Fig. 2

Convergent inflammatory signaling through NF-κB potentiates BRD4-dependent transcription of VI mediators, a result suppressed by apabetalone. a MCP-1, LPS, IL-1β, and TNFα all signal through NF-κB. The stimulants MCP-1, LPS, IL-1β, and TNFα activate their cognate receptors CCR2, TLR, IL-1R, and TNFR respectively. The receptors translate the signal through AKT, MYD88 and TRADD, phosphorylating NF-κB (yellow “p” circles) and releasing RelA-p50 subunits from IκBα. RelA translocates to the nucleus where it binds to consensus DNA binding sequences and is acetylated at K310 by p300 (black “a” circles). BRD4 recognizes and binds to these acetylation marks, recruiting pTEFb to activate RNA Pol II to drive inflammatory gene expression (cytokines, chemokines, and adhesion molecules). b Apabetalone (green 7-point star) competitively inhibits BRD4 BD2 interactions with acetylated lysine marks on RelA. This prevents pTEFb recruitment and Pol II activation, inhibiting the transcription of VI mediators and components of the NF-κB pathway. Green boxes and red arrows indicate genes in the illustration whose expression is reduced by apabetalone