Dapsone suppresses human neutrophil superoxide production and elastase release in a calcium-dependent manner

Suda, Takane; Suzuki, Yoshihiro; Matsui, Takashi; Inoue, Takuya; Niide, Osamu; Yoshimaru, Tetsuro; Suzuki, Hiromi; Ra, Chisei; Ochiai, Toyoko

doi:10.1111/j.1365-2133.2005.06559.x

Cited by 71 publications

(62 citation statements)

References 27 publications

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“…26,27 We confirmed this for murine neutrophils, finding a dose-dependent reduction in ROS production at decreasing concentrations of extracellular calcium (supplemental Figure 3A-B).…”

Section: Stim1-deficient Neutrophils Are Defective In Gpcr-and Tyrosisupporting

confidence: 67%

STIM1 calcium sensor is required for activation of the phagocyte oxidase during inflammation and host defense

Zhang¹,

Clemens

Liu

et al. 2014

Blood

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“…26,27 We confirmed this for murine neutrophils, finding a dose-dependent reduction in ROS production at decreasing concentrations of extracellular calcium (supplemental Figure 3A-B).…”

Section: Stim1-deficient Neutrophils Are Defective In Gpcr-and Tyrosisupporting

confidence: 67%

STIM1 calcium sensor is required for activation of the phagocyte oxidase during inflammation and host defense

Zhang¹,

Clemens

Liu

et al. 2014

Blood

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“…In addition to its antibacterial activity, DDS has been reported to be involved in other cellular processes that occur in eukaryotic cells, such as inflammation, migration, and apoptosis (6). However, there has been controversy over the issue of whether DDS acts as a pro-oxidant (especially when a higher dose of DDS is used rather than a standard dose) or antioxidant (7)(8)(9). Most studies on the pro-oxidant effects of DDS have been based on its use at high concentrations.…”

mentioning

confidence: 99%

DDS, 4,4′-diaminodiphenylsulfone, extends organismic lifespan

Cho

Park

Keam

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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DDS, 4,4′-diaminodiphenylsulfone, is the most common drug prescribed to treat Hansen disease patients. In addition to its antibacterial activity, DDS has been reported to be involved in other cellular processes that occur in eukaryotic cells. Because DDS treatment significantly enhances the antioxidant activity in humans, we examined its effect on lifespan extension. Here we show that DDS extends organismic lifespan using Caenorhabditis elegans as a model system. DDS treatment caused a delay in aging and decreased the levels of a mitochondrial complex. The oxygen consumption rate was also significantly lowered. Consistent with these data, paraquat treatment evoked less reactive oxygen species in DDS-treated worms, and these worms were less sensitive to paraquat. Interestingly enough, all of the molecular events caused by DDS treatment were consistently reproduced in mice treated with DDS for 3 mo and in the C2C12 muscle cell line. Structural prediction identified pyruvate kinase (PK) as a protein target of DDS. Indeed, DDS bound and inhibited PK in vitro and inhibited it in vivo, and a PK mutation conferred extended lifespan of C. elegans. Supplement of pyruvate to the media protected C2C12 cells from apoptosis caused by paraquat. Our findings establish the significance of DDS in lowering reactive oxygen species generation and extending the lifespan, which renders the rationale to examining the possible effect of DDS on human lifespan extension.F irst synthesized a century ago, 4,4′-diaminodiphenylsulfone (DDS) is a drug still used to treat many skin diseases. Specifically, DDS is a principal drug in a multidrug regimen recommended by the World Health Organization for the treatment of leprosy (1-4). DDS acts as an antibiotic in a manner similar to sulphonamides by inhibiting bacterial synthesis of dihydrofolic acid through competition with para-aminobenzoic acid (PABA) for the active site of dihydropteroate synthetase (DHPS) (5). In addition to its antibacterial activity, DDS has been reported to be involved in other cellular processes that occur in eukaryotic cells, such as inflammation, migration, and apoptosis (6). However, there has been controversy over the issue of whether DDS acts as a pro-oxidant (especially when a higher dose of DDS is used rather than a standard dose) or antioxidant (7-9). Most studies on the pro-oxidant effects of DDS have been based on its use at high concentrations. For example, in human dermal fibroblasts, a high dose of DDS (1.5 mM) induced oxidative stress and glutathione depletion (10), but in rat livers, DDS administration at a dose of 30 mg/kg body weight resulted in oxidative stress (11). Therefore, the debate regarding the nature of DDS as a pro-oxidant or antioxidant appears to reflect the dosage effect. Another interesting observation is that Hansen disease patients in Korea, who usually have taken DDS for several decades, had a longer lifespan in spite of their socioeconomical disadvantages (12). This finding prompted us to examine whether and how DDS treatment extends an...

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“…Previously, DDS has been known to suppress ROS production in phagocytic neutrophils (Suda et al, 2005). In addition, we also showed that DDS effectively suppresses ROS generation in non-phagocytic cells by inhibiting the NADPH oxidase (NOX) system (Cho et al, 2010a).…”

Section: Introductionmentioning

confidence: 59%

Protective effect of 4,4'-diaminodiphenylsulfone against paraquat-induced mouse lung injury

et al. 2011

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Although 4,4'-diaminodiphenylsulfone (DDS, dapsone) has been used to treat several dermatologic conditions, including Hansen disease, for the past several decades, its mode of action has remained a topic of debate. We recently reported that DDS treatment significantly extends the lifespan of the nematode C. elegans by decreasing the generation of reactive oxygen species. Additionally, in in vitro experiments using non-phagocytic human fibroblasts, we found that DDS effectively counteracted the toxicity of paraquat (PQ). In the present study, we extended our work to test the protective effect of DDS against PQ in vivo using a mouse lung injury model. Oral administration of DDS to mice significantly attenuated the lung tissue damage caused by subsequent administration of PQ.Moreover, DDS reduced the local expression of mRNA transcripts encoding inflammation-related molecules, including endothelin-1 (ET-1), macrophage inflammatory protein-1α (MIP-1α), and transforming growth factor-β (TGF-β). In addition, DDS decreased the PQ-induced expression of NADPH oxidase mRNA and activation of protein kinase Cμ (PKCμ). DDS treatment also decreased the PQ-induced generation of superoxide anions in mouse lung fibroblasts. Taken together, these data suggest the novel efficacy of DDS as an effective protective agent against oxidative stress-induced tissue damages.

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Dapsone suppresses human neutrophil superoxide production and elastase release in a calcium-dependent manner

Abstract: 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.

Cited by 71 publications

References 27 publications

STIM1 calcium sensor is required for activation of the phagocyte oxidase during inflammation and host defense

STIM1 calcium sensor is required for activation of the phagocyte oxidase during inflammation and host defense

DDS, 4,4′-diaminodiphenylsulfone, extends organismic lifespan

Protective effect of 4,4'-diaminodiphenylsulfone against paraquat-induced mouse lung injury

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