the DCs that developed in the presence of simvastatin were different from classical CD11chi DCs or CD11cloB220hi plasmacytoid DCs.

We then examined the effect of different doses of simvastatin on the expression of B220 on DCs. B220 expression was augmented by simvastatin in a dose-dependent fashion leveling off at a dose of 5 μM (Fig. 1D). This up-regulation of B220 was confirmed to be a statin-specific effect, because it could be reversed by the addition of mevalonate (Fig. 1D).

To address whether simvastatin treatment affects DC viability, DCs were cultured with different concentrations of simvastatin, and cell death was determined by using propidium iodide. Simvastatin treatment did not induce cell death in DCs at lower doses (1 μM), but appreciable cell death was observed at higher doses of simvastatin (10 μM) (data not shown). Therefore, all further experiments were performed by using 1 μM simvastain.

Simvastatin Promotes Th2 Development and Inhibits Th1 Development in Vitro.

DCs are instrumental in the differentiation of naïve T cells into Th1 or Th2 effector cells. To determine whether CD4+ T cells respond differently to simvastatin-treated DCs, naïve CD4 T cells from DO11.10 TCR transgenic mice were incubated with control or simvastatin-treated DCs for 5 days in the presence of OVA peptide, which is specific for the DO.11 TCR, and without further addition of statin. The simvastatin-treated DCs were extensively washed before coculture to remove any adhering statin. At the end of the 5-day culture period, supernatants were harvested for estimation of cytokine production, and nuclear extracts were prepared from the cells to investigate the expression of the transcription factors T-bet, which is Th1-specific (21), and GATA-3, which is Th2-specific (3, 4). As shown in Fig. 2, as expected, untreated DCs induced T cells to secrete a mixture of both Th1-type (IFN-γ) and Th2-type cytokines (IL-4, IL-5, and IL-13). When CD4+ T cells were cocultured with simvastatin-treated DCs, production of Th2 cytokines was augmented, whereas IFN-γ secretion was inhibited (Fig. 2A). The cytokine secretion profile correlated with increased expression of GATA-3 and decreased expression of T-bet by the T cells cultured with simvastatin-treated DCs. Used as a negative control, incubation of either DC type with T cells in the absence of antigenic peptide gave no detectable response (data not shown). Because Th1 cells are more prone to apoptosis compared with Th2 cells, we also investigated T cell proliferation. Simvastatin-pretreated DCs were found to be as efficient as control DCs in inducing proliferation of antigen-specific or allogeneic (data not shown) T cells (Fig. 2C). Taken together, our results demonstrate that pretreatment of DCs with simvastatin alters DC function that, in turn, influences T cell differentiation.

Fig. 2.
DCs treated with simvastatin polarize naïve CD4+ T cells toward the Th2 phenotype in vitro. (A) DCs were treated with simvastatin (1 μM) or left untreated for 2 days. Cells were then washed and cultured with naïve DO11.10 CD4+ ...

The impact of DCs on T cell polarization is influenced by many factors, including the specific DC subset, the activation status of DCs, and the cytokine microenvironment. Because some studies suggest a role for the costimulatory molecules CD80 and CD86 in T cell polarization, we investigated whether simvastatin modulated expression of these molecules on DCs. As reported in ref. 14, simvastatin treatment did not impact the expression of these molecules on DCs (Fig. 3A). Simvastatin pretreatment did not modulate CD40 expression either, which is important for Th1 polarization (Fig. 3A). Analysis of other DC cell surface molecules such as OX40L, ICOSL, and ICAM-1, which are known to influence Th polarization, also was not modulated by simvastatin (data not shown). As reported, when using lovastatin (22), simvastatin-treated DCs were found to have a similar ability as control DCs to endocytose antigen (Fig. 6, which is published as supporting information on the PNAS web site).

Fig. 3.
(A) Effect of simvastatin on the expression of costimulatory molecules on DCs. Thin lines indicate staining with isotype controls. (B) Addition of IFN-γ did not reverse Th2 polarization induced by simvastatin-treated DCs. Although IFN-γ ...

T helper differentiation is largely determined by the cytokine microenvironment, and Th1 and Th2 cytokines are known to cross-regulate each other (7). For example, although IL-4 promotes Th2 differentiation but inhibits Th1 differentiation, IFN-γ promotes Th1 differentiation but inhibits Th2 differentiation (7). In this context, GATA-3 and T-bet, as well as STATs, play an important role in cross-regulation between Th1 and Th2 cells. Because IL-12 produced by antigen-presenting cells promotes Th1 differentiation, we assessed the level of IL-12p70 and IL-12p40 in culture supernatants of simvastatin-treated and control DCs. Although IL-12p70 was low in either supernatant, IL-12p40 was readily detectable, but its secretion was lower from simvastatin-treated DCs (Fig. 7, which is published as supporting information on the PNAS web site). Inhibition of p40 induction by simvastatins, in turn, would inhibit IL-12 production by DCs that would down-regulate IFN-γ production by T cells. We next investigated whether inhibition of IFN-γ production by simvastatin-treated DCs played a role in the promotion of Th2 development. Toward this end, simvastatin-treated DCs were cocultured with DO.11 T cells and antigen in the presence or absence of recombinant IFN-γ. Although addition of IFN-γ enhanced T-bet expression in the CD4+ T cells, it did not inhibit GATA-3 expression, even at the higher dose of the cytokine (250 units/ml). In fact, for reasons presently unclear, IL-13 secretion was greater at the higher dose of IFN-γ. These results suggested that the increase in Th2 differentiation by simvastatin-treated DCs was a dominant Th2-skewing effect of the DCs that was not subject to inhibition by IFN-γ.

We examined whether the Th2-skewing effect of simvastatin-treated DCs was subject to inhibition by IL-12. As shown in Fig. 3C, both GATA-3 expression and Th2-cytokine production were significantly reduced in the presence of IL-12 in a dose-dependent fashion. Thus, statin is unable to stimulate DCs to induce Th2 skewing in the presence of IL-12. Collectively, our data suggest that IL-12-induced signaling pathways, such as STAT4 but not IFN-γ-induced pathways (such as STAT1), block the ability of statin to promote Th2 differentiation.

Ym-1 Induces the Development of Th2-Type Responses.

To further elucidate the mechanism underlying Th2 polarization by simvastatin, we performed microarray analysis of RNA samples isolated from DCs cultured with or without simvastatin. RNA was hybridized to Codelink Uniset Mouse Expression Bioarray (GE Healthcare), which identifies 10,012 unique murine genes. RNA was isolated from the two sets of DCs in three independent experiments. For data analysis, scoregene (23) was used for comparisons between the processed arrays and for calculating fold change in transcript levels of genes by using various statistical methods. The genes whose expression was consistently increased or decreased were selected and were further filtered based on Student’s t test. The microarray analysis identified 408 genes that were either significantly repressed or induced by simvastatin (P < 0.05). Interestingly, the Ym1 gene, which was previously shown to be up-regulated by Th2 cytokines in macrophages (24), was up-regulated by simvastatin treatment. Increased expression of Ym1 at the protein level in simvastatin-treated DCs was confirmed by immunoblot analysis of cell lysates by using an anti-Ym1 antibody (Fig. 4). In previous studies, stimulation of bone marrow-derived DCs with IL-4 was shown to induce Ym1 expression (25). Because Ym1 is known to be a secreted protein (24, 25), we also checked the level of Ym1 in the culture supernatants by immunoblotting techniques. As expected from our analysis of cell lysates, a higher level of Ym1 was detected in the culture supernatant of simvastatin-treated DCs. To determine whether Ym1 is expressed on the DC plasma membrane in addition to being secreted by DCs, we performed immunofluorescence studies. As shown in Fig. 8, which is published as supporting information on the PNAS web site, Ym1 does not appear to be expressed on the DC plasma membrane. Ym1 has been shown to be induced in macrophages in a STAT6-dependent manner (26). Therefore, we investigated Ym1 induction by simvastatin in STAT6-deficient DCs. The induction of Ym1 appeared to be strictly regulated by STAT6, because we did not detect any secretion of Ym1 in the absence of STAT6 (Fig. 4). Because multiple groups have shown that Ym1 is up-regulated by the Th2 cytokines IL-4 and IL-13 (24, 26), we further investigated whether the absence of Ym1 influences the Th2-inducing ability of statin-treated DCs. Statin-treatment of STAT6-deficient DCs did not enhance IL-13 production in CD4+ T cells, suggesting that Ym1 might play an important role in the ability of simvastatin-pretreated DCs to promote Th2 polarization. Activation of STAT6 is downstream of IL-4/IL-13 signaling mediated by the common IL-4Rα subunit in the IL-4 and IL-13 receptor complexes. To investigate the involvement of IL-4Rα in Ym1 up-regulation by statin, IL-4Rα-deficient DCs were treated with statin and analyzed for Ym1 production. As shown in Fig. 4C, no Ym1 was detected from the DCs lacking IL-4Rα, indicating that simvastatin does require IL-4Rα to up-regulate Ym1. Also, similar to STAT6-deficient DCs, DCs lacking IL-4Rα did not promote Th2 differentiation upon simvastatin treatment (Fig. 4C). Because both IL-4Rα and STAT6 participate in signaling by IL-4 and IL-13 and DCs do not produce either IL-4 or IL-13, we examined Ym1 induction by simvastatin in the presence of neutralizing anti-IL-4 or anti-IL-13 antibody to exclude the possibility of any IL-4 or IL-13 contamination in our cultures. As shown in Fig. 4D, the level of simvastatin-induced Ym1 did not change in the presence of either of the neutralizing antibodies. It is unclear how statin utilizes the IL-4Rα/STAT6 axis for up-regulation of Ym1 expression, and it will be interesting to see possible effects of statins on positive (JAKs) and negative regulators (SOCS and SHP-1) of STAT6.

Fig. 4.
Increased STAT6-dependent Ym1 expression in DCs treated with simvastatin. Cell lysates (A) and culture supernatants (B) of control and simvastatin-treated DCs were subjected to immunoblotting with anti-Ym1 antibody. The experiment was repeated three times ...

Because Ym1 is a secreted molecule and the effect of simvastatin on Th2 polarization is detected even after washing off any adhering statin from the DCs, we investigated whether simvastatin-treated DCs continue to make Ym1, even after removal of statin from the culture. DCs were treated with simvastatin for 2 days, extensively washed to remove statin, and then cultured for another 3 days in the absence of statin. Ym1 expression then was examined in the cell lysates. A high level of Ym1 still was observed in these DCs as compared with a low, but detectable, basal level of Ym1 in the untreated cells (Fig. 4E).

To further confirm a direct association between Ym1 up-regulation by simvastatin and the observed Th2-promoting effect of the statin-treated DCs, different doses of the anti-Ym1 antibody were added to DC-T cell cocultures. As shown in Fig. 5A and B, both GATA-3 expression and Th2 cytokine production were reduced significantly in the presence of anti-Ym1 but not control antibody in the cocultures. These data indicate that Ym1 plays an important role in the ability of simvastatin-pretreated DCs to promote Th2 polarization and provides a mechanism for the observed Th2 skewing of T cells by simvastatin-treated DCs.

Fig. 5.
Anti-Ym1 antibody reverses the ability of DCs treated with simvastatin to drive Th2 polarization. Bone marrow DCs were treated with simvastatin for 2 days and then cocultured with CD4+ T cells from DO11.10 mice in the presence of different doses of anti-Ym1 ...

To determine whether Ym1 up-regulation by simvastatin-pretreated DCs is the mechanism by which DCs polarize naïve T cells toward Th2, irrespective of the source/origin of DCs, we cocultured simvastatin-treated splenic DCs with naïve T cells. Similar to bone marrow DCs, splenic DCs also enhanced Th2 development upon simvastatin treatment. Splenic DCs then were cocultured with naïve T cells in the presence of a anti-Ym1 or control antibody. Addition of anti-Ym1 to the cultures completely abrogated the development of Th2 cells in a dose-dependent manner (Fig. 5 C and D).

Because the concentration of statin used in our study corresponds to therapeutic doses (1–10 μM), we were curious whether our in vitro results might reflect similar effects of simvastatin in vivo. Mice were fed a diet containing simvastatin for 4 weeks, and expression of Ym1 in lung DCs and the effect of these DCs, in turn, on CD4+ T cells were studied. The results of this experiment (Fig. 9, which is published as supporting information on the PNAS web site) support a Th2-promoting effect of simvastatin in vivo. It would be important to determine whether statin intake over a longer period further consolidates the Th2 response.

In summary, we have shown that simvastatin instructs DCs to drive T cell differentiation toward the Th2 lineage. Our studies provide a mechanism for the recently described Th2-promoting effects of statins (11) via up-regulation of Ym1 production by DCs. Although Ym1 expression has been shown to be induced by Th2 cytokines in macrophages and DCs (2426), we show that Ym1 produced by DCs also exerts effects on T cells to promote Th2 differentiation. Interestingly, 10% of transcripts induced in macrophages by helminths encode Ym1 (27), and these macrophages promote Th2 differentiation (28). Ym1 is a lectin with heparin-binding characteristics (18). T cell differentiation is regulated at many levels by many factors (6, 7, 2931). Although heparan sulfate proteoglycan expressed by T cells has been associated with cytokine and chemokine binding to T cells and with cell adhesion (32, 33), its role in T cell differentiation is presently unclear. It will be interesting to see whether the Th2-inducing property of Ym1, as identified in this study, is mediated by interactions with heparan sulfate expressed on T cells.

Materials and Methods

Animals and Reagents.

Male 6- to 8-week-old BALB/c mice, STAT-6−/− mice, and IL-4Rα−/− mice were purchased from The Jackson Laboratory. DO11.10 T cell TCR-transgenic mice were bred and maintained in the Department of Laboratory Animal Resources at the University of Pittsburgh. All studies with animals were approved by the Institutional Animal Care and Use Committee.

Recombinant granulocyte/macrophage colony-stimulating factor was purchased from PeproTech (Rocky Hill, NJ). Mevalonate was obtained from Sigma. Simvastatin was a gift from Merck. Antibodies were purchased from BD Biosciences and Southern Biotech (Birmingham, AL). Anti-Ym1 was generated as described in ref. 25. Anti-DEC-205 (biotin) was a gift of Dr. Robert Hendricks (University of Pittsburgh).

Bone Marrow-Derived Dendritic Cell Generation.

Femurs of mice were aseptically removed and cleared from surrounding muscle. Bone marrow cells were isolated by flushing femurs, and the cells were grown in a medium supplemented with 10 ng/ml granulocyte/macrophage colony-stimulating factor. At day 6, nonadherent cells were collected, and CD11c+ cells were purified by positive selection with MACS CD11c microbeads (Miltenyi Biotec, Auburn, CA) according to the manufacturer’s instructions.

Isolation and Purification of Spleen Dendritic Cells.

Spleen DCs were isolated by minor modifications of ref. 34; see also Supporting Methods, which is published as supporting information on the PNAS web site).

Phenotypic Evaluation of DCs.

Cell surface-antigen expression on DCs was evaluated by flow cytometry as described in ref. 20.

Light and Scanning Electron Microscopy.

For light microscopy, cytospin preparations of cells were used. Cells were stained with Hema-3 reagents (Fisher Scientific). For scanning electron microscopy, cells were allowed to settle onto glass coverslips in PBS for 1 h at 37°C, fixed, and analyzed as described in ref. 20.

T Cell Proliferation Assay.

CD4+ T cells were isolated by positive selection and cocultured with γ-irradiated DCs. After 72 h, the cultures were pulsed with 1;Ci [3H]thymidine (1 Ci = 37 GBq) for 16 h before harvesting.

Preparation of Nuclear Extracts and Immunoblot Analysis.

Nuclear extracts were prepared as described in ref. 3 and analyzed by immunoblotting techniques.

Cytokine Assays.

Cytokine concentrations were measured by ELISA with commercially available kits for IL-4, IL-5, IFN-γ, and IL-10 (R & D Systems).

RNA Isolation, Microarray, and Data Analysis.

Total RNA was isolated from DCs incubated with or without simvastatin and was used to probe Codelink arrays. Probe synthesis and hybridization were performed, and the hybridized chip was scanned by using GenePix 400 B array scanner. The scanned images were analyzed by using different statistical methods.

Statistical Analysis.

All results are expressed as the mean ± SEM. Student’s t tests were performed, and differences between the groups were considered significant if P < 0.05.

Supplementary Material

Supporting Information:


We thank members of the Center for Biologic Imaging at the University of Pittsburgh for help with electron microscopy, M. Yarlagadda for technical assistance, T. Richards and N. Kaminski for help with microarray analysis, and Winifred Huang for assistance with fluorescence microscopy. This work was supported by National Institutes of Health Grants R01 HL60207, R01 HL69810, R01 HL77430, and R01 AI48927 and a grant from the Wellcome Trust.


dendritic cell.


Conflict of interest statement: No conflicts declared.

This paper was submitted directly (Track II) to the PNAS office.


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