Abstract

Background: Dendritic cell (DC) activation induces expression of co-stimulatory surface molecules, as well as migration into secondary lymphoid organs, where they activate naïve T cells. A family of plant derivatives, eremophilanetype petasite sesquiterpenes can regulate the immune system through DC targeting due to their anti-inflammatory effects. Peroxisome proliferator activated receptor gamma (PPARγ) is involved in inhibition of inflammatory responses and induction of DCs to acquire a mucosal phenotype.
Objective: Since mucosal DCs are central in innate immune responses, we hypothesized that eremophilane-type petasite sesquiterpenes exerted their anti-inflammatory effects by inhibiting DC maturation and activation, through PPARγ.
Methods: This study assessed the bicyclic eremophilane-type petasite sesquiterpene compounds Fukinone and 10βH-8α,12-Epidioxyeremophil-7(11)-en-8β-ol (ZYFDC21 and ZYFDC22), in the maturation and activation of mouse dendritic cells, measured by surface expression of co-stimulatory molecules and cytokine production upon LPS stimulation, in the presence or absence of PPARγ agonists. DCs were generated from mouse bone marrow cells in media supplemented with GM-CSF+IL-4, and were harvested on day 8 and activated for 3 h with bicyclic eremophilanetype petasite sesquiterpenes ZYFDC21 or ZYFDC22 in presence or absence of synthetic PPARγ agonists (GW1929, TGZ), or the natural PPARγ ligand 15d-PGJ2, followed by overnight activation with LPS.
Results: Effects on DC maturation were evaluated by surface expression of the co-stimulatory molecule CD86 by flow cytometry, and for DC activation, by relevant cytokines released in cell-free supernatants measured by ELISAs. We observed differences in the upregulation of surface expression of CD86, along with release levels of TNF, IL-6 and IL-12p70 in DCs stimulated with LPS when using combinations of bicyclic eremophilane-type petasite sesquiterpenes ZYFDC21 or ZYFDC22, and PPARγ agonists, in particular the PPARγ ligand 15d-PGJ2.
Conclusion: These results indicate that bicyclic eremophilane-type petasite sesquiterpenes Fukinone and 10βH- 8α,12-Epidioxyeremophil-7(11)-en-8β-ol inhibit maturation and activation of DC, and this activity is augmented upon PPARγ activation.

Keywords: Inflammation; Plant derivatives; Transcription factor; Peroxisome proliferator activated receptor gamma