Abstract
The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor expressed in dendritic cells (DCs), where it exerts anti-inflammatory responses against TLR4-induced inflammation. Recently, microRNA-511 (miR-511) has also emerged as a key player in controlling TLR4-mediated signalling and in regulating the function of DCs. Interestingly, PPARγ has been previously highlighted as a putative target of miR-511 activity; however, the link between miR-511 and PPARγ and its influence on human DC function within the context of LPS-induced inflammatory responses is unknown. Using a selection of miR-511-3p-specific inhibitors and mimics, we demonstrate for the first time that knockdown or overexpression of miR-511-3p inversely correlates with PPARγ mRNA levels and affects its transcriptional activity following treatment with rosiglitazone (RSG; PPARγ agonist), in the presence or absence of LPS. Additionally, we show that PPARγ-mediated suppression of DC activation and pro-inflammatory cytokine production in miR-511-3p knockdown DCs is abrogated following overexpression of miR-511-3p. Lastly, PPARγ activation suppressed LPS-mediated induction of indoleamine 2,3-dioxygenase (IDO) activity in DCs, most likely due to changes in miR-511-3p expression. Our data thus suggests that PPARγ-induced modulation of DC phenotype and function is influenced by miR-511-3p expression, which may serve as a potential therapeutic target against inflammatory diseases.
Highlights
Introduction iationsThe innate immune system rapidly responds to endotoxin exposure through the induction of acute inflammatory responses [1]
We measured the expression of peroxisome proliferator-activated receptor γ (PPARγ) by comparative qRT-PCR and showed for the first time that knockdown of miR-511-3p, resulted in a significant increase in PPARγ mRNA levels (Figure 1A), whereas a significant decrease in PPARγ expression was observed in miR-511-3p overexpressed cells (Figure 1B)
Having demonstrated the influence of miR-511-3p expression on PPARγ activity in human dendritic cells (DCs), we examined the levels of IL-6 and IL-10, cytokines produced by miR-511-3p-inhibitor and miR-511-3p-mimic DCs in culture supernatant. miR-511-3pinhibitor and miR-511-3p-mimic DCs were treated with RSG, LPS or both for 24 h in the presence or absence of PPARγ antagonist GW9662
Summary
The innate immune system rapidly responds to endotoxin exposure through the induction of acute inflammatory responses [1]. Endotoxins such as LPS, a major cell wall component of Gram-negative bacteria, can induce potent inflammatory responses through the release of an array of mediators such as cytokines, chemokines, and growth factors. DCs are highly sensitive to even low concentrations of LPS in the environment and detect the presence of LPS (for instance, during bacterial infection) via Toll-like receptor 4 (TLR4).
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