Dapsone suppresses human neutrophil superoxide production and elastase release in a calcium-dependent manner.
BACKGROUND
Dapsone (4,4'-diaminodiphenyl sulphone) is a powerful therapeutic tool in many skin diseases including neutrophilic dermatoses. The drug has an outstanding therapeutic efficacy against many skin diseases characterized by neutrophil-rich infiltrates; however, mechanisms of its action are poorly understood.


OBJECTIVE
We investigated the effects of dapsone on respiratory and secretory functions of human neutrophils triggered by the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), the physiological agonist C5a, and phorbol myristate acetate (PMA).


METHODS
Human neutrophils were isolated from venous blood obtained from healthy donors. We detected extracellular production of superoxide (O(2) (-)) by cytochrome C reduction assay, and intracellular production of O(2) (-) by flow cytometry. Neutrophil elastase release was measured by the cleavage of the specific elastase substrate N-methoxysuccinyl-Ala-Ala-Pro-Val-p-nitroanilide. Measurement of cytosolic free calcium concentration was performed using the calcium-reactive fluorescence probe, Fluo-3.


RESULTS
Dapsone suppressed intra- and extracellular production of O(2) (-) and elastase release triggered by fMLP and C5a, but not by PMA. Both fMLP and C5a signalled the above pathways by inducing calcium influx, but PMA functions bypassed calcium influx. Dapsone was capable of antagonizing the induction of calcium influx.


CONCLUSIONS
These findings suggest that one mechanism of the anti-inflammatory action of dapsone is inhibition of calcium-dependent functions of neutrophils including release of tissue-damaging oxidants and proteases in the affected skin.
Suda
T
T
Department of Dermatology, Nihon University School of Medicine, 30-1 Oyaguchi-kamimachi, Itabashi-ku, Tokyo 173-8610, Japan.
Suzuki
Y
Y
Matsui
T
T
Inoue
T
T
Niide
O
O
Yoshimaru
T
T
Suzuki
H
H
Ra
C
C
Ochiai
T
T
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D015936:Complement C5a / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003622:Dapsone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010196:Pancreatic Elastase / Q000378:metabolism*; D016897:Respiratory Burst / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015936:Complement C5a; D003622:Dapsone; D010196:Pancreatic Elastase; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium