title: Granzyme A produces bioactive IL-1β through a nonapoptotic inflammasome-independent pathway.
abstract: Bacterial components are recognized by the immune system through activation of the inflammasome, eventually causing processing of the proinflammatory cytokine interleukin-1? (IL-1?), 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? 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-?? 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? maturation independently of caspase-1 and without inducing cytotoxicity. These findings show that macrophages can induce an IL-1?-initiated immune response independently of inflammasome activity.
authors.affiliation: Department für Infektiologie, Medizinische Mikrobiologie und Hygiene, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Hildebrand
authors.affiliation: Department für Infektiologie, Medizinische Mikrobiologie und Hygiene, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Konrad A
authors.initials: KA
authors.lastname: Bode
authors.affiliation: Department für Infektiologie, Medizinische Mikrobiologie und Hygiene, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Rieß
authors.affiliation: Department für Infektiologie, Medizinische Mikrobiologie und Hygiene, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cerny
authors.affiliation: Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Trogerstraße 30, 81675 München, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Waldhuber
authors.affiliation: Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Trogerstraße 30, 81675 München, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Römmler
authors.affiliation: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität Freiburg, Albertstraße 25, 79104 Freiburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Strack
authors.affiliation: Labor Lademannbogen MVZ GmbH, Lademannbogen 61-63, 22339 Hamburg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Korten
authors.affiliation: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität Freiburg, Albertstraße 25, 79104 Freiburg, Germany.
authors.forename: Joachim H C
authors.initials: JH
authors.lastname: Orth
authors.affiliation: Institut für Medizinische Mikrobiologie und Hygiene, Medizinische Fakultät Mannheim der Universität Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Miethke
authors.affiliation: Department für Infektiologie, Medizinische Mikrobiologie und Hygiene, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Heeg
authors.affiliation: Department für Infektiologie, Medizinische Mikrobiologie und Hygiene, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany. Electronic address: kubatzky@uni-heidelberg.de.
authors.forename: Katharina F
authors.initials: KF
authors.lastname: Kubatzky
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001426:Bacterial Proteins / Q000494:pharmacology; D001427:Bacterial Toxins / Q000494:pharmacology; D020170:Caspase 1 / Q000378:metabolism; D053804:Granzymes / Q000378:metabolism*; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D054353:Perforin / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; D058847:Inflammasomes; D053583:Interleukin-1beta; D016328:NF-kappa B; C062258:Pasteurella multocida toxin; D050791:STAT Transcription Factors; D051193:Toll-Like Receptors; D054353:Perforin; D053612:Janus Kinases; D054460:rho-Associated Kinases; D053804:Granzymes; D020170:Caspase 1; D020742:rhoA GTP-Binding Protein