Abstract
The migration of dendritic cells (DCs) from the epithelia to the lymphoid organs represents a tightly regulated multistep event involved in the induction of the immune response. In this process fatty acid derivatives positively and negatively regulate DC emigration. In the present study we investigated whether activation of peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptors activated by naturally occurring derivatives of arachidonic acid, could control DC migration from the peripheral sites of Ag capture to the draining lymph nodes (DLNs). First, we show that murine epidermal Langerhans cells (LCs) express PPAR gamma, but not PPAR alpha, mRNA, and protein. Using an experimental murine model of LC migration induced by TNF-alpha, we show that the highly potent PPAR gamma agonist rosiglitazone specifically impairs the departure of LCs from the epidermis. In a model of contact allergen-induced LC migration, PPAR gamma activation not only impedes LC emigration, and their subsequent accumulation as DCs in the DLNs, but also dramatically prevents the contact hypersensitivity responses after challenge. Finally, after intratracheal sensitization with an FITC-conjugated Ag, PPAR gamma activation inhibits the migration of DCs from the airway mucosa to the thoracic LNs and also profoundly reduces the priming of Ag-specific T lymphocytes in the DLNs. Our results suggest a novel regulatory pathway via PPAR gamma for DC migration from epithelia that could contribute to the initiation of immune responses.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Migration Inhibition*
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Cell Movement / immunology*
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Cells, Cultured
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Cytokines / antagonists & inhibitors
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Cytokines / biosynthesis
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Dendritic Cells / cytology*
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Dendritic Cells / immunology*
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Dendritic Cells / physiology
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Dermatitis, Contact / prevention & control
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Epidermis / immunology
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Epidermis / metabolism
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Female
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Fluorescein-5-isothiocyanate / administration & dosage
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Haptens / administration & dosage
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Haptens / immunology
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Immunosuppressive Agents / pharmacology
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Langerhans Cells / cytology
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Langerhans Cells / immunology
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Langerhans Cells / physiology
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Lung / cytology
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Lung / drug effects
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Lung / immunology
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Lymph Nodes / cytology
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Lymph Nodes / drug effects
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Lymph Nodes / immunology
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Lymph Nodes / metabolism
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Lymphocyte Activation / drug effects
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Mice
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Mice, Inbred BALB C
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Mice, Transgenic
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Ovalbumin / administration & dosage
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Ovalbumin / immunology
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Receptors, Cytoplasmic and Nuclear / biosynthesis
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, Cytoplasmic and Nuclear / physiology*
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Rosiglitazone
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Thiazoles / pharmacology
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Thiazolidinediones*
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Thorax
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Transcription Factors / biosynthesis
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Transcription Factors / metabolism
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Transcription Factors / physiology*
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Transcriptional Activation / immunology
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Cytokines
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Haptens
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Immunosuppressive Agents
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Receptors, Cytoplasmic and Nuclear
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Thiazoles
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Thiazolidinediones
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Transcription Factors
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Tumor Necrosis Factor-alpha
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Rosiglitazone
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Ovalbumin
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Fluorescein-5-isothiocyanate