Pollen-derived E1-phytoprostanes signal via PPAR-gamma and NF-kappaB-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 (PPE(1)) were identified to modulate dendritic cell (DC) function: PPE(1) 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 PPE(1) act on DC remained elusive. We thus analyzed candidate signaling elements and their role in PPE(1)-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, PPE(1) hardly induced cAMP and the inhibitory effect on IL-12 production was mostly independent of EP2 and EP4. Instead, PPE(1) inhibited the LPS-induced production of IL-12 p70 by a mechanism involving the nuclear receptor PPAR-gamma. Finally, PPE(1) efficiently blocked NF-kappaB signaling in DCs by inhibiting IkappaB-alpha degradation, translocation of p65 to the nucleus, and binding to its target DNA elements. We conclude that pollen-derived PPE(1) modulate DC function via PPAR-gamma dependent pathways that lead to inhibition of NFkappaB activation and result in reduced DC IL-12 production and consecutive T(H)2 polarization.
Gilles
Stefanie
S
Division of Environmental Dermatology and Allergy Helmholz Center Munich, Zentrum Allergie und Umwelt, Technische Universität Munich, Munich, Germany.
Mariani
Valentina
V
Bryce
Martina
M
Mueller
Martin J
MJ
Ring
Johannes
J
Jakob
Thilo
T
Pastore
Saveria
S
Behrendt
Heidrun
H
Traidl-Hoffmann
Claudia
C
D000293:Adolescent; D000328:Adult; D029662:Betula / Q000276:immunology; D002478:Cells, Cultured; D000242:Cyclic AMP; D003517:Cyclopentanes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005231:Fatty Acids, Unsaturated / Q000276:immunology*; D006801:Humans; D007155:Immunologic Factors; D018664:Interleukin-12 / Q000096:biosynthesis*; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D011058:Pollen / Q000276:immunology*; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction / Q000276:immunology*; D018418:Th2 Cells; D055815:Young Adult
D003517:Cyclopentanes; D005231:Fatty Acids, Unsaturated; D007155:Immunologic Factors; D016328:NF-kappa B; D047495:PPAR gamma; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D018664:Interleukin-12; D000242:Cyclic AMP