Neutral endopeptidase modulates substance P-induced activation of human neutrophils.
Neutral endopeptidase (NEP; EC 3.4.24.11) is well recognized as a regulatory peptidase for substance P (SP)-induced responses in various tissues. To determine whether NEP regulates SP-induced activation of human neutrophils, we examined the effect of the NEP inhibitor phosphoramidon on SP-induced superoxide generation and chemotaxis in human blood neutrophils. SP (10(-6)-10(-4) M) induced superoxide generation and chemotaxis in the neutrophils dose dependently. The NEP inhibitor enhanced the SP-induced responses. Thus, phosphoramidon (10(-6) M) shifted the dose-response curves of SP-induced superoxide generation and chemotaxis of the neutrophils to the left by 0.5-0.6 log. Phosphoramidon prevented the hydrolysis of SP by the neutrophils, the NEP activity of the neutrophils being assessed as 125 +/- 13 pmol of SP/min/10(6) cells. The N-terminal peptide SP (up to 3 x 10(-4) M), which was a major degrading product by NEP of the neutrophils, did not activate the neutrophils. We conclude that NEP modulates SP-induced activation of human neutrophils.
Iwamoto
I
I
Second Department of Internal Medicine, Chiba University School of Medicine, Japan.
Kimura
A
A
Yamazaki
H
H
Nakagawa
N
N
Tomioka
H
H
Yoshida
S
S
D006801:Humans; D066298:In Vitro Techniques; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000502:physiology*; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D010446:Peptide Fragments / Q000494:pharmacology; D013373:Substance P / Q000378:metabolism / Q000494:pharmacology*
D010446:Peptide Fragments; D013373:Substance P; D015260:Neprilysin