A synthetic compound, I-BET, was developed to suppress inflammatory gene expression by interfering with the recognition of acetylated histones by the Bromodomain and Extra Terminal domain (BET) family of proteins. BET proteins, including BRD2, BRD3, and BRD4, regulate the assembly of histone acetylation-dependent chromatin complexes that control inflammatory gene expression. I-BET mimics acetylated histones and disrupts these chromatin complexes, leading to the suppression of key inflammatory genes in activated macrophages. This action protects against LPS-induced endotoxic shock and sepsis. I-BET selectively binds to BET proteins, as demonstrated by its high affinity interaction with the acetyl-lysine (AcK)–binding pocket of BRD4-bromodomain 1. The compound's structure allows it to bind to the tandem bromodomains of BET with high affinity. I-BET displaces acetylated histone H4 peptides from BET bromodomains, indicating its ability to interfere with the recognition of acetylated histones. I-BET is highly selective, as it does not interact with other bromodomain-containing proteins or a panel of 38 unrelated proteins. In experiments with bone marrow-derived macrophages (BMDMs), I-BET significantly reduced the expression of LPS-inducible genes, including cytokines and chemokines such as IL-6, IFNβ, IL-1β, IL-12a, CXCL9, and CCL12. It also suppressed the expression of the IL-1β processing enzyme MEF15, indicating its potential to control the IL-1β inflammatory circuit. I-BET reduced the expression of transcription factors REL, IRF4, and IRF8, suggesting its ability to curtail the initial wave of inflammatory gene expression. The selective effect of I-BET on gene expression was linked to the epigenetic state of the genes. Genes that were not affected by I-BET (naI-BET genes) had higher basal levels of histone acetylation and were already primed for transcription. In contrast, genes that were suppressed by I-BET (sI-BET genes) had low basal levels of histone acetylation and were more susceptible to suppression. The mechanism of I-BET's action involves preventing BET from binding to acetylated histones, increasing the accessibility of these histones to histone deacetylases (HDACs), and disrupting the formation of multi-molecular complexes that include histone acetyltransferases (HATs) and other histone modifying enzymes. In vivo studies showed that I-BET effectively suppressed inflammation in mice. It prevented or attenuated death in mice subjected to LPS- or heat-killed Salmonella Typhimurium-induced endotoxic shock. A single dose of I-BET administered 1.A synthetic compound, I-BET, was developed to suppress inflammatory gene expression by interfering with the recognition of acetylated histones by the Bromodomain and Extra Terminal domain (BET) family of proteins. BET proteins, including BRD2, BRD3, and BRD4, regulate the assembly of histone acetylation-dependent chromatin complexes that control inflammatory gene expression. I-BET mimics acetylated histones and disrupts these chromatin complexes, leading to the suppression of key inflammatory genes in activated macrophages. This action protects against LPS-induced endotoxic shock and sepsis. I-BET selectively binds to BET proteins, as demonstrated by its high affinity interaction with the acetyl-lysine (AcK)–binding pocket of BRD4-bromodomain 1. The compound's structure allows it to bind to the tandem bromodomains of BET with high affinity. I-BET displaces acetylated histone H4 peptides from BET bromodomains, indicating its ability to interfere with the recognition of acetylated histones. I-BET is highly selective, as it does not interact with other bromodomain-containing proteins or a panel of 38 unrelated proteins. In experiments with bone marrow-derived macrophages (BMDMs), I-BET significantly reduced the expression of LPS-inducible genes, including cytokines and chemokines such as IL-6, IFNβ, IL-1β, IL-12a, CXCL9, and CCL12. It also suppressed the expression of the IL-1β processing enzyme MEF15, indicating its potential to control the IL-1β inflammatory circuit. I-BET reduced the expression of transcription factors REL, IRF4, and IRF8, suggesting its ability to curtail the initial wave of inflammatory gene expression. The selective effect of I-BET on gene expression was linked to the epigenetic state of the genes. Genes that were not affected by I-BET (naI-BET genes) had higher basal levels of histone acetylation and were already primed for transcription. In contrast, genes that were suppressed by I-BET (sI-BET genes) had low basal levels of histone acetylation and were more susceptible to suppression. The mechanism of I-BET's action involves preventing BET from binding to acetylated histones, increasing the accessibility of these histones to histone deacetylases (HDACs), and disrupting the formation of multi-molecular complexes that include histone acetyltransferases (HATs) and other histone modifying enzymes. In vivo studies showed that I-BET effectively suppressed inflammation in mice. It prevented or attenuated death in mice subjected to LPS- or heat-killed Salmonella Typhimurium-induced endotoxic shock. A single dose of I-BET administered 1.