Granzyme A Produces Bioactive IL-1β through a Nonapoptotic Inflammasome-Independent Pathway

Bacterial components are recognized by the immune system through activation of the inflammasome, eventually causing processing of the proinflammatory cytokine interleukin-1β (IL-1β), a pleiotropic cytokine and one of the most important mediators of inflammation, through the protease caspase-1. Synth...

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Veröffentlicht in:Cell reports (Cambridge) 2014-11, Vol.9 (3), p.910-917
Hauptverfasser: Hildebrand, Dagmar, Bode, Konrad A., Rieß, David, Cerny, Daniela, Waldhuber, Anna, Römmler, Franziska, Strack, Julia, Korten, Simone, Orth, Joachim H.C., Miethke, Thomas, Heeg, Klaus, Kubatzky, Katharina F.
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Sprache:eng
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Zusammenfassung:Bacterial components are recognized by the immune system through activation of the inflammasome, eventually causing processing of the proinflammatory cytokine interleukin-1β (IL-1β), a pleiotropic cytokine and one of the most important mediators of inflammation, through the protease caspase-1. Synthesis of the precursor protein and processing into its bioactive form are tightly regulated, given that disturbed control of IL-1β release can cause severe autoinflammatory diseases or contribute to cancer development. We show that the bacterial Pasteurella multocida toxin (PMT) triggers Il1b gene transcription in macrophages independently of Toll-like receptor signaling through RhoA/Rho-kinase-mediated NF-κΒ activation. Furthermore, PMT mediates signal transducer and activator of transcription (STAT) protein-controlled granzyme A (a serine protease) expression in macrophages. The exocytosed granzyme A enters target cells and mediates IL-1β maturation independently of caspase-1 and without inducing cytotoxicity. These findings show that macrophages can induce an IL-1β-initiated immune response independently of inflammasome activity. [Display omitted] •PMT triggers IL-1β transcription through RhoA/ROCK-activated NF-кB•Granzyme A is expressed in macrophages through STAT activation•Granzyme A cleaves IL-1β intracellularly into bioactive IL-1β•PMT stimulates IL-1β maturation through an inflammasome-independent pathway Bacterial components are recognized by the immune system through activation of the inflammasome, eventually causing processing of the proinflammatory cytokine interleukin-1β (IL-1β) through the protease caspase-1. Hildebrand et al. describe a mechanism that bypasses inflammasome activation. Instead, Pasteurella multocida toxin stimulates the expression of the serine protease granzyme A that mediates maturation of IL-1β into a bioactive cytokine.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2014.10.003