Tuesday May 12, 12.00 to 13.00
Celine MOLLE

"Differential involvement of IRF members in IL-27 synthesis induced by TLR ligation"

Interleukin (IL)-27, a member of the IL-12 family, is a heterodimeric cytokine composed of Epstein-Barr virus-induced gene 3 (EBI3) and p28. Produced by dendritic cells (DCs) in response to Toll-like receptor (TLR) ligands, IL-27 recently emerged as a key regulatory cytokine of inflammatory responses. We focused on the molecular pathways implicated in TLR induced IL-27 expression. In a previous work, we demonstrated that interferon regulatory factor (IRF) 3, activated downstream of TRIF, acts as a master switch for IL-27p28 synthesis by LPS-stimulated DCs. Herein, we further explored the role of other members of the IRF family in IL-27 production in response to TLR agonists, type I and type II interferons (IFN). We first observed that type I IFN signaling was required for p28 expression downstream of TLR3 and TLR4. Using DC derived from knock-out mice, we then assessed the role of different IRF members in the regulation of IL-27. The positive role of IRF9 and IRF1 was confirmed in electrophoretic mobility shift assays and reporter gene experiments. We found that the different IRF members activated synergistically the IL-27p28 promoter. Finally, we assessed the role of these transcription factors in IL-27 expression in vivo upon injection of TLR ligands in knock-out mice. Taken together, our results indicate that IRF members are differentially implicated in the regulation of IL-27p28 gene synthesis.