The P2X 7 receptor (P2X 7 R) is an ATP-gated ion channel expressed by monocytes and macrophages. To directly address the role of this receptor in interleukin (IL)-1 post-translational processing, we have generated a P2X 7 R-deficient mouse line. P2X 7 R ؊/؊ macrophages respond to lipopolysaccharide and produce levels of cyclooxygenase-2 and pro-IL-1 comparable with those generated by wild-type cells. In response to ATP, however, pro-IL-1 produced by the P2X 7 R ؊/؊ cells is not externalized or activated by caspase-1. Nigericin, an alternate secretion stimulus, promotes release of 17-kDa IL-1 from P2X 7 R ؊/؊ macrophages. In response to in vivo lipopolysaccharide injection, both wild-type and P2X 7 R ؊/؊ animals display increases in peritoneal lavage IL-6 levels but no detectable IL-1. Subsequent ATP injection to wild-type animals promotes an increase in IL-1, which in turn leads to additional IL-6 production; similar increases did not occur in ATPtreated, LPS-primed P2X 7 R ؊/؊ animals. Absence of the P2X 7 R thus leads to an inability of peritoneal macrophages to release IL-1 in response to ATP. As a result of the IL-1 deficiency, in vivo cytokine signaling cascades are impaired in P2X 7 R-deficient animals. Together these results demonstrate that P2X 7 R activation can provide a signal that leads to maturation and release of IL-1 and initiation of a cytokine cascade.
A new class of glutathione transferases has been discovered by analysis of the expressed sequence tag data base and sequence alignment. Glutathione S-transferases (GSTs) of the new class, named Omega, exist in several mammalian species and Caenorhabditis elegans. In humans, GSTO 1-1 is expressed in most tissues and exhibits glutathione-dependent thiol transferase and dehydroascorbate reductase activities characteristic of the glutaredoxins. The structure of GSTO 1-1 has been determined at 2.0-Å resolution and has a characteristic GST fold (Protein Data Bank entry code 1eem). The Omega class GSTs exhibit an unusual N-terminal extension that abuts the C terminus to form a novel structural unit. Unlike other mammalian GSTs, GSTO 1-1 appears to have an active site cysteine that can form a disulfide bond with glutathione.
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