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

作者：Hildebrand Dagmar; Bode Konrad A; Riess David; Cerny Daniela; Waldhuber Anna; Roemmler Franziska; Strack Julia; Korten Simone; Orth Joachim H C; Miethke Thomas; Heeg Klaus; Kubatzky Katharina F^*

来源：Cell Reports, 2014, 9(3): 910-917.

DOI：10.1016/j.celrep.2014.10.003

Bacterial components are recognized by the immune system through activation of the inflammasome, eventually causing processing of the proinflammatory cytokine interleukin-1 beta (IL-1 beta), 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-1 beta 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-kappa B 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-1 beta maturation independently of caspase-1 and without inducing cytotoxicity. These findings show that macrophages can induce an IL-1 beta-initiated immune response independently of inflammasome activity.

• 出版日期2014-11-6
• 单位河北医科大学