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Pollen-Derived E₁-Phytoprostanes Signal via PPAR- and NF-B-Dependent Mechanisms¹

Stefanie Gilles^*, Valentina Mariani, Martina Bryce^*, Martin J. Mueller, Johannes Ring, Thilo Jakob^¶, Saveria Pastore, Heidrun Behrendt^* and Claudia Traidl-Hoffmann^2,*

^* Zentrum Allergie und Umwelt, Division of Environmental Dermatology and Allergy Helmholz Center Munich, Technische Universität Munich, Munich, Germany; Istituto dermopatico dell immacolata, Rome, Italy; Department of Dermatology and Allergy Biederstein, Technische Universität München, Munich, Germany; Julius-von-Sachs-Institute of Biosciences, Division of Pharmaceutical Biology, University of Würzburg, Würzburg, Germany; and ^¶ Allergy Research Group, University Medical Center Freiburg, Freiburg, Germany

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 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-. Finally, PPE₁ efficiently blocked NF-B signaling in DCs by inhibiting IB- 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- dependent pathways that lead to inhibition of NFB activation and result in reduced DC IL-12 production and consecutive T_H2 polarization.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ The study was supported in parts by a grant to C.T.H. from the Faculty of Medicine of the Technische Universität München (KKF Nr. 8760167), a grant to T.J. and C.T.H. from the German Federal Ministry of Science and Education (BMBF 01GC0104) and a grant to C.T.H. from the Bayerische Forschungsstiftung (PIZ69/05 and DOK-27-02).

² Address correspondence and reprint requests to Dr. Claudia Traidl-Hoffmann, Division of Environmental Dermatology and Allergy, Helmhotz Zentrum Munich, Zentrum Allergie und Umwelt, Technische Universität München, Biedersteinerstrasse 29, München, Germany. E-mail address: traidl-hoffmann{at}lrz.tum.de

³ Abbreviations used in this paper: PALM, pollen-associated lipid mediator; DC, dendritic cell; PP, phytoprostane; PPE₁, E₁-phyotprostane; APE, aqueous pollen extract; Bet.-APE, aqueous birch pollen extract; moDC, monocyte-derived DC.