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 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 (