Pollen-Derived E1-Phytoprostanes Signal via PPAR-γ and NF-κB-Dependent Mechanisms

In a humid milieu such as mucosal surfaces, pollen grains do not only release allergens but also proinflammatory and immunomodulatory lipids, termed pollen-associated lipid mediators. Among these, the E-1-phytoprostanes (PPE1) were identified to modulate dendritic cell (DC) function: PPE1 inhibit the DC's capacity to produce IL-12 and enhance DC mediated T(H)2 polarization of naive T cells. The mechanism(s) by which PPE1 act on DC remained elusive. We thus analyzed candidate signaling elements and their role in PPE1-mediated regulation of DC function. Aqueous birch pollen extracts induced a marked cAMP response in DC that could be blocked partially by EP2 and EP4 antagonists. In contrast, PPE1 hardly induced cAMP and the inhibitory effect on IL-12 production was mostly independent of EP2 and EP4. Instead, PPE1 inhibited the LPS-induced production of IL-12 p70 by a mechanism involving the nuclear receptor PPAR-gamma. Finally, PPE1 efficiently blocked NF-kappa B signaling in DCs by inhibiting I kappa B-alpha degradation, translocation of p65 to the nucleus, and binding to its target DNA elements. We conclude that pollen-derived PPE1 modulate DC function via PPAR-gamma dependent pathways that lead to inhibition of NF kappa B activation and result in reduced DC IL-12 production and consecutive T(H)2 polarization. The Journal of Immunology, 2009, 182: 6653-6658.