期刊
BLOOD
卷 106, 期 10, 页码 3474-3482出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2005-03-1327
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- NCI NIH HHS [CA109446-01] Funding Source: Medline
- NIAID NIH HHS [AI 034879-17] Funding Source: Medline
- BLRD VA [I01 BX000513] Funding Source: Medline
Mycobacterium bovis bacillus Calmette-Guerin (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 a (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.
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