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.
Attakpa
Eugène
E
Laboratoire de Pharmacologie et d'Hormonologie, Département de Physiologie Animale, Faculté des Sciences et Techniques/Université d'Abomey-Calavi et Institut des Sciences Biomédicales Appliquées (ISBA), Cotonou, Benin.
Hichami
Aziz
A
Simonin
Anne Marie
AM
Sansón
Esther García
EG
Dramane
Karim L
KL
Khan
Naim Akhtar
NA
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes; D002454:Cell Differentiation; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D015536:Down-Regulation; D050990:GATA3 Transcription Factor / Q000502:physiology*; D007371:Interferon-gamma / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D047493:PPAR alpha / Q000235:genetics*; D010766:Phosphorylation; D012333:RNA, Messenger; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D020825:T-Box Domain Proteins / Q000378:metabolism*; D013601:T-Lymphocytes / Q000473:pathology*; D018417:Th1 Cells / Q000276:immunology; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation
D050990:GATA3 Transcription Factor; D047493:PPAR alpha; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D004281:Docosahexaenoic Acids; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases