Pollen-drived E₁-pytoprostanes 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 E₁-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 _H2 polarization of naive T cells. The mechanism(s) by which PPE ₁ 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-γ. Finally, PPE₁ efficiently blocked NF-κB signaling in DCs by inhibiting IκB-α 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-γ dependent pathways that lead to inhibition of NFκB activation and result in reduced DC IL-12 production and consecutive T_H2 polarization.