The aim of the present work was to decipher the cellular basis of the immunoregulatory role of peroxisome proliferator-activated receptor (PPAR)-α in cutaneous hypersensitivity reactions. After challenge with a contact allergen, we observed augmented hypersensitivity reactions with increased numbers of activated T lymphocytes in the skin of PPAR-α-/- mice. Furthermore, following antigen challenge, the percentages of Tregs in the blood, draining lymph nodes and skin were decreased in these mice. PPAR-α deficiency impaired the production of IL-2 in lymph nodes, whereas TGF-β levels remained unchanged. Injection of IL-2 into PPAR-α-/- mice restored the Treg population in the skin-draining lymph nodes of allergen-challenged mice. In vivo induction of Tregs from WT CD4+ CD25- T cells was impaired when adoptively transferred into PPAR-α-/- mice as compared with transfer into WT mice, and reversed by injection of IL-2 into PPAR-α-/- mice. Furthermore, the suppressive capacity of PPAR-α-/- Tregs was impaired when compared to WT Tregs in vitro and in co-adoptive transfer experiments. Finally, injection of IL-2 to PPAR-α-/- mice decreased skin inflammation to a level similar to WT mice. In conclusion, the pro-inflammatory skin phenotype of PPAR-α-/- mice is due to lack of IL-2-mediated Treg induction in these mice.
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