title: Neutrophil stimulation with Mycobacterium bovis bacillus Calmette-Guerin (BCG) results in the release of functional soluble TRAIL/Apo-2L.
abstract: Mycobacterium bovis bacillus Calmette-Guérin (BCG) has been used to treat bladder cancer for almost 30 years; however, the effector mechanism of the BCG-induced antitumor response remains enigmatic. Most BCG research has focused on the mononuclear-cell infiltrate, but growing evidence supports a role for neutrophils in the antitumor response. Previously, we demonstrated increased urinary tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo-2L) levels from BCG-responsive patients compared to nonresponders. Interestingly, neutrophils isolated from the urine expressed TRAIL/Apo-2L, leading us to investigate the neutrophil response to BCG. BCG-stimulated neutrophils expressed surface-bound and released functional soluble TRAIL/Apo-2L. Whereas neither interferon alpha (IFN-alpha) nor IFN-gamma directly induced TRAIL/Apo2L expression by neutrophils, IFN-alpha did stimulate TRAIL gene transcription, and IFN-primed neutrophils contained and released more TRAIL/Apo-2L after BCG stimulation than did unprimed neutrophils. In unstimulated neutrophils TRAIL/Apo-2L was present predominantly in the azurophilic granules and plasma-membrane-enriched/secretory-granule fraction. Finally, we observed that killed BCG, Toll-like receptor 2 (TLR2) and TLR4 agonists, and an M tuberculosis cell-wall fraction were each capable of inducing the release of soluble TRAIL/Apo-2L from neutrophils. These results further characterize the potential role neutrophils may play in initiating the antitumor response described with BCG treatment for superficial bladder cancer.
authors.affiliation: Department of Urology, Interdisciplinary Graduate Program in Immunolgy, University of Iowa, Iowa City, 52242, USA.
authors.forename: Troy J
authors.initials: TJ
authors.lastname: Kemp
authors.forename: Aaron T
authors.initials: AT
authors.lastname: Ludwig
authors.forename: James K
authors.initials: JK
authors.lastname: Earel
authors.forename: Jill M
authors.initials: JM
authors.lastname: Moore
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Vanoosten
authors.forename: Bonita
authors.initials: B
authors.lastname: Moses
authors.forename: Kevin
authors.initials: K
authors.lastname: Leidal
authors.forename: William M
authors.initials: WM
authors.lastname: Nauseef
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Griffith
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism*; D002473:Cell Wall / Q000737:chemistry; D002478:Cells, Cultured; D045424:Complex Mixtures / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D009163:Mycobacterium bovis / Q000276:immunology*; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D022142:Secretory Vesicles / Q000276:immunology / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000276:immunology / Q000382:microbiology / Q000628:therapy
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D045424:Complex Mixtures; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma