Cutting edge: Synchronization of IRF1, JunB, and C/EBPβ activities during TLR3-TLR7 cross-talk orchestrates timely cytokine synergy in the proinflammatory response

Multiple pathogen-Associated molecular pattern-induced TLR pathway cross-talk provokes proinflammatory cytokine synergy in macrophages, which is important for pathogen resistance and immune homeostasis. However, the detailed mechanisms are unclear. In this article, we demonstrate viral RNA analog-induced transcription synergy of Il6 and Il12b via IFN regulatory factor (IRF)1 (TLR3-TIR domain-containing adaptor inducing IFN-β [TRIF] responsive), C/EBPβ (TLR7-MyD88 responsive), and JunB (all responsive). Coactivation of the TLR3 and TLR7 pathways synchronizes the interaction of IRF1, JunB, and C/EBPβ with the Il6 and Il12b promoters, facilitating maximal gene expression. MyD88 pathway activation suppresses TRIFinduced IRF1 in a delayed manner, controlling the magnitude and timing of cytokine expression. Our findings provide novel mechanisms of cooperation of different TLR pathways to achieve optimal immune responses, with the potential for immunomodulatory strategies.