title: A20 promotes Brucella intracellular growth via inhibition of macrophage cell death and activation.
abstract: The zinc-finger protein A20 has crucial physiological functions as a dual inhibitor of macrophage activation and apoptosis in tumor necrosis factor receptor1 (TNFR1) signaling pathway. Brucella infection can induce A20 expression in macrophages. Here, we hypothesize that A20 promotes Brucella intracellular growth via inhibition of activation and apoptosis of macrophages. To test this hypothesis, we stably incorporated mouse A20-shRNA into the RAW264.7 cells by lentiviral gene transfer to successfully knockdown A20. A20-deficient RAW264.7 cells were subsequently challenged with Brucella abortus and colony formation units (CFUs) of bacteria, TNFα production, NF-kB activation, macrophages apoptosis and cell death were evaluated. The A20 knockdown was shown to effectively promote B. abortus-stimulated TNFα release, NF-kB activation and macrophage cell death, which suppressed B. abortus intracellular replication. Unexpectedly, deficiency of A20 failed to lead to B. abortus-induced macrophage apoptosis. A20 deficiency coupled NF-kB inhibition promoted caspase-8 dependent B. abortus-induced macrophage apoptosis. These findings provide a novel mechanism by which Brucella intracellular growth within macrophages occurs through up-regulation of A20 thereby limiting activation and macrophages cell death.
authors.affiliation: Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, Jilin University, Changchun 130062, People's Republic of China.
authors.forename: Pan
authors.initials: P
authors.lastname: Wei
authors.affiliation: Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, Jilin University, Changchun 130062, People's Republic of China.
authors.forename: Guimei
authors.initials: G
authors.lastname: Cui
authors.affiliation: Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, Jilin University, Changchun 130062, People's Republic of China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, Jilin University, Changchun 130062, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, Jilin University, Changchun 130062, People's Republic of China.
authors.forename: Zhenhong
authors.initials: Z
authors.lastname: Guan
authors.affiliation: Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, Jilin University, Changchun 130062, People's Republic of China.
authors.forename: Wanchun
authors.initials: W
authors.lastname: Sun
authors.affiliation: Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, Jilin University, Changchun 130062, People's Republic of China.
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University, Qilu Hospital, Jinan City, Shandong 250012, People's Republic of China.
authors.forename: Shuangxi
authors.initials: S
authors.lastname: Wang
authors.affiliation: Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, Jilin University, Changchun 130062, People's Republic of China. Electronic address: Qishengpeng@yahoo.com.
authors.forename: Qisheng
authors.initials: Q
authors.lastname: Peng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002003:Brucella abortus / Q000254:growth & development*; D002006:Brucellosis / Q000382:microbiology*; D053181:Caspase 8 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D055785:Gene Knockdown Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D042541:Intracellular Space / Q000382:microbiology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D053181:Caspase 8; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse
keywords: A20; Activation; Brucella abortus; Macrophage