The suppression of granulocyte functions by lipophilic antioxidants.
The effects of several antioxidants on the three major functions of human neutrophils--oxidative burst, secretion and leukotriene formation--were investigated with special emphasis on the lipophilicity. The most striking differences were obtained when ascorbate and the lipophilic ester ascorbyl palmitate were compared. As expected, the luminol- and lucigenin-dependent chemiluminescence was inhibited by all antioxidants to a different degree. Ascorbyl palmitate was able to block the biphasic luminol-dependent response completely with IC50 values of 10 and 25 microM for the first and second phase, respectively. In contrast, ascorbate only blocked efficiently the first phase of the response. The secretion of elastase was inhibited by ascorbyl palmitate dose-dependently with an IC50 value of around 200 microM, whereas ascorbate was completely inactive. Electron microscopy supported the assumption that inhibition was due to a block in degranulation and not to enzyme inactivation. This was further supported by a parallel, although somewhat lower, inhibition of other secretory enzymes like myeloperoxidase, beta-glucuronidase or lysozyme. Cells treated with the Ca2+-ionophore A23187 responded by LTB4-synthesis which was also inhibited by ascorbyl palmitate. A very efficient inhibition was observed in cell homogenates with an IC50 value of 1.5 microM. No inhibition by ascorbate was detected in both systems. Concomitant with the inhibition of 5-lipoxygenase the activity of 15-lipoxygenase increased. We conclude that cellular reductants may control neutrophil functions and that the inhibition by ascorbyl palmitate of the three processes relevant for inflammatory responses could be of therapeutic importance.
Baader
W J
WJ
Faculty of Biology, University of Konstanz, Federal Republic of Germany.
Hatzelmann
A
A
Ullrich
V
V
D000166:Acridines / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology; D001205:Ascorbic Acid / Q000494:pharmacology; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007975:Leukotriene B4 / Q000096:biosynthesis; D008163:Luminescent Measurements; D008165:Luminol / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism
D000166:Acridines; D000975:Antioxidants; D007975:Leukotriene B4; C033472:10,10'-dimethyl-9,9'-biacridinium; D009240:N-Formylmethionine Leucyl-Phenylalanine; D008165:Luminol; D001094:Arachidonate 5-Lipoxygenase; D001205:Ascorbic Acid