Docosahexaenoic acid modulates the expression of T-bet and GATA-3 transcription factors, independently of PPARalpha, through suppression of MAP kinase activation.

The present study was conducted on CD4(+) T cells, isolated from wild type (WT) and PPARalpha(null) mice, in order to assess the mechanism of action of docosahexaenoic acid (DHA), an n-3 fatty acid, in the modulation of two transcription factors, i.e., T-bet and GATA-3, implicated in T-cell differentiation towards, respectively, T(H)1 and T(H)2 phenotype. The T-cells from PPARalpha(null) mice secreted higher IFN-gamma and lower IL-4 concentrations than WT T-cells. Furthermore, the deletion of PPARalpha gene in T-cells resulted in the upregulation of T-bet and downregulation of GATA-3 both at mRNA and protein levels. DHA exerted not only an inhibitory effect on T-cell proliferation, but also diminished IFN-gamma and stimulated IL-4 secretions in both cell types. DHA also downregulated T-bet and upregulated GATA-3 both at transcription and protein levels. Though the T-cells from PPARalpha(null) mice expressed higher p38 phosphorylation than WT T-cells, DHA diminished the MAP kinase phosphorylation (p38 and ERK1/2) in both the cell types. The pharmacological inhibitors of MAP kinases also downregulated T-bet and upregulated GATA-3 in T-cells. Altogether, these results demonstrate that DHA, via its action on MAP kinases, modulates the expression of transcription factors. These results also explain the mechanism of action of this fatty acid on T-cell differentiation in disease and health.