Acciones de los nitro-ácidos grasos sobre la activación de los linfocitos T

Abstract

Fatty acid nitroalkene derivatives (NO2-FA) are products of unsaturated fatty acid nitration that exhibit anti-inflammatory actions in a variety of cellular and animal models. By reversible post-translational nitroalkylation of nucleophilic residues on key regulatory proteins, these electrophilic compounds can interfere with multiple intracellular signalling pathways that contribute to inflammation. To date, several proteins and transcription factors have been identified as targets of NO2-FA, resulting in antioxidant and antiinflammatory effects. In this regard, nitro-oleic acid (NO2-OA) mediates nitroalkylation reactions with transcription factors such as peroxisome proliferator-activated receptor (PPAR)-γ, nuclear factor (NF)-κB, Signal Transducer and Activator of Transcription 3 (STAT3) or Kelch Like ECH Associated Protein 1 (Keap1), among others, thus modifying their activity and promoting changes in transcriptional gene expression. Here, we have examined the effects of NO2-OA in T cell activation, showing that 9-and 10-nitro-oleic acid (9NOA and 10NOA, respectively), but not their corresponding oleic acid (OA) precursor, reduce T cell proliferation, expression of activation markers interleukin-2 receptor α chain (CD25) and transferrin receptor (CD71) on the plasma membrane, and interleukin (IL)-2, IL-4 and Interferon (IFN)-γ cytokine gene expression. Moreover, we have found that NO2-OA inhibits the transcriptional activity of the nuclear factor of activated T cells (NFAT), and that this inhibition takes place through the regulation of the phosphatase activity of calcineurin (CaN) since NO2-OA inhibits NFAT dephosphorylation, and nuclear translocation in activated T cells. Finally, by means of proteomic approaches, we found that NO2-OA nitroalkylates calcineurin A (CaNA) on four Cys (Cys129, 228, 266, and 372), of which nitroalkylation on Cys372 was of importance for the regulation of CaN phosphatase activity in cells, disturbing functional CaNA/CaNB heterodimer formation. These results provide new evidence about the mechanisms by which bioactive electrophilic lipids such as NO2-OA exert their immunomodulatory actions, pointing to their potential as therapeutic drugs for the modulation of T cell-dependent altered immune responses