Limits...
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.

Show MeSH

Related in: MedlinePlus

Statins increase the frequency of CD4+FOXP3+ Treg and mRNA FOXP3. The frequency (a) and absolute number (b) of CD4+FOXP3+ cells were evaluated by flow cytometry. Methylation percentage in the Treg cell-specific-demethylated-region (TSDR) of FOXP3 gene, in DNA of PBMC from individuals before treatment and 30 days after ongoing treatment, is shown (c). FOXP3 mRNA expression relative to UBC housekeeping gene (d). Median, interquartile range (IQR), and P values are shown in the graph; difference between days was tested by Wilcoxon signed-rank test.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4352479&req=5

fig1: Statins increase the frequency of CD4+FOXP3+ Treg and mRNA FOXP3. The frequency (a) and absolute number (b) of CD4+FOXP3+ cells were evaluated by flow cytometry. Methylation percentage in the Treg cell-specific-demethylated-region (TSDR) of FOXP3 gene, in DNA of PBMC from individuals before treatment and 30 days after ongoing treatment, is shown (c). FOXP3 mRNA expression relative to UBC housekeeping gene (d). Median, interquartile range (IQR), and P values are shown in the graph; difference between days was tested by Wilcoxon signed-rank test.

Mentions: At day 30, statin treatment significantly increased the percentages of FOXP3+ cells within the CD4+ population, compared to baseline (P = 0.04, Figure 1(a)). Statins also increased absolute numbers of CD4+ T cells (1148 cells/μL versus 959 cells/μL, P = 0.007). In consequence, statins also increased Treg absolute numbers (P = 0.002, Figure 1(b)) at day 30, compared with day 0. These data are in agreement with previous studies showing that CD4+CD25high T cells or CD4+CD25+FOXP3+ T cell frequency increases upon statin treatment in patients with inflammatory conditions [9, 10]. Interestingly, at day 45 of treatment, the peripheral Treg population returned to baseline numbers (Figures 1(a)-1(b)). A potential mechanism for this finding is that statins can modulate the expression of several chemokines and cell adhesion receptors by targeting the prenylation of small GTPases [21]. Such modulation might promote Treg migration to tissues [22]. Future studies will be needed to clarify this important issue.


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)

Statins increase the frequency of CD4+FOXP3+ Treg and mRNA FOXP3. The frequency (a) and absolute number (b) of CD4+FOXP3+ cells were evaluated by flow cytometry. Methylation percentage in the Treg cell-specific-demethylated-region (TSDR) of FOXP3 gene, in DNA of PBMC from individuals before treatment and 30 days after ongoing treatment, is shown (c). FOXP3 mRNA expression relative to UBC housekeeping gene (d). Median, interquartile range (IQR), and P values are shown in the graph; difference between days was tested by Wilcoxon signed-rank test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Statins increase the frequency of CD4+FOXP3+ Treg and mRNA FOXP3. The frequency (a) and absolute number (b) of CD4+FOXP3+ cells were evaluated by flow cytometry. Methylation percentage in the Treg cell-specific-demethylated-region (TSDR) of FOXP3 gene, in DNA of PBMC from individuals before treatment and 30 days after ongoing treatment, is shown (c). FOXP3 mRNA expression relative to UBC housekeeping gene (d). Median, interquartile range (IQR), and P values are shown in the graph; difference between days was tested by Wilcoxon signed-rank test.
Mentions: At day 30, statin treatment significantly increased the percentages of FOXP3+ cells within the CD4+ population, compared to baseline (P = 0.04, Figure 1(a)). Statins also increased absolute numbers of CD4+ T cells (1148 cells/μL versus 959 cells/μL, P = 0.007). In consequence, statins also increased Treg absolute numbers (P = 0.002, Figure 1(b)) at day 30, compared with day 0. These data are in agreement with previous studies showing that CD4+CD25high T cells or CD4+CD25+FOXP3+ T cell frequency increases upon statin treatment in patients with inflammatory conditions [9, 10]. Interestingly, at day 45 of treatment, the peripheral Treg population returned to baseline numbers (Figures 1(a)-1(b)). A potential mechanism for this finding is that statins can modulate the expression of several chemokines and cell adhesion receptors by targeting the prenylation of small GTPases [21]. Such modulation might promote Treg migration to tissues [22]. Future studies will be needed to clarify this important issue.

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