[논문]Anisomycin protects against sepsis by attenuating IκB kinase-dependent NF-κB activation and inflammatory gene expression

Park, Gyoung Lim; Park, Minkyung; Min, Jeong-Ki; Park, Young-Jun; Chung, Su Wol; Lee, Seon-Jin

doi:10.5483/bmbrep.2021.54.11.063

Abstract ▼ AI-Helper

Anisomycin is known to inhibit eukaryotic protein synthesis and has been established as an antibiotic and anticancer drug. However, the molecular targets of anisomycin and its mechanism of action have not been explained in macrophages. Here, we demonstrated the anti-inflammatory effects of anisomyci...

Anisomycin is known to inhibit eukaryotic protein synthesis and has been established as an antibiotic and anticancer drug. However, the molecular targets of anisomycin and its mechanism of action have not been explained in macrophages. Here, we demonstrated the anti-inflammatory effects of anisomycin both in vivo and in vitro. We found that anisomycin decreased the mortality rate of macrophages in cecal ligation and puncture (CLP)- and lipopolysaccharide (LPS)-induced acute sepsis. It also declined the gene expression of proinflammatory mediators such as inducible nitric oxide synthase, tumor necrosis factor-α, and interleukin-1β as well as the nitric oxide and proinflammatory cytokines production in macrophages subjected to LPS-induced acute sepsis. Furthermore, anisomycin attenuated nuclear factor (NF)-κB activation in LPS-induced macrophages, which correlated with the inhibition of phosphorylation of NF-κB-inducing kinase and IκB kinase, phosphorylation and IκBα proteolytic degradation, and NF-κB p65 subunit nuclear translocation. These results suggest that anisomycin prevented acute inflammation by inhibiting NF-κB-related inflammatory gene expression and could be a potential therapeutic candidate for sepsis.

Keyword

표/그림 (4)

그림 Fig. 1. Anisomycin decreases the mortality of mice subjected to lipopolysaccharide (LPS)- and cecal ligation and puncture (CLP)-induced sepsis. (A) Mice were performed to CLP or sham operation, then intraperitoneally injected with or without anisomycin (20 mg/kg). Mortality of each group, namely, CLP with phosphate-buffered saline (PBS; sham operation, white) and CLP with anisomycin (black) was monitored daily for five days after surgery. (B) C57BL/6 mice were subjected with LPS (10 mg/kg) intraperitoneally with or without anisomycin (20 mg/kg). Mortality of each group namely LPS only (black box) and LPS + anisomycin (white box) was monitored daily for 12 days after injection. n = 10 per group.
그림 Fig. 2. Anisomycin downregulates TNF-α, IL-6, and IL-1β secretion in tissues of mice subjected to CLP-stimulated sepsis. Mice performed to CLP were injected with anisomycin or phosphate-buffered saline. (A, D, G) TNF-α, (B, E, H) IL-1β, and (C, F, I) IL-6 levels in mouse serum, and organs as lung, and liver tissues at 24 h after the injection. The levels of TNF-α, IL-6, and IL-1β secretion were measured using enzyme-linked immunosorbent assay. Data are represented as mean ± standard deviation (n = 10). *P ＜ 0.05, #P ＜ 0.01.
그림 Fig. 3. Anisomycin decreases the induction of inflammatory enzymes and cytokines in lipopolysaccharide (LPS)-stimulated macrophages. (A) Anisomycin inhibited production of nitric oxide (NO) in a timedependent manner in J774A.1 cells. (B) RAW264.7 cells were activated with LPS (1 μg/ml) with or without different concentrations of anisomycin, and NO₂ levels were measured by Griess reaction. Data are represented as mean ± standard deviation (each group per triplicates). (C) After stimulation for 16 hour, cells were isolated and iNOS, COX-2, TNF-α, and IL-1β levels were measured using western blotting. The blot was rehybridized with β-actin antibody to verify equal loading of protein. (D) TNF-α, (E) IL-1β, and (F) IL-6 production in RAW264.7 following treatment with 1 μg/ml of LPS for the indicated time with or without 100 μM of anisomycin. *P ＜ 0.05, ^#P ＜ 0.01.
그림 Fig. 4. Anisomycin inhibits the transcriptional activity of proinflammatory mediators through attenuating IKK activation in lipopolysaccharide (LPS)-stimulated macrophages. (A) iNOS, (B) COX-2, (C) TNF-α, and (D) IL-1β expression after stimulating RAW264.7 cells with 1 μg/ml of LPS for the indicated time durations with or without 100 nM of anisomycin. (E) Western blot analysis of p-IκBα and IκBα levels after preincubation with DMSO or anisomycin (100 nM) for two h and subsequent stimulation with 1 μg/ml of LPS for the indicated time durations (F) Western blot analysis to detect NIK (upper panel) and IKKβ (lower panel) phosphorylation after induction with 1 μg/ml of LPS for the indicated time durations, with or without anisomycin (100 μM) pretreatment for two h. (G) Western blot analysis of the NF-κB nuclear translocation after pretreatment with or without 20 μM of erastin for two h followed by induction with medium containing 1 μg/ml of LPS for 0.5 h. (H) Phosphorylated AKT and AKT (upper panel) or phosphorylated ERK and ERK (lower panel) levels by western blot analysis after preincubation with DMSO or anisomycin (100 nM) for two hours and subsequent stimulation with LPS (1 μg/ml) for the indicated time durations. *P ＜ 0.05, ^#P ＜ 0.01.

참고문헌 (16)

1 Maurizio C Laura E Mitchell L Andrew R 2018 Sepsis and septic shock Lancet 92 75 87 10.1016/S0140-6736(18)30696-2 29937192

상세보기
2 Min H Shaoli C Jingqian S 2019 The pathogenesis of sepsis and potential therapeutic targets Int J Mol Sci 20 5736 10.3390/ijms20215376 31671729

상세보기
3 Zhengle T Feiyue X Di C 2012 In vivo toxicological evaluation of anisomycin Toxicol Lett 208 1 11 10.1016/j.toxlet.2011.10.001 22004851

상세보기
4 Lee SM Lee SJ Coronata AA 2014 Carbon mono-xide confers protection in sepsis by enhancing beclin 1-dependent autophagy and phagocytosis Antioxid Redox Signal 20 432 442 10.1089/ars.2013.5368 23971531

상세보기
5 Park YJ Yoon SJ Suh HW 2013 TXNIP deficiency exacerbates endotoxic shock via the induction of excessive nitric oxide synthesis PLoS Pathog 9 e1003646 10.1371/journal.ppat.1003646 24098117

상세보기
6 Lee SJ Bai SK Lee KS 2003 Astaxanthin inhibits nitric oxide production and inflammatory gene expression by suppressing iκb kinase-dependent nf-κb activation Mol Cells 16 97 105 14503852
7 Su L Tu Y Kong DP 2020 Drug repurposing of anti-infective clinical drugs: discovery of two potential anticytokine storm agents Biomed Pharmacother 131 110643 10.1016/j.biopha.2020.110643 32846329

상세보기
8 Xing F Yu Z Liu J 2008 Anisomycin inhibits the behaviors of T cells and the allogeneic skin transplantation in mice J Immunother 31 858 870 10.1097/CJI.0b013e3181869873 18833001

상세보기
9 Marina MS Genaro VV Jacqueline HD 2010 Anisomycin is a multifunctional drug: more than just a tool to inhibit protein synthesis Curr Opin Chem Biol 4 124 132 10.2174/187231310791170793
10 Hong SS Qian H Zhao P 2007 Anisomycin protects cortical neurons from prolonged hypoxia with differential regulation of p38 and ERK Brain Res 1149 76 86 10.1016/j.brainres.2007.02.062 17391655

상세보기
11 Shaheen ZR Naatz A Corbett JA 2015 CCR5-dependent activation of mTORC1 regulates translation of iNOS and COX-2 during EMCV infection J Immunol 195 4406 4414 10.4049/jimmunol.1500704 26408666

상세보기
12 Quintana VM Selisko B Brunetti JE 2020 Antiviral activity of the natural alkaloid anisomycin against dengue and ZIKA viruses Antiviral Res 176 104749 10.1016/j.antiviral.2020.104749 32081740

상세보기
13 Shukla P Rao GM Pandey G 2014 Therapeutic interventions in sepsis: current and anticipated pharmacological agents Br J Pharmacol 171 5011 5031 10.1111/bph.12829 24977655

상세보기
14 Sun SC 2017 The non-canonical NF-κB pathway in immunity and inflammation Nat Rev Immunol 17 545 558 10.1038/nri.2017.52 28580957

상세보기
15 Kim MO Lee SJ Shin SS 2007 Novel natural killer cell-mediated cancer immunotherapeutic activity of anisomycin against hepatocellular carcinoma cells Sci Rep 8 10668 10.1038/s41598-018-29048-8 30006566

상세보기
16 Zappavigna S Cossu AM Grimaldi A 2020 Anti-inflammatory drugs as anticancer agents Int JMol Sci 21 2605 10.3390/ijms21072605 32283655

상세보기

이 논문을 인용한 문헌

LOADING...

활용도 분석정보

상세보기

다운로드

내보내기

활용도 Top5 논문

해당 논문의 주제분야에서 활용도가 높은 상위 5개 콘텐츠를 보여줍니다.
더보기 버튼을 클릭하시면 더 많은 관련자료를 살펴볼 수 있습니다.

내보내기 구분	파일저장 인쇄 메일전송
구성항목	기본정보 상세정보 관리번호, 논문명, 저널/프로시딩명, 저자 , 발행년, 권, 호, 시작페이지, 끝페이지, 발행기관 관리번호, 논문명, 대등논문명, 저자 , 저널/프로시딩명, 발행기관, 발행년, 발행언어, 권, 호, 시작페이지, 끝페이지, ISBN, ISSN, 주제분야, 키워드, 초록(한글), 초록(영문), 저자(소속기관)
저장형식	Text(ASCII format) Excel format RefWorks Direct Export RIS format (for Reference Manager, ProCite, EndNote), Scholar's Aids, Mendeley
메일정보	받는사람 (필수) @ 보내는사람 (선택) @ 제목 내용 KISTI 검색결과 이메일 서비스
안내	총 건의 자료가 검색되었습니다. 다운받으실 자료의 인덱스를 입력하세요. (1-10,000) 검색결과의 순서대로 최대 10,000건 까지 다운로드가 가능합니다. 데이타가 많을 경우 속도가 느려질 수 있습니다.(최대 2~3분 소요) 다운로드 파일은 UTF-8 형태로 저장됩니다. 파일의 내용이 제대로 보이지 않을실 때는 웹브라우저 상단의 보기 -> 인코딩 -> 자동선택 여부를 확인하십시오. ~ Text(ASCII format) Excel format

연합인증

[국내논문] Anisomycin protects against sepsis by attenuating IκB kinase-dependent NF-κB activation and inflammatory gene expression 원문보기

Abstract ▼ AI-Helper

Keyword

표/그림 (4)

표/그림 (4)

참고문헌 (16)

이 논문을 인용한 문헌

연구과제 타임라인

활용도 분석정보

활용도 Top5 논문

관련 콘텐츠

원문 보기

원문 URL 링크

연관된 기능

AI-Helper ※ AI-Helper는 오픈소스 모델을 사용합니다.

선택된 텍스트

연합인증

[국내논문] Anisomycin protects against sepsis by attenuating IκB kinase-dependent NF-κB activation and inflammatory gene expression 원문보기

Abstract ▼ AI-Helper

Keyword

표/그림 (4) 모든 표/그림 보기

표/그림 (4) 슬라이드로 보기

참고문헌 (16)

이 논문을 인용한 문헌

연구과제 타임라인

전체(0) 논문(0) 특허(0) 보고서(0)

전체(0) 논문(0) 특허(0) 보고서(0)

활용도 분석정보

활용도 Top5 논문 더보기

관련 콘텐츠

원문 보기

원문 URL 링크

연관된 기능

AI-Helper ※ AI-Helper는 오픈소스 모델을 사용합니다.

선택된 텍스트

표/그림 (4)

표/그림 (4)

활용도 Top5 논문