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Statins increase the frequency of circulating CD4+ FOXP3+ regulatory T cells in healthy individuals.

Rodríguez-Perea AL, Montoya CJ, Olek S, Chougnet CA, Velilla PA - J Immunol Res (2015)

Bottom Line: We found that both statins significantly increased Treg frequency and FOXP3 mRNA levels at day 30.Therefore, statins appear to have inflammation-independent immune-modulatory effects.Thus, the increase in Treg cells frequency likely contributes to immunomodulatory effect of statins, even in healthy individuals.

View Article: PubMed Central - PubMed

Affiliation: Grupo Inmunovirología, Facultad de Medicina, Universidad de Antioquia (UdeA), Calle 70 No. 52-21, Medellín, Colombia.

ABSTRACT
Statins have been shown to modulate the number and the suppressive function of CD4(+)FOXP3(+) T cells (Treg) in inflammatory conditions. However, it is not well established whether statin could also affect Treg in absence of inflammation. To address this question, eighteen normocholesterolemic male subjects were treated with lovastatin or atorvastatin daily for 45 days. The frequency and phenotype of circulating Treg were evaluated at days 0, 7, 30, and 45. mRNA levels of FOXP3, IDO, TGF-β, and IL-10 were measured in CD4(+) T cells. We found that both statins significantly increased Treg frequency and FOXP3 mRNA levels at day 30. At day 45, Treg numbers returned to baseline values; however, TGF-β and FOXP3 mRNA levels remained high, accompanied by increased percentages of CTLA-4- and GITR-expressing Treg. Treg Ki-67 expression was decreased upon statin treatment. Treg frequency positively correlated with plasma levels of high-density lipoprotein cholesterol (HDL-c), suggesting a role for HDL-c in Treg homeostasis. Therefore, statins appear to have inflammation-independent immune-modulatory effects. Thus, the increase in Treg cells frequency likely contributes to immunomodulatory effect of statins, even in healthy individuals.

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Increase in the HDL levels correlated with Treg frequency. Correlation of HDL levels with the percentage of Treg in the individuals of the study. Spearman coefficient (r) and P values are shown in the graph.
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fig4: Increase in the HDL levels correlated with Treg frequency. Correlation of HDL levels with the percentage of Treg in the individuals of the study. Spearman coefficient (r) and P values are shown in the graph.

Mentions: Reduction of cardiovascular risk by statins has been associated not only with diminished LDL-c levels but also with increased serum HDL-c levels. In addition to reverse cholesterol transport from the peripheral organs to the liver, HDL-c, along with its main apolipoprotein (ApoA-1), plays an anti-inflammatory role [31]. Indeed, ApoA-I has recently been shown in a murine model to increase Treg frequency, leading to decreased autoimmune responses [32]. We also found an increase of HDL-c levels after treatment with statins, mainly at day 45 (Table 1). Interestingly, HDL-c levels positively correlated with Treg frequency (r = 0.3245, P = 0.0084, Figure 4). Since HDL-c levels are negatively correlated with the frequency of proinflammatory T cell subsets [33] and anti-inflammatory and immunomodulatory properties of HDL-c have been widely reported [34], our results thus suggest that HDL-c could regulate Treg homeostasis. Interestingly, Treg were recently shown to directly affect fat metabolism and consequently modulate blood lipid levels, by regulating lipoprotein catabolism. Indeed, Treg depletion in murine models led to increased levels of large, cholesterol-rich, VLDL particles, due to their reduced clearance, and this effect appeared independent of vascular inflammation [35]. Altogether, these findings suggest that statin-induced Treg could also be beneficial in the context of atherosclerosis, due to the Treg control of hepatic fat metabolism.


Statins increase the frequency of circulating CD4+ FOXP3+ regulatory T cells in healthy individuals.

Rodríguez-Perea AL, Montoya CJ, Olek S, Chougnet CA, Velilla PA - J Immunol Res (2015)

Increase in the HDL levels correlated with Treg frequency. Correlation of HDL levels with the percentage of Treg in the individuals of the study. Spearman coefficient (r) and P values are shown in the graph.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4352479&req=5

fig4: Increase in the HDL levels correlated with Treg frequency. Correlation of HDL levels with the percentage of Treg in the individuals of the study. Spearman coefficient (r) and P values are shown in the graph.
Mentions: Reduction of cardiovascular risk by statins has been associated not only with diminished LDL-c levels but also with increased serum HDL-c levels. In addition to reverse cholesterol transport from the peripheral organs to the liver, HDL-c, along with its main apolipoprotein (ApoA-1), plays an anti-inflammatory role [31]. Indeed, ApoA-I has recently been shown in a murine model to increase Treg frequency, leading to decreased autoimmune responses [32]. We also found an increase of HDL-c levels after treatment with statins, mainly at day 45 (Table 1). Interestingly, HDL-c levels positively correlated with Treg frequency (r = 0.3245, P = 0.0084, Figure 4). Since HDL-c levels are negatively correlated with the frequency of proinflammatory T cell subsets [33] and anti-inflammatory and immunomodulatory properties of HDL-c have been widely reported [34], our results thus suggest that HDL-c could regulate Treg homeostasis. Interestingly, Treg were recently shown to directly affect fat metabolism and consequently modulate blood lipid levels, by regulating lipoprotein catabolism. Indeed, Treg depletion in murine models led to increased levels of large, cholesterol-rich, VLDL particles, due to their reduced clearance, and this effect appeared independent of vascular inflammation [35]. Altogether, these findings suggest that statin-induced Treg could also be beneficial in the context of atherosclerosis, due to the Treg control of hepatic fat metabolism.

Bottom Line: We found that both statins significantly increased Treg frequency and FOXP3 mRNA levels at day 30.Therefore, statins appear to have inflammation-independent immune-modulatory effects.Thus, the increase in Treg cells frequency likely contributes to immunomodulatory effect of statins, even in healthy individuals.

View Article: PubMed Central - PubMed

Affiliation: Grupo Inmunovirología, Facultad de Medicina, Universidad de Antioquia (UdeA), Calle 70 No. 52-21, Medellín, Colombia.

ABSTRACT
Statins have been shown to modulate the number and the suppressive function of CD4(+)FOXP3(+) T cells (Treg) in inflammatory conditions. However, it is not well established whether statin could also affect Treg in absence of inflammation. To address this question, eighteen normocholesterolemic male subjects were treated with lovastatin or atorvastatin daily for 45 days. The frequency and phenotype of circulating Treg were evaluated at days 0, 7, 30, and 45. mRNA levels of FOXP3, IDO, TGF-β, and IL-10 were measured in CD4(+) T cells. We found that both statins significantly increased Treg frequency and FOXP3 mRNA levels at day 30. At day 45, Treg numbers returned to baseline values; however, TGF-β and FOXP3 mRNA levels remained high, accompanied by increased percentages of CTLA-4- and GITR-expressing Treg. Treg Ki-67 expression was decreased upon statin treatment. Treg frequency positively correlated with plasma levels of high-density lipoprotein cholesterol (HDL-c), suggesting a role for HDL-c in Treg homeostasis. Therefore, statins appear to have inflammation-independent immune-modulatory effects. Thus, the increase in Treg cells frequency likely contributes to immunomodulatory effect of statins, even in healthy individuals.

Show MeSH
Related in: MedlinePlus