Journal of Leukocyte Biology
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Published online before print July 16, 2008
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1007688

Received for publication October 10, 2007.
Revised May 30, 2008.
Accepted for publication June 17, 2008.

Article

Human dendritic cell activities are modulated by the omega-3 fatty acid, docosahexaenoic acid, mainly through PPAR{gamma}:RXR heterodimers—comparison with other polyunsaturated fatty acids

Fernando Zapata-Gonzalez *, Felix Rueda {dagger}, Jordi Petriz {ddagger}, Pere Domingo {sect}, Francesc Villarroya *||, Julieta Diaz-Delfin *||, Maria A. de Madariaga *, and Joan C Domingo *@

*Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain; {dagger}Laboratory of Oncological Immunology, Department of Medical and Molecular Genetics, IDIBELL-Cancer Research Institute, Barcelona, Spain; {ddagger}Laboratory 123, Institut de Recerca, Hospital Universitari Vall d’Hebron, Barcelona, Spain; {sect}Infectious Diseases Unit, Internal Medicine Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; and ||CIBER Fisiopatologia de la Obesidad y Nutrición, Instituto de Salud Carlos III, Barcelona, Spain

@ To whom correspondence should be addressed. E-mail: jcdomingo{at}ub.edu.


  Abstract

There is accumulating evidence that omega-3 fatty acids may modulate immune responses. When monocytes were differentiated to dendritic cells (DCs) in the presence of docosahexaenoic acid (DHA), the expression of costimulatory and antigen presentation markers was altered in a concentration-dependent way, positively or negatively, depending on the markers tested and the maturation stage of the DCs. Changes induced by eicosapentaenoic acid and linoleic acid were similar but less intense than those of DHA, whereas oleic acid had almost no effect. DHA-treated, mature DCs showed inhibition of IL-6 expression and IL-10 and IL-12 secretion, and their lymphoproliferative stimulation capacity was impaired. The phenotypic alterations of DCs induced by DHA were similar to those already reported for Rosiglitazone (Rosi), a peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) activator, and the retinoid 9-cis-retinoic acid (9cRA), a retinoid X receptor (RXR) activator. Moreover, DHA induced the expression of PPAR{gamma} target genes pyruvate dehydrogenase kinase-4 and aP-2 in immature DCs. The combination of DHA with Rosi or 9cRA produced additive effects. Furthermore, when DCs were cultured in the presence of a specific PPAR{gamma} inhibitor, all of the changes induced by DHA were blocked. Together, these results strongly suggest that the PPAR{gamma}:RXR heterodimer is the pathway component activated by DHA to induce its immunomodulatory effect on DCs.

Key Words: lymphocyte proliferation • immunological regulation • nuclear receptors • maturation






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