TY - JOUR
T1 - Mechanisms of the Macrolide-Induced Inhibition of Superoxide Generation by Neutrophils
AU - Nozoe, Kohji
AU - Aida, Yoshitomi
AU - Fukuda, Takao
AU - Sanui, Terukazu
AU - Nishimura, Fusanori
N1 - Funding Information:
This work was supported by a grant-in-aid (26463137) to T.F. from the Ministry of Health of Japan.
Publisher Copyright:
© 2016, Springer Science+Business Media New York.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - The effect of macrolides on the superoxide (O2 −) production by neutrophils was studied. Resting neutrophils become primed by lipopolysaccharide (LPS) or N-formyl-methionyl-leucyl-phenylalanine (fMLP), and primed neutrophils generate O2 − in response to fMLP or adhesion, respectively. Both LPS-primed fMLP-stimulated O2 − generation by macrolide-treated neutrophils and adhesion-stimulated O2 − generation by macrolide-treated fMLP-primed neutrophils were inhibited. Macrolide inhibition of O2 − generation was dependent on serum or pH. Serum could be substituted by NaHCO3. The intensity of inhibition was azithromycin = roxithromycin > clarithromycin > erythromycin, in that order. Non-antimicrobial derivatives of erythromycin, that is, EM703 and EM900, inhibited O2 − generation at pH 7.4. NH4Cl abolished the activity of azithromycin (AZ) only when added to neutrophils with AZ but not after incubation with AZ, suggesting that NH4Cl prevented the influx of AZ. AZ did not affect the expression of alkaline phosphatase, CD11b, and cytochrome b558 in both resting and LPS-primed neutrophils. These results suggested that macrolides did not affect granule mobilization but inhibited O2 − generation selectively.
AB - The effect of macrolides on the superoxide (O2 −) production by neutrophils was studied. Resting neutrophils become primed by lipopolysaccharide (LPS) or N-formyl-methionyl-leucyl-phenylalanine (fMLP), and primed neutrophils generate O2 − in response to fMLP or adhesion, respectively. Both LPS-primed fMLP-stimulated O2 − generation by macrolide-treated neutrophils and adhesion-stimulated O2 − generation by macrolide-treated fMLP-primed neutrophils were inhibited. Macrolide inhibition of O2 − generation was dependent on serum or pH. Serum could be substituted by NaHCO3. The intensity of inhibition was azithromycin = roxithromycin > clarithromycin > erythromycin, in that order. Non-antimicrobial derivatives of erythromycin, that is, EM703 and EM900, inhibited O2 − generation at pH 7.4. NH4Cl abolished the activity of azithromycin (AZ) only when added to neutrophils with AZ but not after incubation with AZ, suggesting that NH4Cl prevented the influx of AZ. AZ did not affect the expression of alkaline phosphatase, CD11b, and cytochrome b558 in both resting and LPS-primed neutrophils. These results suggested that macrolides did not affect granule mobilization but inhibited O2 − generation selectively.
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U2 - 10.1007/s10753-016-0333-3
DO - 10.1007/s10753-016-0333-3
M3 - Article
C2 - 26983705
AN - SCOPUS:84961210447
SN - 0360-3997
VL - 39
SP - 1039
EP - 1048
JO - Inflammation
JF - Inflammation
IS - 3
ER -