Delay of neutrophil apoptosis by the neuropeptide substance P: involvement of caspase cascade.
Neutrophil apoptosis is an important event in the resolution of inflammation. The role of substance P (SP) in neutrophil apoptosis has not been previously investigated. We found that substance P delays apoptosis in neutrophils. Human neutrophils were isolated and cultured up to 24 hours. Apoptosis was detected by light and electron microscopy, as well as DNA-fragmentation assays. Substance P delayed the spontaneous apoptosis of neutrophils at 6, 12, 18 and 24 hours in a dose-dependent fashion in the range of 10-100 microM. Whereas the both peptide neurokinin-1 (NK-1) receptor antagonists [D-Pro(2), D-Trp(7,9)]-SP and GR 82334 inhibited the substance P effect on neutrophils, the nonpeptide NK(1) receptor antagonist L-703.606 itself, an analogue of CP-96,345, induced apoptosis of neutrophils. Surprisingly, the effect of L-703.606 could be prevented by substance P. Western blotting results showed that the neuropeptide substance P inhibited the spontaneous apoptosis-associated caspase-3 activation in the same concentration range as described above. Parallel the inhibition of cleavage of focal adhesion kinase (FAK), a substrate of caspases could be observed by substance P. In conclusion, our results extend the range of biological effects of the neuropeptide substance P and provide new insight to the role of this tachykinin in the modulation of the inflammatory response by the nervous system.
Böckmann
S
S
Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty, University of Rostock, Germany. sabine.boeckmann@med.uni-rostock.de
Seep
J
J
Jonas
L
L
D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D008854:Microscopy, Electron; D064729:Neurokinin-1 Receptor Antagonists; D009504:Neutrophils / Q000166:cytology* / Q000648:ultrastructure; D013373:Substance P / Q000502:physiology*
D064729:Neurokinin-1 Receptor Antagonists; D013373:Substance P