A model for IRF5-RelA–mediated induction of TNF in myeloid cells. LPS-induced recruitment of NF-κB RelA-containing complexes (gray ovals) to the 5′ upstream and 3′ downstream regions leads to transient TNF expression in MDMs. The mechanisms of transmitting the activating signal from 3′ downstream to Pol II requires further investigation. IRF5 binding to DNA at the 5′ upstream and to RelA at the 3′ downstream establishes the possibility for region circularization and recycling of Pol II molecules, leading to sustained TNF expression in MDDCs.