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. 2013 Dec 5;8(12):e82717.
doi: 10.1371/journal.pone.0082717. eCollection 2013.

High transcript levels of vitamin D receptor are correlated with higher mRNA expression of human beta defensins and IL-10 in mucosa of HIV-1-exposed seronegative individuals

Wbeimar Aguilar-Jiménez  1 , Wildeman Zapata  2 , Antonio Caruz  3 , María T Rugeles  1
Affiliations

High transcript levels of vitamin D receptor are correlated with higher mRNA expression of human beta defensins and IL-10 in mucosa of HIV-1-exposed seronegative individuals

Wbeimar Aguilar-Jiménez et al. PLoS One. .

Abstract

Vitamin D (VitD) is an endogenous immunomodulator that could protect from HIV-1 infection reducing immune activation and inducing the expression of anti-HIV-1 peptides. To establish a correlation between VitD and natural resistance to HIV-1 infection, a case-control study using blood and mucosa samples of 58 HIV-1-exposed but seronegative (HESN) individuals, 43 HIV-1 seropositives (SPs) and 59 non-exposed healthy controls (HCs) was carried out. The VitD concentration in plasma was determined by ELISA, and mRNA relative units (RU) of VDR, IL-10, TGF-β, TNF-α and IL-1β in peripheral blood mononuclear cells (PBMCs), oral and genital mucosa was quantified by qRT-PCR. mRNA levels of human beta-defensin (HBD) -2 and -3 were previously reported and used for correlations. Significantly higher levels of VitD were found in plasma as well as higher mRNA RU of VDR in PBMCs, and in genital mucosa from HESN compared to HCs. In addition, higher mRNA RU of TNF-α, IL-1β and IL-10, and lower mRNA RU of TGF-β were found in PBMC from HESNs compared to HCs. We also observed higher IL-10 mRNA RU in genital mucosa of HESNs compared to HCs, and the mRNA levels of TNF-α in oral and genital mucosa of SPs were higher compared to HESNs. Furthermore, positive correlations between VDR and IL-10 mRNA RU in PBMCs and genital mucosa of HESNs were found. Finally, HBD-2 and HBD-3 mRNA RU were positively correlated with VDR mRNA expression in oral mucosa from HESNs. These results suggest that high levels of VitD and its receptor are associated with natural resistance to HIV-1 infection. Up-regulation of the anti-inflammatory IL-10, and the induction of anti-HIV-1 defensins in mucosa might be part of the mechanisms involved in this association. However, further studies are required to define causal associations.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. High Vitamin D levels and VDR mRNA expression in HESN individuals.
The box and whisker plots show significantly higher levels of 25(OH)D levels in plasma (A), relative mRNA units, RU, of VDR in PBMCs (B), vaginal (C) and genital mucosa (vaginal and endocervical mucosa, together) (D) of HESNs (blue) compared to HCs (green). Significantly higher levels of VDR RU in PBMCs of HESNs than in SPs (red) are also shown (B). Plasma levels of 25(OH)D from all populations was positively correlated with VDR mRNA RU in PBMCs (r=0.56, p=0.0008, n=32) (E). VDR mRNA RU was obtained by normalizing it with β-actin and phosphoglycerate kinase 1 (PGK1) mRNA expression levels. Box: 25–75 percentile range; whiskers: 10–90 percentile range; outliers are plotted as black circles; medians are the black lines in the boxes and means plotted as a plus and Bonferroni adjusted significant p values are displayed in each graph. A two-tailed parametric t test was used to compare the levels of 25(OH)D, and the non-parametric test (Mann-Whitney U-two-tailed test) to compare VDR mRNA RU between pairs of groups. The correlations were evaluated using the Spearman coefficient rank (r). *unadjusted p-value=0.0332.
Figure 2
Figure 2. Activation status of HESNs is variable comparing mucosa, versus PBMCs.
The box and whisker plots show the median value and 10-90 percentiles of mRNA RU of anti-inflammatory IL-10, TGB-β and pro-inflammatory cytokines TNF-α and IL-1β in vaginal mucosa (A), genital mucosa (vaginal and endocervical mucosa, together) (B), oral mucosa (C) and in PBMCs (D) of HESNs (blue), HCs (green) and SPs (red). A non-parametric test (Mann-Whitney U-two-tailed test) was used to compare mRNA RU between study groups. Outliers are plotted as black circles and Bonferroni adjusted significant p values are displayed in each graph. Significantly lower mRNA RU of TNF-α in vaginal, genital and oral mucosa of HESNs than SPs (A-C) and significantly higher mRNA RU of IL-10 in vaginal mucosa (A) and PBMCs (D) of HESNs than HCs are shown. In contrast, the PBMCs of HESNs showed higher levels of the proinflammatory cytokines TNF-α and IL-1β (D).
Figure 3
Figure 3. VDR mRNA expression is correlated with mRNA of IL-10 and antimicrobial peptides (HBD-2 and HBD-3) in HESNs.
There was a significant positive correlation between the mRNAs of VDR and the IL-10 in PBMCs (r=0.68; p=0.0137, n=13) (A), and in the genital mucosa (r=0.37; p=0.0304, n=34) (B) of HESN individuals. There were also significant positive correlations between the mRNAs of VDR and the antimicrobial peptides HBD-2 (r=0.61, p=0.0006, n=28) (C), and HBD-3 (r=0.62, p=0.0006, n=27) (D) in oral mucosa of HESN individuals. The correlations were evaluated using the Spearman coefficient ranks (r), which are displayed in each graph with the best linear fit lines and p values.
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This work was supported by COLCIENCIAS (code 111549326091), Colombia; Universidad de Antioquia (Sostenibilidad 2013-2014 and CODI N°255), Colombia; Fondo de Investigaciones Sanitarias (PI021205) and Junta de Andalucía (PI-0335/2009), Spain. WAJ is recipient of a doctoral scholarship from COLCIENCIAS, Colombia. The funders had no role in the design of the study, data collection and analysis, decision to publish, or preparation of the manuscript.