Lipid mediators elicit the activation of IL23A transcription via ATF2 phosphorylation

Abstract

The cytokines IL-12 p70 and IL-23 released by dendritic cells (DC) polarize the immune response into the Th1 and Th17 types, respectively. These cytokines share a common chain, p40 (gene IL12B) and differ in a specific subunit, p35 (gene IL12A) for IL-12 p70, and p19 (gene IL23A) for IL-23. The balance IL-12 p70/IL-23 is relevant to the development of fungal infection (1) and autoimmunity (2). As regards IL12A, a mechanism of transcriptional repression has been reported via the NAD+-dependent deacetylation of histones by SIRT1 (3, 4). Likewise, the transcription of IL23A is regulated by c-Rel and ATF2, which in turn depends on the complementary phosphorylation of its Thr-71 and Thr-69 by PKC and MAPKs (5). To disclose the mechanism of activation of IL23A transcription by fungal patterns; biochemical, pharmacological, and analytical approaches were conducted. The fungal mimic zymosan induced a massive release of arachidonic acid (AA), and the production of PAF (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine), leukotriene B4, and cysteinyl-leukotrienes. The combined antagonism of the receptors CysLT1, BLT1, and PAF-R inhibited the binding of P-Thr71-ATF2 to the IL23A promoter and IL23A transcription in response to zymosan. Unlike zymosan, the combination of agonists of those receptors increased the binding of P-Thr71-ATF2 to the IL23A promoter and IL23A transcription in response to LPS, thus suggesting that LPS elicits the production of those mediators at a concentration below the threshold necessary for an optimal response. These data indicate that fungal pattern receptors induce a rapid activation of the cytosolic phospholipase A2, which generates a massive release of AA, available for the biosynthesis of the eicosanoids and lyso-PAF (1-alkyl-2-lyso-snglycero-3-phosphocholine) for the biosynthesis of PAF, together with acetyl-CoA generated by stimulated DC. The engagement of G-protein coupled receptors by their cognate ligands gathers an array of autocrine signals that favor activation of IL23A transcription through the phosphorylation of ATF2.