Neutrophil detox
http://www.100md.com
《实验药学杂志》
Neucalcin-1 treatment (bottom) prevents TNF- induced calcium flux (yellow and orange) in neutrophils.
On page 353, Han and colleagues describe a novel chemical inhibitor that shuts down the production of inflammation-induced oxidants by neutrophils, but does not compromise the ability of the cell to attack invading pathogens. This selective neutrophil disarmament may provide a way to limit the tissue-damaging side effects of neutrophil activation without crippling anti-microbial defenses—a feat presumed by many to be impossible.Neutrophils are among the immune system's earliest responders against invading pathogens. If these cells are missing or unable to function properly, life-threatening bacterial and fungal infections ensue. Neutrophil assault on invading pathogens is mediated in part by the release of reactive oxygen intermediates (ROIs) that damage microbes. But the benefits of this protection come at a cost. The same ROIs that help kill microbes contribute to the tissue damage that is often associated with prolonged inflammation.
As a result of this double-edged sword, a major challenge of anti-inflammatory therapy is to block the damaging side effects of neutrophils without crippling their anti-microbial functions. Han and colleagues have now found a chemical inhibitor that meets this tall order. The inhibitor blocked ROI production by neutrophils in response to the inflammatory cytokine tumor necrosis factor (TNF), but not in response to bacterial pathogens or a phorbol ester. Other neutrophil functions, including bacterial killing, migration, and degranulation were also unaffected by the inhibitor. This suggests that it is indeed possible to dissect neutrophil activation, a biological response that, according to senior author Carl Nathan, "was always presumed to be monolithic."
The inhibitor—dubbed neucalcin-1—worked by blocking the build-up of intracellular calcium that is normally triggered by TNF. The defective calcium flux prevented the activation of soluble adenylyl cyclase, which was required for the activation of a guanosine triphosphatase that associates with the ROI-producing enzyme complex on the plasma membrane. Although many details of this pathway remain to be unraveled, these data identify a completely new branch of TNF signaling and demonstrate the possibility of fine-tuning neutrophil inhibition without blocking TNF, which is required for the activation of other cell types and for protection against many bacterial infections.(Heather L. Van Epps)
On page 353, Han and colleagues describe a novel chemical inhibitor that shuts down the production of inflammation-induced oxidants by neutrophils, but does not compromise the ability of the cell to attack invading pathogens. This selective neutrophil disarmament may provide a way to limit the tissue-damaging side effects of neutrophil activation without crippling anti-microbial defenses—a feat presumed by many to be impossible.Neutrophils are among the immune system's earliest responders against invading pathogens. If these cells are missing or unable to function properly, life-threatening bacterial and fungal infections ensue. Neutrophil assault on invading pathogens is mediated in part by the release of reactive oxygen intermediates (ROIs) that damage microbes. But the benefits of this protection come at a cost. The same ROIs that help kill microbes contribute to the tissue damage that is often associated with prolonged inflammation.
As a result of this double-edged sword, a major challenge of anti-inflammatory therapy is to block the damaging side effects of neutrophils without crippling their anti-microbial functions. Han and colleagues have now found a chemical inhibitor that meets this tall order. The inhibitor blocked ROI production by neutrophils in response to the inflammatory cytokine tumor necrosis factor (TNF), but not in response to bacterial pathogens or a phorbol ester. Other neutrophil functions, including bacterial killing, migration, and degranulation were also unaffected by the inhibitor. This suggests that it is indeed possible to dissect neutrophil activation, a biological response that, according to senior author Carl Nathan, "was always presumed to be monolithic."
The inhibitor—dubbed neucalcin-1—worked by blocking the build-up of intracellular calcium that is normally triggered by TNF. The defective calcium flux prevented the activation of soluble adenylyl cyclase, which was required for the activation of a guanosine triphosphatase that associates with the ROI-producing enzyme complex on the plasma membrane. Although many details of this pathway remain to be unraveled, these data identify a completely new branch of TNF signaling and demonstrate the possibility of fine-tuning neutrophil inhibition without blocking TNF, which is required for the activation of other cell types and for protection against many bacterial infections.(Heather L. Van Epps)