Effects of leukotriene B4 and prostaglandin E2 on the differentiation of murine Foxp3+ T regulatory cells and Th17 cells.

Leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) are shown to be potent immunoregulatory lipid mediators. Here, we examined the effects of LTB4 and PGE2 on the differentiation of immunosuppressive CD4+CD25+Foxp3+ T regulatory cells (Treg) and pro-inflammatory IL-17-producing cells (Th17) from murine naïve CD4+ T cells. Using MACS-purified murine CD4+CD62L+ naïve T cells, we found that three days later in the presence of TGF-beta1, (28.65+/-6.83)% cells were converted into Treg cells, the mRNA expression of the key transcription factor Foxp3 peaked at 36h. Both LTB4 and PGE2 dose-dependently decreased the percentage of Treg cells and the mRNA expression of Foxp3. When the CD4+CD62L+ T cells were activated under Th17-promoting conditions in the presence of TGF-beta1 plus IL-6, three days later the production of IL-17 was markedly increased and the key transcription factor RORgammat mRNA peaked at 48h. LTB4 dose-dependently increased the secretion of IL-17 and the expression of RORgammat mRNA, whereas PGE2 decreased the secretion of IL-17 and the RORgammat mRNA expression. Our results suggest a distinct mode of immunoregulative action by PGE2 and LTB4, which may further our understanding of the role for lipid inflammatory mediators in the physiopathology of autoimmune diseases such as rheumatoid arthritis.