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
Year: 2004
Type: article
Abstract: 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-1β 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-1β.These inflammatory symptoms can be eliminated by antagonists to the IL-1β receptor, stressing the role of elevated IL-1β 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-1β 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 NFκB-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.
Author: Kahlenberg, Joanne Michelle
Institution: Case Western Reserve University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W6998537542