Dendritic cell (DC) activation induces expression of co-stimulatory surface molecules, as well as migration into secondary lymphoid organs, where they activate naive T-cells. A family of plant derivatives, eremophilane-type petasite sesquiterpenes, can regulate the immune system through DC targeting due to their anti-inflammatory effects. Peroxisome proliferator- activated receptor gamma (PPAR gamma) is involved in inhibition of inflammatory responses and induction of DCs to acquire a mucosal phenotype. Since mucosal DCs are central in innate immune responses, we hypothesized that eremophilanetype petasite sesquiterpenes exerted their anti-inflammatory effects by inhibiting DC maturation and activation through PPAR gamma. This study assessed the bicyclic eremophilane-type petasite sesquiterpene compounds Fukinone and 10 beta H-8 alpha,12-Epidioxyeremophil-7(11)-en-8 beta-ol (ZYFDC21 and ZYFDC22) in the maturation and activation of mouse DC. We measured surface expression of co-stimulatory molecules by flow cytometry and cell-free supernatant cytokine production upon lipopolysaccharide stimulation by enzyme-linked immunosorbent assays (ELISAs) in the presence or absence of PPAR gamma agonists. DCs were generated from C57BU6 mice bone marrow cells and harvested. Cells were exposed to bicyclic eremophilanetype petasite sesquiterpenes ZYFDC21 or ZYFDC22 in the presence or absence of synthetic PPARy agonists (GW 1929 and TGZ) or the natural PPAR gamma ligand 15d-PGJ(2), followed by overnight activation with LPS. We observed differences in the upregulation of surface expression of CD86, along with TNF, IL-6, and IL-12p70 released by DCs stimulated with LPS, when using combinations of bicyclic eremophilane-type petasite sesquiterpenes ZYFDC21 or ZYFDC22, and PPAR gamma agonists, in particular the PPAR gamma ligand 15d-PGJ(2). Our results indicate that bicyclic eremophilane-type petasite sesquiterpenes ZYFDC21 or ZYFDC22 inhibit maturation and activation of DC, and this activity is augmented upon PPAR gamma activation.
[1]Natl Res Council Canada, Nanotechnol Res Ctr, 11421 Saskatchewan Dr NW, Edmonton, AB T6G 2M9, Canada.
[2]Shanghai Univ Tradit Chinese Med, Sch Pharm, Shanghai, Peoples R China.
[3]Univ Alberta, Dept Med Microbiol & Immunol, Edmonton, AB, Canada.
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