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Peroxisome proliferator-activated receptor gamma activators affect the maturation of human monocyte-derived dendritic
P Gosset1, A S Charbonnier, P Delerive
1Mécanismes cellulaires et moléculaires de la réaction inflammatoire allergique, INSERM U416, Institut Pasteur de Lille, Lille, France. Philippe.Gosset@pasteur-lille.fr
Abstract:
Peroxisome proliferator-activated receptor gamma (PPARgamma ), a member of the nuclear receptor superfamily, has recently been described as a modulator of macrophage functions and as an inhibitor of T cell proliferation. Here, we investigated the role of PPARgamma in dendritic cells (DC), the most potent antigen-presenting cells. We showed that PPARgamma is highly expressed in immature human monocyte-derived DC (MDDC) and that it may affect the immunostimulatory function of MDDC stimulated with lipopolysaccharide (LPS) or via CD40 ligand (CD40L). We found that the synthetic PPARgamma agonist rosiglitazone (as well as pioglitazone and troglitazone) significantly increases on LPS- and CD40L-activated MDDC, the surface expression of CD36 (by 184% and 104%, respectively) and CD86 (by 54% and 48%), whereas it reduces the synthesis of CD80 (by 42% and 42%). Moreover, activation of PPARgamma resulted in a dramatic decreased secretion of the Th1-promoting factor IL-12 in LPS- and CD40L-stimulated cells (by 47% and 62%), while the production of IL-1beta, TNF-alpha, IL-6 and IL-10 was unaffected. Finally, PPARgamma ligands down-modulate the synthesis of IFN-gamma -inducible protein-10 (recently termed as CXCL10) and RANTES (CCL5), both chemokines involved in the recruitment of Th1 lymphocytes (by 49% and 30%), but not the levels of the Th2 cell-attracting chemokines,macrophage-derived chemokine (CCL22) and thymus and activation regulated chemokine (CCL17), in mature MDDC. Taken together, our data suggest that activation of PPARgamma in human DC may have an impact in the orientation of primary and secondary immune responses by favoring type 2 responses.
Insights
Activation of Peroxisome proliferator-activated receptor gamma (PPARgamma) in human dendritic cells (DC) influences immune responses. PPARgamma ligands promote a shift towards type 2 immune responses by modulating DC function.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor influencing macrophage and T cell functions.
- Dendritic cells (DC) are potent antigen-presenting cells crucial for initiating immune responses.
- The role of PPARgamma in DC function remained largely unexplored.
Purpose of the Study:
- To investigate the role and impact of PPARgamma activation in human monocyte-derived dendritic cells (MDDC).
- To determine how PPARgamma ligands affect the immunostimulatory properties of MDDC.
- To elucidate the effect of PPARgamma on immune response polarization.
Main Methods:
- Human monocyte-derived dendritic cells (MDDC) were generated and treated with PPARgamma agonists (rosiglitazone, pioglitazone, troglitazone).
- Cells were stimulated with lipopolysaccharide (LPS) or CD40 ligand (CD40L).
- Surface marker expression (CD36, CD86, CD80) and cytokine/chemokine secretion (IL-12, IL-1beta, TNF-alpha, IL-6, IL-10, CXCL10, CCL5, CCL22, CCL17) were analyzed.
Main Results:
- PPARgamma activation significantly increased CD36 and CD86 expression while decreasing CD80 on activated MDDC.
- Activation of PPARgamma markedly reduced the secretion of the Th1-promoting cytokine IL-12.
- PPARgamma ligands downregulated Th1-associated chemokines (CXCL10, CCL5) but not Th2-associated chemokines (CCL22, CCL17).
Conclusions:
- Activation of PPARgamma in human dendritic cells modulates their immunostimulatory functions.
- PPARgamma signaling in DC favors the development of type 2 immune responses.
- Targeting PPARgamma in DC may offer a strategy to reorient immune responses in various diseases.