Prostaglandin E2 Receptor Signaling Induces IL-23p19 Expression through CREB and STAT-3 Transcriptional Regulation (98.2)

Abstract

Abstract Previously, we have shown that PGE2 inhibits IL-12p35 expression & promotes IL-23p19 expression in dendritic cells (DC) treated with LPS or Poly I:C. The effect is mediated through EP4 and to a lesser degree EP2 receptors and induction of cAMP. This study is focused on essential transcriptional factors and signaling pathways involved in PGE1-OH (EP4 agonist) induced p19 expression. Previous studies reported involvement of NFkB (c-Rel), ATF-2, SMAD-3 & AP-1. CREB is a target of cAMP-activated PKA and two CREB binding sites have been identified in the p19 promoter. Therefore, CREB is a potential transcription factor activated by PGE. Experiments with p19-luciferase constructs containing wt & CREB-mutated sites indicate the importance of CREB sites in p19 transcriptional activity. PGE2/PGE1-OH also induced STAT-3 tyrosine phosphorylation in DC and in the DC cell line. Blocking STAT-3 phosphorylation with the chemical inhibitor S3I-201 and the specific peptide inhibitor PpYLKTK-mts reduced p19 expression in DC. Although no STAT-3 binding site was found in the p19 promoter, STAT-3 was proposed to act as a co-activator for c-Rel to induce p19 expression. These data show for the first time that CREB and STAT-3 are important regulators of PGE2-induced p19 expression in DC. These observations show the versatility that prostaglandins have to differentially regulate expression patterns of cytokines that orchestrate an immune response.