title: Mycobacterial infection induces the secretion of high-mobility group box 1 protein.
abstract: High-mobility group box protein 1 (HMGB1) is a non-histone nuclear protein that acts as a pro-inflammatory cytokine and is released by monocytes and macrophages. Necrotic cells also release HMGB1 at the site of tissue damage which induces a variety of cellular responses, including the expression of pro-inflammatory mediators. This study investigated the secretion of HMGB1 in mycobacterial infection by macrophages in vitro and in the lungs of infected guinea pigs. We observed that infection by mycobacterium effectively induced HMGB1 release in both macrophage and monocytic cell cultures. Culture filtrate proteins from Mycobacterium tuberculosis induced maximum release of HMGB1 compared with different subcellular fractions of mycobacterium. We demonstrated that HMGB1 is released in lungs during infection of M. tuberculosis in guinea pigs and increased HMGB1 secretion in lungs of guinea pigs was delayed by prior vaccination with Mycobacterium bovis BCG. The secretion of cytokines like tumour necrosis factor alpha (TNF-alpha) and Interleukin-1beta was significantly increased when M. bovis BCG-infected cultures of J774A.1 cells were incubated with HMGB1. Among different mycobacterial toll-like receptor ligands, heat-shock protein 65 (HSP65) was found to be more potent in inducing HMGB1 secretion in RAW 264.7 cells. Pharmacological suppression of p38 or extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases with specific inhibitors failed to inhibit HSP65-induced HMGB1 release, but inhibition of c-Jun NH(2)-terminal kinase activation attenuated HMGB1 release. Inhibition of the inducible NO synthase and neutralizing antibodies against TNF-alpha also reduced HMGB1 release stimulated by HSP65. We conclude that HMGB1 is secreted by macrophages during tuberculosis and it may act as a signal of tissue or cellular injury and enhances immune response.
authors.affiliation: Department of Microbiology, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Grover
authors.forename: Jennifer
authors.initials: J
authors.lastname: Taylor
authors.forename: Jolynn
authors.initials: J
authors.lastname: Troudt
authors.forename: Andrew
authors.initials: A
authors.lastname: Keyser
authors.forename: Kirsa
authors.initials: K
authors.lastname: Sommersted
authors.forename: Alan
authors.initials: A
authors.lastname: Schenkel
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Izzo
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage; D001426:Bacterial Proteins / Q000502:physiology; D002460:Cell Line; D018834:Chaperonin 60; D018833:Chaperonins / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis; D006168:Guinea Pigs; D024243:HMGB1 Protein / Q000378:metabolism*; D007279:Injections, Subcutaneous; D008168:Lung / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009164:Mycobacterium Infections / Q000276:immunology / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000737:chemistry; D014611:Vaccination
chemical_list: D001500:BCG Vaccine; D001426:Bacterial Proteins; D018834:Chaperonin 60; D016207:Cytokines; D024243:HMGB1 Protein; C074119:heat-shock protein 65, Mycobacterium; D018833:Chaperonins