Interaction of pathogens with cells of the immune system results in activation of inflammatory gene expression. This response, while vital for immune defence, is frequently deleterious to the host due to the exaggerated production of inflammatory proteins. The scope of inflammatory responses reflects the activation state of signalling proteins upstream of inflammatory genes as well as signal-induced assembly of nuclear chromatin complexes that support mRNA expression1–4. Recognition of post-translationally modified histones by nuclear proteins that initiate mRNA transcription and support mRNA elongation is a critical step in the regulation of gene expression5–10. Here we present a novel pharmacological approach that targets inflammatory gene expression by interfering with the recognition of acetylated histones by the Bromodomain and Extra Terminal domain (BET) family of proteins. We describe a synthetic compound (I-BET) that by “mimicking” acetylated histones disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages and confers protection against LPS-induced endotoxic shock and bacteria-induced sepsis. Our findings suggest that synthetic compounds specifically targeting proteins that recognize post-translationally modified histones can serve as a new generation of immunomodulatory drugs.

SummaryMany nervous system pathologies are associated with increased levels of apolipoprotein D (ApoD), a lipocalin also expressed during normal development and aging. An ApoD homologous gene in Drosophila , Glial Lazarillo, regulates resistance to stress, and neurodegeneration in the aging brain. Here we study for the first time the protective potential of ApoD in a vertebrate model organism. Loss of mouse ApoD function increases the sensitivity to oxidative stress and the levels of brain lipid peroxidation, and impairs locomotor and learning abilities. Human ApoD overexpression in the mouse brain produces opposite effects, increasing survival and preventing the raise of brain lipid peroxides after oxidant treatment. These observations, together with its transcriptional up-regulation in the brain upon oxidative insult, identify ApoD as an acute response protein with a protective and therefore beneficial function mediated by the control of peroxidated lipids.

PYRIN-containing Apaf1-like proteins (PYPAFs) are members of the nucleotide-binding site/leucine-rich repeat (NBS/LRR) family of signal transduction proteins. We report here that PYPAF7 is a novel PYPAF protein that activates inflammatory signaling pathways. The expression of PYPAF7 is highly restricted to immune cells, and its gene maps to chromosome 19q13.4, a locus that contains a cluster of genes encoding numerous PYPAF family members. Co-expression of PYPAF7 with ASC results in the recruitment of PYPAF7 to distinct cytoplasmic loci and a potent synergistic activation of NF-B. To identify other proteins involved in PYPAF7 and ASC signaling pathways, we performed a mammalian twohybrid screen and identified pro-caspase-1 as a binding partner of ASC. Co-expression of PYPAF7 and ASC results in the synergistic activation of caspase-1 and a corresponding increase in secretion of interleukin-1␤. In addition, PYPAF1 induces caspase-1-dependent cytokine processing when co-expressed with ASC. These findings indicate that PYPAF family members participate in inflammatory signaling by regulating the activation of NF-B and cytokine processing.

CCR3 is a chemokine receptor initially thought specific to eosinophils but subsequently identified on TH2 cell subsets, basophils, mast cells, neural tissue, and some epithelia. Because of the prominent role of these cells in allergic disease, including asthma, we generated mice deficient in CCR3 to determine its contribution in a model of allergic airway disease. Here we show that CCR3 is important for the basal trafficking of eosinophils to the intestinal mucosa but not the lung. In contrast, CCR3 disruption significantly curtails eosinophil recruitment to the lung after allergen challenge, with the majority of the eosinophils being arrested in the subendothelial space. Further, a role for CCR3 in mast cell homing has been identified; after sensitization and allergen challenge, we find increased numbers of intraepithelial mast cells in the trachea of knockout mice. Physiologically, we find that the net result of these complex cell fates after sensitization and allergen challenge is a paradoxical increase in airway responsiveness to cholinergic stimulation. These data underscore a more complex role for CCR3 in allergic disease than was anticipated.

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The BET family of chromatin adaptors promotes TH17 differentiation, and inhibition of BET proteins protects against autoimmune diseases, including collagen-induced arthritis and EAE, in mice.

The PYRIN domain is a recently identified proteinprotein interaction domain that is found at the N terminus of several proteins thought to function in apoptotic and inflammatory signaling pathways. We report here that PYPAF1 (

PYRIN-containing Apaf-1-like proteins (PYPAFs) are a recently identi¢ed family of proteins thought to function in apoptotic and in£ammatory signaling pathways. PYPAF1 and PYPAF7 proteins have been found to assemble with the PYRIN^CARD protein ASC and coordinate the activation of NF-U UB and pro-caspase-1. To determine if other PYPAF family members function in pro-in£ammatory signaling pathways, we screened ¢ve other PYPAF proteins (PYPAF2, PYPAF3, PY-PAF4, PYPAF5 and PYPAF6) for their ability to activate NF-U UB and pro-caspase-1. Co-expression of PYPAF5 with ASC results in a synergistic activation of NF-U UB and the recruitment of PYPAF5 to punctate structures in the cytoplasm. The expression of PYPAF5 is highly restricted to granulocytes and T-cells, indicating a role for this protein in in£ammatory signaling. In contrast, PYPAF2, PYPAF3, PYPAF4 and PYPAF6 failed to colocalize with ASC and activate NF-U UB. PYPAF5 also synergistically activated caspase-1-dependent cytokine processing when co-expressed with ASC. These ¢ndings suggest that PYPAF5 functions in immune cells to coordinate the transduction of pro-in£ammatory signals to the activation of NF-U UB and pro-caspase-1.