Activation of peroxisome proliferator-activated receptor-gamma in dendritic cells inhibits the development of eosinophilic airway inflammation in a mouse model of asthma
Peroxisome proliferator-activated receptors (PPARs) are activated by an array of polyunsaturated fatty acid derivatives, oxidized fatty acids, and phospholipids and are proposed to be important modulators of immune and inflammatory responses. Recently, we showed that activation of PPAR-gamma alters the maturation process of dendritic cells (DCs), the most potent antigen-presenting cells. In the present report, we investigated the possibility that, by targeting DCs, PPAR-gamma activation may be involved in the regulation of the pulmonary immune response to allergens. Using a model of sensitization, based on the intratracheal transfer of ovalbumin (OVA)-pulsed DCs, we show that rosiglitazone, a selective PPAR-gamma agonist, reduces the proliferation of Ag-specific T cells in the draining mediastinal lymph nodes but, surprisingly enough, dramatically increases the production of the immunoregulatory cytokine interleukin (IL)-10 by T cells, as compared to control mice sensitized with OVA-pulsed DCs. After aerosol challenge, the recruitment of eosinophils in the bronchoalveolar lavage fluids was strongly reduced compared to control mice. Finally, T cells from the mediastinal lymph nodes produced higher amounts of IL-10 and interferon-gamma. Inhibition of IL-10 activity with anti-IL-10R antibodies partly restored the inflammation. The specificity of the phenomenon was confirmed by treating OVA-pulsed DCs with ciglitazone, another PPAR-gamma agonist, and by using GW9662, a PPAR-gamma antagonist. Our data suggest that PPAR-gamma activation prevents induction of Th2-dependent eosinophilic airway inflammation and might contribute to immune homeostasis in the lung.
|Keywords||Anilides/pharmacology, Animals, Asthma/*immunology/pathology, Cell Movement/drug effects/immunology, Comparative Study, Cytokines/drug effects/immunology, Dendritic Cells/immunology/*metabolism/transplantation, Disease Models, Animal, Eosinophils/immunology, Inflammation/immunology, Lung/immunology/*pathology, Mice, Mice, Inbred BALB C, Ovalbumin, Receptors, Cytoplasmic and Nuclear/*agonists/*metabolism, Research Support, Non-U.S. Gov't, T-Lymphocytes/drug effects/immunology, Thiazolidinediones/pharmacology, Transcription Factors/*agonists/*metabolism, Vasodilator Agents/pharmacology|
Hammad, H., de Heer, H.J., Soullié, T., Angeli, V., Trottein, F., Hoogsteden, H.C., & Lambrecht, B.N.M.. (2004). Activation of peroxisome proliferator-activated receptor-gamma in dendritic cells inhibits the development of eosinophilic airway inflammation in a mouse model of asthma. American Journal of Pathology. Retrieved from http://hdl.handle.net/1765/10279