Activation of Caspase-1 Signaling Complexes by the P2X7 Receptor Requires Intracellular K ^+ Efflux and Protein Synthesis Induced by Priming with Toll-Like Receptor Ligands

 
 
 
 

Activation of Caspase-1 Signaling Complexes by the P2X7 Receptor Requires Intracellular K ^+ Efflux and Protein Synthesis Induced by Priming with Toll-Like Receptor Ligands

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Title: Activation of Caspase-1 Signaling Complexes by the P2X7 Receptor Requires Intracellular K ^+ Efflux and Protein Synthesis Induced by Priming with Toll-Like Receptor Ligands
Author: Kahlenberg, Joanne Michelle
Description: Recent advances in understanding of the biology underlying hereditary inflammatory diseases have focused attention on the importance of regulating levels of the proinflammatory cytokine IL-1beta to prevent systematic inflammation. Diseases such as Muckle-Wells Syndrome and Familial Mediterranean Fever are characterized by inflammatory arthritis, episodic fevers and rashes, and amyloid deposition as well as elevated serum levels of IL-1beta. These inflammatory symptoms can be eliminated by antagonists to the IL-1beta receptor, stressing the role of elevated IL-1beta levels in inducing these inflammatory phenotypes. Additionally, the identification of genetic mutations underlying these inflammatory diseases has aided in the identification of a complex of molecules, termed the inflammasome, which recruits and activates caspase-1, the enzyme responsible for the cleavage of IL-1beta to its active form. The mechanisms regulating formation of the inflammasome remain ill defined but critical for the treatment and prevention of these and other inflammatory diseases. In this thesis, the mechanisms of caspase-1 activation between human monocyte (THP-1) and murine macrophage (Bac1) model systems are explored and defined. In particular, the assembly of caspase-1 activating complexes by a well-characterized activator of caspase-1, the P2X7 Receptor (P2X7R), is addressed. We show that intracellular K ^+ efflux following P2X7R activation is important for the induction of stable caspase-1 activating complexes, such as the inflammasome. This induction most likely requires the activity of Ca ^++ -independent phospholipase A2. Additionally, we demonstrate that Toll-Like Receptor (TLR) activation of NFkappaB-mediated transcription is essential for the P2X7R to activate caspase-1, suggesting that essential components of the inflammasome are not present in Bac1 macrophages at basal levels. Thus, we demonstrate that in order to rapidly assemble the inflammasome, cells must be treated with TLR agonists before activation of the P2X7R or treatment with other K ^+ release stimuli. These findings are among the first to show that activation of the P2X7R results in inflammasome assembly and caspase-1 activation, and they suggest that there is an important link between the P2X7R and innate immune signaling mechanisms.
Permanent Link: http://rave.ohiolink.edu/etdc/view?acc_num=case1088450614
http://hdl.handle.net/2374.OX/16686
Date: 2004

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