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Effect of the Ag3PO4 on Staphylococcus aureus Growth and Human Immunity
Biomed Sci Letters 2018;24:30-34
Published online March 31, 2018;  https://doi.org/10.15616/BSL.2018.24.1.30
© 2018 The Korean Society For Biomedical Laboratory Sciences.

Mi Kyung Kim1,†, and Dae-Sik Kim2

1Department of Systems Biology, College of Life Science, Yonsei University, Seoul 03722, Korea,
2Department of Clinical Laboratory Science, Dongnam Health University, Suwon 16328, Korea
Correspondence to: Mi Kyung Kim. Department of Systems Biology, College of Life Science, Yonsei University, Seoul 03722, Korea. Tel: +82-2-2123-2709, Fax: +82-2-312-5657, e-mail: biokyung@gmail.com
Received January 3, 2018; Revised March 12, 2018; Accepted March 13, 2018.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
 Abstract

Silver (Ag) has been widely used in commercial products and medical fields since ancient times because of its antibacterial effect. It is harmless and non-toxic to the human body. For this reason, recent research has actively evaluated antimicrobial activity using silver (Ag). In this study, we investigated the inhibitory effect of a silver-based compound, silver phosphate (Ag3PO4) on the growth of Staphylococcus aureus and the activation of human immunity. First, the inhibitory effect of Ag3PO4 on the growth of Staphylococcus aureus was confirmed by a growth curve and a colony-ounting method. As a result, the growth inhibitory effect increased as the concentration of Ag3PO4 increased. Specifically, treatment with 5 μg/mL of Ag3PO4 resulted in no bacteria growth, and the colony-counting method showed a remarkable inhibition. In addition, the expression of cytokine IL-8 by Ag3PO4 was examined to investigate the cellular immune system activation by Ag3PO4. After pretreatment of Staphylococcus aureus for 1 hour with 50 μg/mL Ag3PO4, an increased IL-8 mRNA expression resulted. In cells treated with Ag3PO4, we found that the expression of IL-8 was enhanced in a time-dependent fashion compared to non-treated cells. These results indicate that Ag3PO4 induces antimicrobial activity against Staphylococcus aureus and activates human immunity. These results are expected to contribute to the future study of the mechanism of silver (Ag) and silver-based compounds in relation to antibacterial activity.

Keywords : Silver, Staphylococcus aureus, Antibacterial, Immunity
꽌濡

(Ag, silver) 빆洹 슚怨 븣臾몄뿉 怨좊遺꽣 긽뾽 젣뭹 諛 쓽猷 遺꾩빞뿉꽌 떎뼇븯寃 궗슜릺怨 엳떎(Klaine et al., 2008). 理쒓렐뿉뒗 씠삩(Ag+)씠 諛뺥뀒由ъ븘쓽 궗寃쎈줈瑜 뼲젣븯뿬 ROS 깮궛쓣 쑀룄븯怨 씠 蹂솕媛 뵒꽕뙆씠뱶 寃고빀 삎꽦쓣 뼲젣븿쑝濡쒖뜥 留 닾怨쇱꽦쓣 利앷떆耳 諛뺥뀒由ъ븘 꽭룷궗硫몄쓣 쑀룄븳떎뒗 寃껋씠 諛앺議뚮떎(Morones-Ramirez et al., 2013). 삉븳 Ag3PO4媛 떇臾 以꾧린 留덈쫫蹂묒쓽 썝씤洹좎씤 Pseudomonas syrigae쓽 꽦옣쓣 뼲젣븯怨 떇臾쇰㈃뿭泥닿퀎瑜 쑀룄븿씠 諛앺졇 슚怨쇱쟻씤 떇臾 吏덈퀝 議곗젅젣濡쒖꽌쓽 궗슜媛뒫꽦씠 젣떆릺뿀떎(Kim et al., 2016). Staphylococcus aureus뒗 洹몃엺뼇꽦洹좎씤 룷룄긽援ш퇏쓽 븳 醫낆쑝濡 떇以묐룆肉먮쭔 븘땲씪 뵾遺쓽 솕냽 · 以묒씠뿼 · 諛⑷킅뿼 벑 솕냽꽦 吏덊솚쓣 씪쑝궎뒗 썝씤洹좎씠떎(Masalha et al., 2001). 럹땲떎由(硫뷀떚떎由, 뵒肄쒕줉궗떎由, 궔떎由, 삦궗떎由 쇅)怨 꽭뙏濡쒖뒪룷由곗쓣 룷븿븳 β-씫깘怨 빆깮臾쇱쭏뿉 궡꽦쓣 쉷뱷븳 솴깋 룷룄긽援ш퇏 硫뷀떚떎由 궡꽦 솴깋 룷룄긽援ш퇏(Methicillin-resistant Staphylococcus aureus, MRSA)씠씪 븯뒗뜲, 궗엺뿉寃 媛먯뿼릺뼱 뿬윭 媛吏 蹂묒쓣 씪쑝耳 臾몄젣媛 릺怨 엳떎(Gurusamy et al., 2013). 蹂 끉臾몄뿉꽌뒗 Staphylococcus aureus뿉 븳 쓽 빆洹 슚怨 諛 硫댁뿭諛섏쓳쓣 議곗궗븯뿬 洹 寃곌낵瑜 蹂닿퀬븯怨좎옄 븳떎.

옱猷 諛 諛⑸쾿

떎뿕옱猷

蹂 뿰援ъ뿉 궗슜맂 떆빟 Ag3PO4 (Sigma-Aldrich, USA)씠떎. 떎뿕뿉꽌 궗슜맂 誘몄깮臾쇱 Staphylococcus aureus ATCC 6538濡쒖꽌 깮臾쇱옄썝꽱꽣뿉꽌 遺꾩뼇諛쏆븘 궗슜븯떎. 諛곗뼇諛곗뒗 Tryptic soy broth (TSB)瑜 궗슜븯떎. 궗슜븳 꽭룷뒗 鍮꾩냼꽭룷룓븫 꽭룷二쇱씤 H1299 (Korean Cell Line Bank, Korea)씠떎. 諛곗뼇諛곗뒗 DMEM (Hyclone, UK)뿉 10% Fetal Bovine Serum (FBS) (Hyclone)瑜 泥④븯뿬 궗슜븯떎. 諛곗뼇 37°C, 5% CO2 씤걧踰좎씠꽣뿉꽌 吏꾪뻾븯떎.

Ag3PO4쓽 빆洹 슚怨

24떆媛 룞븞 怨꾨諛곗뼇븳 Staphylococcus aureus瑜 깉濡쒖슫 諛곗뼇諛곗뿉 A600nm=0.06 릺룄濡 씗꽍븳 洹좎<뿉 Ag3PO4瑜 泥④븯吏 븡嫄곕굹 泥④븯뿬 37°C뿉꽌 諛곗뼇븯떎. 0씪吏몃꽣 7씪吏멸퉴吏 洹좎<瑜 궎슦硫댁꽌 젙빐吏 떆媛꾩뿉 A600nm뿉꽌 씉愿묐룄瑜 痢≪젙븯뿬 꽦옣怨≪꽑쓣 洹몃졇떎. 삉븳 肄쒕줈땲 移댁슫똿 諛⑸쾿 쐞 媛숈 諛⑸쾿쑝濡 궎슫 Staphylococcus aureus瑜 10諛곗닔 怨꾩뿴씗꽍 10-1뿉꽌 10-8源뚯 씗꽍븯뿬 媛곴컖쓽 colony 닔瑜 怨꾩궛븯떎.

Ag3PO4뿉 쓽븳 硫댁뿭옉슜 솢꽦솕(떎떆媛 젙웾 PCR瑜 씠슜븳 IL-8 mRNA쓽 젙웾)

H1299 꽭룷瑜 six-well plates containing ~106 cells/well 릺룄濡 떖뿀떎. 16떆媛 썑 Staphylococcus aureus瑜 1떆媛 꽑泥섎━ 썑 50 μg/mL쓽 Ag3PO4瑜 24, 48떆媛 룞븞 泥섎━븯떎. 씠븣 extracellular bacteria瑜 젣嫄고븳 썑 gentamicin (50 μg/mL)씠 泥④맂 諛곗뼇븸뿉꽌 諛곗뼇븯뿬 궓븘엳뒗 extracellular bacteria瑜 셿쟾엳 젣嫄고븯떎(Kim et al., 1998; Eckmann et al., 1993). 씠썑쓽 怨쇱젙 떎쓬怨 媛숇떎.

RNA 遺꾨━ 諛 젙웾: 諛곗뼇븳 H1299 꽭룷濡쒕꽣 RNA瑜 遺꾨━븯湲 쐞븯뿬 TRIzol reagent (Gibco, USA)쓣 궗슜븯뿬 젣옉궗쓽 꽕紐낆꽌뿉 뵲씪 遺꾨━븯떎. 媛 議곌뎔怨 떎뿕援곗쑝濡쒕꽣 遺꾨━븳 RNA瑜 60°C water bath뿉꽌 10遺꾧컙 媛뿴떆耳 single strand濡 遺꾨━븳 썑 spectrophotometer (Biophotometer, Germany)瑜 씠슜븯뿬 RNA 냽룄 諛 닚닔룄瑜 痢≪젙븯떎.

뿭쟾궗 諛섏쓳(Reverse transcription): 媛곴컖쓽 議곌뎔怨 떎뿕援곗쑝濡쒕꽣 遺꾨━븯뿬 젙웾, 蹂댁젙븳 RNA 1 μg뿉 RNA PCR Kit Ver2.1 (TaKaRa, Japan)瑜 씠슜븯뿬 젣옉궗쓽 꽕紐낆꽌뿉 뵲씪 뿭쟾궗 諛섏쓳쓣 떎뻾븯떎.

떎떆媛 젙웾 PCR (Real time quantitative polymerase chain reaction): cDNA IL-8 쑀쟾옄쓽 primers (Forward 5’-TGCCAAGGAGTGCTAAAG-3’, Reverse 5’-CTTCTCCA-CAACCCTCTG-3’)濡 뵒옄씤븳 Light Cycler probes (Sigma-Aldrich) 洹몃━怨 Light Cycler reaction protocol뿉 뵲씪 留뚮뱺 mixture瑜 꽎뼱 留뚮뱺 媛곴컖쓽 諛섏쓳 샎빀븸쓣 tube뿉, 븳 떎뿕 媛쒖껜떦 20 μL뵫 梨꾩슫 떎쓬, 95°C 1遺(1쉶), 95°C 10珥(1쉶), [60°C 15珥, 72°C 15珥](40쉶)쓽 thermal cycling condition뿉꽌 Light Cycler (Roche, Germany)瑜 씠슜븯뿬 떎떆媛 젙웾 PCR (RT-PCR)쓣 吏꾪뻾떆耳곕떎. Beta-actin 쑀쟾옄瑜 湲곗 몴吏옄濡 씠슜븯떎.

寃곌낵

Ag3PO4뿉 쓽븳 Staphylococcus aureus쓽 꽦옣 뼲젣 슚怨

Ag3PO4뿉 쓽븳 Staphylococcus aureus쓽 꽦옣 뼲젣 슚怨쇰 議곗궗븯湲 쐞빐 諛곗뼇븸뿉꽌쓽 냽룄媛 媛곴컖 0.5, 5 μg/mL 릺룄濡 泥④븯뿬 Staphylococcus aureus쓽 꽦옣怨≪꽑쓣 愿李고븯떎(Fig. 1A). Ag3PO4媛 0.5 μg/mL 泥④맂 寃쎌슦뿉뒗 Ag3PO4瑜 泥④븯吏 븡 議곌뎔怨 鍮꾧탳븯뿬 꽦옣 뼲젣 슚怨쇰 굹궡뿀떎. 븳렪 5 μg/mL뿉꽌뒗 洹좎씠 꽦옣븯吏 紐삵븯떎. Ag3PO4뿉 쓽븳 Staphylococcus aureus쓽 꽦옣 뼲젣 슚怨쇰 뜑 솗씤븯湲 쐞빐 肄쒕줈땲 移댁슫똿 諛⑸쾿쓣 씠슜븯뿬 떎뿕븯떎. Ag3PO4媛 0.5 μg/mL媛 泥④맂 寃쎌슦뿉뒗 꽦옣 뼲젣 슚怨쇰 蹂댁씠떎媛 4씪 썑뿉뒗 議곌뎔怨 鍮꾩듂븳 닔以쑝濡 릺룎븘 媛붾떎. 洹몃윭굹 5 μg/mL뿉꽌뒗 떆媛꾩씠 吏굹룄 슌졆븳 꽦옣 뼲젣 슚怨쇰 蹂댁떎(Fig. 1B).

Fig. 1.

Inhibition of Staphylococcus aureus growth by Ag3PO4. Overnight-grown bacteria were diluted and aliquoted into new tubes with A600nm=0.06. They were further grown with or without the indicated amounts of Ag3PO4. Bacterial growth was then analyzed at the indicated time points by measuring values of A600nm (A) or by counting bacterial colonies (B). Data represent mean ± SD from three biological replications.


Ag3PO4뿉 쓽븳 硫댁뿭옉슜 솢꽦솕

슦由 紐몄 蹂묒썝꽦洹 移⑥엯떆 씠뿉 빆븯湲 쐞븳 꽑泥쒖꽦 硫댁뿭諛섏쓳쓣 넻빐 NF-κB媛 솢꽦솕릺怨 솢꽦솕맂 NF-κB뒗 썑泥쒖꽦 硫댁뿭諛섏쓳쓣 쑀룄븯뿬 뿬윭 吏덈퀝쑝濡쒕꽣 슦由 紐몄쓣 蹂댄샇븳떎(Kim et al., 1998; Elewaut et al., 1999; O’Neill et al., 2013; Yusa et al., 2017). 씠윭븳 NF-κB 솢꽦솕뒗 궗씠넗移댁씤(cytokine)怨 媛숈 硫댁뿭諛섏쓳 臾쇱쭏쓣 쑀룄븯뿬 꽭룷쓽 利앹떇/궗硫몄쓣 利앷떆궎뒗 寃껋쑝濡 븣젮졇 엳떎(Kim et al., 1998; Elewaut et al., 1999; O’Neill et al., 2013). Ag3PO4뿉 쓽븳 Staphylococcus aureus쓽 꽦옣 뼲젣 슚怨쇰 솗씤븯뒗뜲(Fig. 1), 씠윭븳 寃곌낵뒗 硫댁뿭옉슜 솢꽦솕 愿젴 엳쓣 媛뒫꽦씠 겕떎. 씠瑜 븣븘蹂닿퀬옄 NF-κB뿉 쓽빐 諛쒗쁽씠 議곗젅릺뒗 쑀쟾옄 以 몴쟻씤 궗씠넗移댁씤 씤 interleukin-8 (IL-8)쓽 쟾궗媛 Ag3PO4뿉 쓽빐 쁺뼢쓣 諛쏅뒗吏 議곗궗븯떎. Staphylococcus aureus瑜 1떆媛 꽑泥섎━ 썑 50 μg/mL쓽 Ag3PO4瑜 泥섎━븳 썑 IL-8쓽 諛쒗쁽뼇쓣 젙웾븳 쐞븳 RT-PCR 寃곌낵뒗 떎쓬怨 媛숇떎(Table 1). Staphylococcus aureus 泥섎━ 썑 50 μg/mL쓽 Ag3PO4瑜 泥섎━빐 二쇱뿀쓣 븣 IL-8쓽 mRNA 諛쒗쁽씠 利앷릺뒗 寃껋쓣 솗씤븯떎(Fig. 2). IL-8쓽 mRNA 諛쒗쁽 Ag3PO4瑜 泥섎━븳 떆媛꾩씠 뒛뼱궇닔濡 利앷븯떎. 븳렪, Ag3PO4瑜 泥섎━븯吏 븡 議곌뎔 IL-8쓽 mRNA 諛쒗쁽씠 利앷븯吏 븡븯떎.

RT-PCR data

Ag3PO4 treatment time (h)IL-8Beta-actinΔCTRatio
0 h (no)30.7224.745.980.015843
24 h (no)30.5824.635.950.016176
48 h (no)30.524.575.930.016402
0 h30.4424.595.850.017337
24 h30.2625.015.250.026278
48 h30.5126.474.040.060791

Fig. 2.

Induction of human immune responses by Ag3PO4. Ag3PO4 induces the expression of IL-8. H1299 cells were treated with or without 50 μg/mL Ag3PO4 for the indicated time. RNA extracts were then subject to real time RT-PCR analysis with a LightCycler® Nano System (Roche). Primers used were; 5’-TGCCAAGGAGTGCTAAAG-3’ and 5’-CTTCTCCACAACCCTCTG for IL-8, and 5’-GTTGCTATCCAGGCTGTG and 5’-TGATCTTGATCTTCATTGTG for β-actin. Relative transcript amounts of IL-8 were normalized against β-actin. Bar, mean ± SD from three biological replications. *, P<0.05 in comparison to non-treated cells.


怨좎같

蹂 뿰援щ뒗 Staphylococcus aureus뿉 븳 쓽 빆洹 슚怨 諛 硫댁뿭諛섏쓳쓣 議곗궗븯뿬 洹 寃곌낵瑜 븣븘蹂닿퀬옄 吏꾪뻾릺뿀떎. (Ag, silver)씠 Escherichia coli, Pseudomonas syrigae 벑쓽 諛뺥뀒由ъ븘쓽 꽦옣쓣 뼲젣븳떎怨 蹂닿퀬릺뿀떎(Morones-Ramirez et al., 2013; Kim et al., 2016). 蹂 뿰援ъ쭊 Ag3PO4瑜 씠슜븯뿬 떎瑜 諛뺥뀒由ъ븘쓽 븳 醫낅쪟씤 Staphylococcus aureus瑜 씠슜븯뿬 Ag3PO4쓽 꽦옣 뼲젣 슚怨쇰 愿李고븯떎. Ag3PO4뿉 쓽븳 Staphylococcus aureus쓽 꽦옣 뼲젣 슚怨쇰 꽦옣怨≪꽑怨 肄쒕줈땲 移댁슫똿 諛⑸쾿쓣 씠슜븯뿬 솗씤븳 寃곌낵 Ag3PO4쓽 냽룄媛 利앷븷닔濡 꽦옣 뼲젣 슚怨쇨 利앷븯뒗 寃껋쓣 솗씤븯떎. 듅엳, 5 μg/mL쓽 Ag3PO4瑜 泥섎━븳 寃쎌슦뒗 洹좎씠 꽦옣븯吏 紐삵븯怨 肄쒕줈땲 移댁슫똿 諛⑸쾿뿉꽌뒗 슌졆븳 꽦옣 뼲젣 뼇긽쓣 蹂댁떎. 씠뒗 醫낆쟾뿉 諛쒗몴맂 씠삩 諛 굹끂 엯옄뿉 쓽븳 빆洹좎옉슜怨 鍮꾩듂븳 寃곌낵瑜 蹂댁떎(Chen et al., 2011; Li et al., 2010).

Ag3PO4媛 떇臾 以꾧린 留덈쫫蹂묒쓽 썝씤洹좎씤 Pseudomonas syrigae쓽 꽦옣쓣 뼲젣븯怨 떇臾쇰㈃뿭泥닿퀎瑜 쑀룄븿씠 諛앺議뚮떎(Kim et al., 2016). 삉븳 슦由 紐몄 蹂묒썝꽦洹 移⑥엯떆 씠뿉 빆븯湲 쐞븳 꽑泥쒖꽦 硫댁뿭諛섏쓳쓣 넻빐 NF-κB媛 솢꽦솕릺怨 솢꽦솕맂 NF-κB뒗 썑泥쒖꽦 硫댁뿭諛섏쓳쓣 쑀룄븯뒗뜲, 궗씠넗移댁씤怨 媛숈 硫댁뿭諛섏쓳 臾쇱쭏쓣 遺꾨퉬븯뿬 뿬윭 吏덈퀝쑝濡쒕꽣 슦由 紐몄쓣 蹂댄샇븳떎(Kim et al., 1998; Elewaut et al., 1999; O’Neill et al., 2013; Yusa et al., 2017). 蹂묒썝꽦洹 移⑥엯떆 NF-κB뿉 쓽빐 諛쒗쁽씠 議곗젅릺뒗 쑀쟾옄 以 몴쟻씤 궗씠넗移댁씤 IL-8씠떎(Kim et al., 1998; Elewaut et al., 1999; O’Neill et al., 2013; Yusa et al., 2017). 씠瑜 諛뷀깢쑝濡 Ag3PO4媛 슦由 紐몄쓽 硫댁뿭泥닿퀎瑜 쑀룄븯뒗吏 븣븘蹂닿린 쐞빐 Staphylococcus aureus瑜 1떆媛 꽑泥섎━ 썑 50 μg/mL쓽 Ag3PO4瑜 泥섎━븳 꽭룷뿉꽌 蹂묒썝꽦洹 移⑥엯떆 솢꽦솕 릺뒗 硫댁뿭諛섏쓳 臾쇱쭏씤 IL-8 쟾궗媛 Ag3PO4뿉 쓽빐 쁺뼢쓣 諛쏅뒗吏 議곗궗븯떎. IL-8 듅씠 primers瑜 씠슜븯뿬 RT-PCR쓣 닔뻾븯떎. 諛쒗쁽맂 IL-8쓽 쟾궗웾쓣 β-actin 쑀쟾옄쓽 mRNA웾怨 긽쟻 鍮꾧탳瑜 넻빐 몴以솕븯뿬 젙웾븳 寃곌낵 Ag3PO4瑜 泥섎━븳 寃곌낵 IL-8쓽 mRNA 諛쒗쁽씠 利앷릺뒗 寃껋쓣 솗씤븯떎(Fig. 2). IL-8쓽 mRNA 諛쒗쁽 Ag3PO4瑜 泥섎━븳 떆媛꾩씠 뒛뼱궇닔濡 利앷븯떎. 븳렪, Ag3PO4瑜 泥섎━븯吏 븡 議곌뎔 IL-8쓽 mRNA 諛쒗쁽씠 利앷븯吏 븡븯떎. 씠윭븳 寃곌낵뒗 Ag3PO4Staphylococcus aureus뿉 諛섏쓳븯뿬 硫댁뿭諛섏쓳쓣 쑀룄븳떎뒗 寃껋쓣 엯利앺빐 二쇰뒗 寃껋씠怨, 슦由 紐몄뿉꽌 (Ag)쓽 빆洹좎옉슜 湲곗옉씠 硫댁뿭諛섏쓳 솢꽦솕 愿젴씠 엳쓬쓣 떆궗빐 以떎. 삉븳 Staphylococcus aureus 쇅 떎瑜 諛뺥뀒由ъ븘쓽 寃쎌슦뿉룄 씠윭븳 빆洹좎옉슜씠 빐떦맆 媛뒫꽦씠 겕硫 씠瑜 엯利앺븯湲 쐞빐꽌뒗 異붽쟻씤 뿰援ш 븘슂븷 寃껋쑝濡 蹂댁씤떎. 씠 媛숈 寃곌낵瑜 넻빐 Ag3PO4Staphylococcus aureus뿉 븳 빆洹좎옉슜怨 슦由 紐몄뿉꽌쓽 硫댁뿭옉슜 솢꽦솕瑜 쑀룄븯뒗 利, 빆洹좎옉슜怨 硫댁뿭옉슜 솢꽦솕 2媛吏 슚怨쇨 엳쓬쓣 솗씤븯떎. 씠윭븳 寃곌낵뒗 븵쑝濡 (Ag)쓽 빆洹좎옉슜怨 옉슜湲곗옉뿉 븳 뿰援ъ뿉 留롮 룄쓣 以 寃껋쑝濡 뿬寃⑥쭊떎.

ACKNOWLEDGEMENTS

None.

CONFLICT OF INTEREST

The authors have no conflicts of interest to disclose.

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