Modulation of the lipoxygenase pathway in bone marrow-derived dendritic cells by PPAR gamma

Hontecillas, R., S. Misyak, and J. Bassaganya-Riera (2009) Modulation of the lipoxygenase pathway in bone marrow-derived dendritic cells by PPAR gamma. AAI Annual Meeting, Seattle, WA. (Abstract #1761)

Enzymes of the lipoxygenase (LOX) family genrate lipid mediators that activate the nuclear receptor peroxisome proliferator activated receptor g (PPARg) and regulate immune and inflammatory reactions. GMCSF upregulates the 5 LOX pathway whereas IL-4 suppresses 5 LOX and upregulates 15 LOX expression. The objective of this study was to evaluate whether, in addition of being a molecular target of the lipid mediators generated from arachidonate oxidation by LOX enzymes, PPARg regulates the expression of both 5 and 15 LOX. We show that during differentiation of BMDC in GMCSF and IL4, the loss of PPARg resulted in upregulation of 15 LOX. Phenotypically, PPARg deficient BMDC differentiated in GMCSF and IL4 expressed more CD40 and less CD36 than PPARg-expressing cells. Also, PPARg-defficient cells differentiated in the presence of GMCSF alone had more 5 LOX mRNA than PPARg-expressing cells, which was paralleled by upregulation of PPAR delta. The loss of PPARg did not change the expression of 5 LOX activating protein. LPS stimulation of mature BMDC induced secretion of LTB4, a product of the 5 LOX pathway, in cells differentiated in GMCSF although the loss of PPARg did not have any effect on the amount of this lipid mediator released. Our results suggest that a negative feed-back loop is initiated following activation of PPARg that regulates further generation of more endogenous ligands.