Distinct expression profiles of TGF-beta1 signaling mediators in pathogenic SIVmac and non-pathogenic SIVagm infections - PubMed (original) (raw)

Comparative Study

Distinct expression profiles of TGF-beta1 signaling mediators in pathogenic SIVmac and non-pathogenic SIVagm infections

Mickaël J-Y Ploquin et al. Retrovirology. 2006.

Abstract

Background: The generalized T-cell activation characterizing HIV-1 and SIVmac infections in humans and macaques (MACs) is not found in the non-pathogenic SIVagm infection in African green monkeys (AGMs). We have previously shown that TGF-beta1, Foxp3 and IL-10 are induced very early after SIVagm infection. In SIVmac-infected MACs, plasma TGF-beta1 induction persists during primary infection 1. We raised the hypothesis that MACs are unable to respond to TGF-beta1 and thus cannot resorb virus-driven inflammation. We therefore compared the very early expression dynamics of pro- and anti-inflammatory markers as well as of factors involved in the TGF-beta1 signaling pathway in SIV-infected AGMs and MACs.

Methods: Levels of transcripts encoding for pro- and anti-inflammatory markers (tnf-alpha, ifn-gamma, il-10, t-bet, gata-3) as well as for TGF-beta1 signaling mediators (smad3, smad4, smad7) were followed by real time PCR in a prospective study enrolling 6 AGMs and 6 MACs.

Results: During primary SIVmac infection, up-regulations of tnf-alpha, ifn-gamma and t-bet responses (days 1-16 p.i.) were stronger whereas il-10 response was delayed (4th week p.i.) compared to SIVagm infection. Up-regulation of smad7 (days 3-8 p.i.), a cellular mediator inhibiting the TGF-beta1 signaling cascade, characterized SIV-infected MACs. In AGMs, we found increases of gata-3 but not t-bet, a longer lasting up-regulation of smad4 (days 1-21 p.i), a mediator enhancing TGF-beta1 signaling, and no smad7 up-regulations.

Conclusion: Our data suggest that the inability to resorb virus-driven inflammation and activation during the pathogenic HIV-1/SIVmac infections is associated with an unresponsiveness to TGF-beta1.

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Figures

Figure 1

Figure 1

Dynamics of pro- and anti-inflammatory markers in PBMC during pathogenic and non-pathogenic SIV infections. A. Tnf-α, ifn-γ and il-10 expressions. B. T-bet and gata-3 expressions. Upper and lower panels represent data from 6 SIVmac-infected rhesus MACs and from 6 SIVagm-infected AGMs, respectively. Relative transcript levels are represented by box plots in a log scale. BI indicates the baseline before infection (n = 42 corresponding to 7 time points for each of the 6 animals) and the following boxes present the gene expression after infection (n = 6 per box). The top and the bottom of the boxes represent the 75th and 25th percentiles, respectively, whereas the horizontal line between the box limits represent the median. Open circles indicate individual values which are not included between the 90th and 10th percentiles. Dark and light grey boxes indicate significant (p < 0.05) increases and decreases, respectively, relative to the baseline. Stars indicate a trend towards significant up-regulation (p < 0.08). The data on AGMs (tnf-α, ifn-γ and il-10) were previously published [1]. The latter are displayed here in a log scale to allow easy and direct comparisons with the data obtained for the pathogenic SIVmac infection.

Figure 2

Figure 2

Dynamics of smad3, smad4 and smad7 expressions in PBMC during pathogenic and non-pathogenic SIV infections. See legend in Figure 1.

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