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Yu H, Shang L, Yang G, Dai Z, Zeng X, Qiao S. Biosynthetic Microcin J25 Exerts Strong Antibacterial, Anti-Inflammatory Activities, Low Cytotoxicity Without Increasing Drug-Resistance to Bacteria Target. Front Immunol 2022; 13:811378. [PMID: 35250983 PMCID: PMC8894198 DOI: 10.3389/fimmu.2022.811378] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 01/27/2022] [Indexed: 12/15/2022] Open
Abstract
Multidrug resistant (MDR) bacterial infection has emerged, raising concerns about untreatable infections, and posing the highest health risks. Antimicrobial peptides (AMPs) are thought to be the best remedy for this problem. Here, we showed biosynthetic microcin J25 (MccJ25) exhibited excellent bactericidal activity against standard and clinically relevant veterinary MDR strains with high stability, no cytotoxicity, and no increase in drug resistance. Analysis of antimicrobial mechanism possessed by sensitive enterotoxigenic Escherichia coli (ETEC) based on electron microscopy and Sytox Green methods was carried out. Results showed excellent activity against ETEC was due to permeabilizing bacterial membranes and strong affinity. MccJ25 exhibited high endotoxin-neutralizing activity in both in vivo and in vitro environments, and mice exposed to lipopolysaccharide (LPS) showed decreased plasma LPS levels and improved survival after administration of MccJ25. In an LPS-treated mouse septicemia model, MccJ25 treatment significantly alleviated inflammatory responses by inhibiting proinflammatory factor secretion and expression. In a mouse E. coli infection model, administration of MccJ25 effectively improved host defense against clinically source cocktail of multidrug-resistant E. coli strains induced intestinal inflammation and bacteria dissemination. Results of studies on anti-inflammatory mechanisms showed that MccJ25 downregulated nuclear factor kappa B kinase and mitogen-activated protein kinase, thereby reducing the production of toll-like receptor 4, myeloid differentiation factor 88 and decreasing the key proinflammatory cytokines. These findings clarify MccJ25 may be an ideal antibacterial/antiendotoxic drug candidate that has the potential to further guide the development of anti-inflammatory and/or antimicrobial agents in the war against MDR bacterial infection.
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Affiliation(s)
- Haitao Yu
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture and Rural Affairs Feed Industry Center, China Agricultural University, Beijing, China
- Department of Immunology, Beijing Key Laboratory of Tumor Systems Biology, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Lijun Shang
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture and Rural Affairs Feed Industry Center, China Agricultural University, Beijing, China
- Beijing Key Laboratory of Biofeed Additives, China Agricultural University, Beijing, China
| | - Guangxin Yang
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture and Rural Affairs Feed Industry Center, China Agricultural University, Beijing, China
- Beijing Key Laboratory of Biofeed Additives, China Agricultural University, Beijing, China
| | - Ziqi Dai
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture and Rural Affairs Feed Industry Center, China Agricultural University, Beijing, China
- Beijing Key Laboratory of Biofeed Additives, China Agricultural University, Beijing, China
| | - Xiangfang Zeng
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture and Rural Affairs Feed Industry Center, China Agricultural University, Beijing, China
- Beijing Key Laboratory of Biofeed Additives, China Agricultural University, Beijing, China
| | - Shiyan Qiao
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture and Rural Affairs Feed Industry Center, China Agricultural University, Beijing, China
- Beijing Key Laboratory of Biofeed Additives, China Agricultural University, Beijing, China
- *Correspondence: Shiyan Qiao,
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Haitao Y, Yifan C, Mingchao S, Shuaijuan H. A Novel Polymeric Nanohybrid Antimicrobial Engineered by Antimicrobial Peptide MccJ25 and Chitosan Nanoparticles Exerts Strong Antibacterial and Anti-Inflammatory Activities. Front Immunol 2022; 12:811381. [PMID: 35126369 PMCID: PMC8807516 DOI: 10.3389/fimmu.2021.811381] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 12/27/2021] [Indexed: 12/27/2022] Open
Abstract
Infection caused by antibiotic-resistant microorganisms (ARMs) has been declared a global threat to public health. Polymeric nanoparticles (PNPs) formed by antimicrobial peptides (AMPs) and synthetic PNPs against ARM infections are emerging. PNPs are also considered to be a promising natural biological preservative that prevents microbial spoilage through food processing and preservation. We engineered CNMs, a novel nanocomposite antibacterial agent based on chitosan nanoparticles and AMP microcin J25. In this study, we aimed to evaluate the comprehensive antimicrobial activity, potential antimicrobial mechanism, and anti-inflammatory activity of CNMs. We demonstrated that CNMs harbor excellent bactericidal activity against clinical foodborne pathogens and ARMs. CNMs caused fast mortality against different growth phases of tetracycline (Tet)-resistant enterotoxigenic E. coli (ETEC) and significantly killed Tet-resistant ETEC in food biological environments. Mechanistically, CNMs have the ability to bind lipopolysaccharides (LPS), neutralize endotoxin, and promote diaphragm permeability by damaging the cell membrane. CNMs did not cause mouse RAW264.7 cell cytotoxicity. Notably, CNMs significantly reduced the cytotoxicity of RAW264.7 macrophages induced by LPS. The LPS-induced inflammatory response was significantly ameliorated by CNMs by reducing the levels of nitric oxide and proinflammatory cytokines, including tumor necrosis factor α, interleukin (IL)-6, IL-8, IL-1β, Toll-like receptor 4, and nuclear factor κB (NF-κB), in LPS-challenged RAW264.7 macrophages. CNMs downregulated the NF-κB and mitogen-activated protein kinase signaling pathways, thereby inhibiting inflammatory responses upon LPS stimulation. Taken together, CNMs could be applied as effective antimicrobial/anti-inflammatory agents with lower cytotoxicity in food, medicine, and agriculture to prevent bacterial contamination and infection, respectively.
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Affiliation(s)
- Yu Haitao
- Institute of Systems Biomedicine, Department of Immunology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing, China
- College of Animal Science and Technology, Hebei Agricultural University, Baoding, China
| | - Chen Yifan
- College of Animal Science and Technology, Hebei Agricultural University, Baoding, China
| | - Sun Mingchao
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing, China
| | - Han Shuaijuan
- College of Animal Science and Technology, Hebei Agricultural University, Baoding, China
- *Correspondence: Han Shuaijuan,
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Niu W, Dong Y, Fu Z, Lv J, Wang L, Zhang Z, Huo J, Ju J. Effects of molecular weight of chitosan on anti-inflammatory activity and modulation of intestinal microflora in an ulcerative colitis model. Int J Biol Macromol 2021; 193:1927-1936. [PMID: 34748786 DOI: 10.1016/j.ijbiomac.2021.11.024] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 10/18/2021] [Accepted: 11/03/2021] [Indexed: 12/12/2022]
Abstract
This study investigated the therapeutic effects and mechanisms of chitosans (CSs) with different molecular weights on ulcerative colitis (UC). Three size classes of CSs (Mw ≤ 3, 50, and 200 kDa) were used in this study. The effect of large CSs (Mw ≤ 200 kDa) on UC was the best, followed by that of medium CSs (Mw ≤ 50 kDa), and that of small CSs (Mw ≤ 3 kDa) was the least in the LPS-induced Raw 264.7 cell model and DSS-induced UC mice model. The therapeutic mechanisms of three CSs are related to anti-oxidation, anti-inflammation, and regulation of immunoglobulin and intestinal flora by attenuating body weight loss, decreasing the disease activity index (DAI) and MPO activity, suppressing proinflammatory cytokines and IgG levels, down-regulating the level of oxidative stress, increasing anti-inflammatory cytokines, SOD activity and Prevotellaceae_UCG-001 levels, and reducing the abundance of Proteobacteria, Actinobacteria, and Escherichia-Shigella. In general, the molecular weight of CSs influences their efficacy against UC. CSs with an optimal molecular weight demonstrate good development prospects for ameliorating UC.
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Affiliation(s)
- Wei Niu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Yuelin Dong
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Ziwei Fu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Jiajie Lv
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Ligui Wang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Zhenhai Zhang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Jiege Huo
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China.
| | - Jianming Ju
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China.
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Xu B, Huang S, Chen Y, Wang Q, Luo S, Li Y, Wang X, Chen J, Luo X, Zhou L. Synergistic effect of combined treatment with baicalin and emodin on DSS-induced colitis in mouse. Phytother Res 2021; 35:5708-5719. [PMID: 34379340 DOI: 10.1002/ptr.7230] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 06/17/2021] [Accepted: 07/14/2021] [Indexed: 12/30/2022]
Abstract
The treatment of combination drugs in complex diseases has been spotlighted. Ulcerative colitis (UC) is a chronic inflammatory disease that has made progress in combination therapy. Baicalin, a flavone from Scutellaria baicalensis Georgi. (Lamiaceae), and emodin, an anthraquinone derivative from Rhei Radix et Rhizoma. (Polygonaceae), both have been reported to possess antiinflammatory activities. Our study investigated whether combined treatment with baicalin and emodin had a synergistic effect in inhibiting colitis inflammation. The results showed that baicalin combined with emodin at a lower dose had the same effect as the two drugs alone significantly alleviated the symptoms of dextran sulfate sodium (DSS)-induced colitis mice, involving the prevention of the loss of body weight and colon shortening, the decrease in the disease activity index (DAI), and intestinal damages. The combined treatment decreased the expression of CD14/TLR4/NF-κB pathway proteins and increased the expression of PPAR-γ protein in the colon of colitis mice. Further study in vitro has shown that baicalin decreased the expression of CD14, whereas emodin increased the expression of PPAR-γ, both of which inhibited the activity of NF-κB and exerted antiinflammatory effects. Furthermore, compared to the treatment using the two drugs individually, baicalin combined with emodin had more significant effects on the expression of CD14 and PPAR-γ. Therefore, emodin combined with baicalin had a synergistic effect on DSS-induced colitis.
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Affiliation(s)
- Bo Xu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shaowei Huang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yanping Chen
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qing Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shuang Luo
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yanyang Li
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaojing Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jinyan Chen
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xia Luo
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lian Zhou
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
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Fu YJ, Xu B, Huang SW, Luo X, Deng XL, Luo S, Liu C, Wang Q, Chen JY, Zhou L. Baicalin prevents LPS-induced activation of TLR4/NF-κB p65 pathway and inflammation in mice via inhibiting the expression of CD14. Acta Pharmacol Sin 2021; 42:88-96. [PMID: 32457419 PMCID: PMC7921675 DOI: 10.1038/s41401-020-0411-9] [Citation(s) in RCA: 114] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Accepted: 03/27/2020] [Indexed: 02/07/2023]
Abstract
Previous studies have shown that baicalin, an active ingredient of the Chinese traditional medicine Huangqin, attenuates LPS-induced inflammation by inhibiting the activation of TLR4/NF-κBp65 pathway, but how it affects this pathway is unknown. It has been shown that CD14 binds directly to LPS and plays an important role in sensitizing the cells to minute quantities of LPS via chaperoning LPS molecules to the TLR4/MD-2 signaling complex. In the present study we investigated the role of CD14 in the anti-inflammatory effects of baicalin in vitro and in vivo. Exposure to LPS (1 μg/mL) induced inflammatory responses in RAW264.7 cells, evidenced by marked increases in the expression of MHC II molecules and the secretion of NO and IL-6, and by activation of MyD88/NF-κB p65 signaling pathway, as well as the expression of CD14 and TLR4. These changes were dose-dependently attenuated by pretreatment baicalin (12.5-50 μM), but not by baicalin post-treatment. In RAW264.7 cells without LPS stimulation, baicalin dose-dependently inhibit the protein and mRNA expression of CD14, but not TLR4. In RAW264.7 cells with CD14 knockdown, baicalin pretreatment did not prevent inflammatory responses and activation of MyD88/NF-κB p65 pathway induced by high concentrations (1000 μg/mL) of LPS. Furthermore, baicalin pretreatment also inhibited the expression of CD14 and activation of MyD88/NF-κB p65 pathway in LPS-induced hepatocyte-derived HepG2 cells and intestinal epithelial-derived HT-29 cells. In mice with intraperitoneal injection of LPS and in DSS-induced UC mice, oral administration of baicalin exerted protective effects by inhibition of CD14 expression and inflammation. Taken together, we demonstrate that baicalin pretreatment prevents LPS-induced inflammation in RAW264.7 cells in CD14-dependent manner. This study supports the therapeutic use of baicalin in preventing the progression of LPS-induced inflammatory diseases.
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Affiliation(s)
- Ya-Jun Fu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Bo Xu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Shao-Wei Huang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Xia Luo
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Xiang-Liang Deng
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
- School of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
- The Second Affiliated Hospital of Guangdong Pharmaceutical University, Yunfu, 527300, China.
| | - Shuang Luo
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Chang Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Qing Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Jin-Yan Chen
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Lian Zhou
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
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Faridvand Y, Bagherpour-Hassanlouei N, Nozari S, Nasiri N, Rajabi H, Ghaffari S, Nouri M. 1, 25-Dihydroxyvitamin D3 activates Apelin/APJ system and inhibits the production of adhesion molecules and inflammatory mediators in LPS-activated RAW264.7 cells. Pharmacol Rep 2019; 71:811-817. [PMID: 31377563 DOI: 10.1016/j.pharep.2019.04.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 04/10/2019] [Accepted: 04/13/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND 1, 25-Dihydroxyvitamin D3 (1, 25(OH)2D3), an active form of vitamin D3, plays a crucial role in the mitigation of inflammation damage. Recent studies have revealed that apelin and its receptor (apelin/APJ system) could significantly ameliorate LPS-induced inflammation-response. This investigation aimed to appraise the effects of 1, 25(OH)2D3 on the apelin/APJ system and production of adhesion molecules and inflammatory mediators in LPS-activated RAW264.7 macrophage cells. METHODS Murine RAW264.7 cells were pretreated with 1, 25(OH)2D3, followed stimulation with LPS (1 μg/mL) for 24 h. The effect of 1, 25(OH)2D3 on LPS-induced cell injury was determined by MTT assay, whereas, enzyme-linked immunosorbent assay (ELISA), qPCR and western blotting were used to evaluate cytokine production and apelin/APJ system expression. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) protein expression were measured by flow cytometry. RESULTS The levels of IL-1β, IL-6, and TNF-α cytokines were significantly increased by incubation with LPS. LPS also increased the protein expression of adhesion molecules, including VCAM-1 and ICAM-1. However, pretreatment with 1, 25(OH)2D3 markedly inhibited LPS-induced production of inflammatory cytokines and adhesion molecules. Moreover, we found that 1, 25(OH)2D3 could induced the apelin/APJ system expression. Further experiments demonstrated the significant increase of apelin/APJ system expression at both the protein and mRNA levels in LPS-activated cells when pretreated with 1, 25(OH)2D3. CONCLUSION Taken together, our results indicated that 1, 25(OH)2D3 confers an anti-inflammatory effect through a likely mechanism involving a reduction in pro-inflammatory mediators and adhesion molecules via up-regulation of the apelin/APJ system in RAW264.7 cells.
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Affiliation(s)
- Yousef Faridvand
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cells Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Samira Nozari
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cells Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nasrin Nasiri
- Department of Cellular and Molecular Biology (Genetic), Faculty of Biological Sciences and Technology, Shahid Ashrafi Esfahani University, Isfahan, Iran
| | - Hadi Rajabi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Samad Ghaffari
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mohammad Nouri
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cells Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cell and Regenerative Medicine (SCARM) Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
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Hou J, Shi J, Chen L, Lv Z, Chen X, Cao H, Xiang Z, Han X. M2 macrophages promote myofibroblast differentiation of LR-MSCs and are associated with pulmonary fibrogenesis. Cell Commun Signal 2018; 16:89. [PMID: 30470231 PMCID: PMC6260991 DOI: 10.1186/s12964-018-0300-8] [Citation(s) in RCA: 136] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 11/13/2018] [Indexed: 01/21/2023] Open
Abstract
Background Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by the histopathological pattern of usual interstitial pneumonia and is associated with a high mortality rate. Recently, lung resident mesenchymal stem cells (LR-MSCs) have been identified as an important contributor to myofibroblast activation in pulmonary fibrosis. Macrophages are also believed to play a critical role in pulmonary fibrosis. However, the underlying connections between LR-MSCs and macrophages in the pathogenesis of pulmonary fibrosis are still elusive. Methods In this study, we investigated the interaction between LR-MSCs and macrophages using a bleomycin-induced mouse pulmonary fibrosis model and a coculture system. Results Here, we show that blocking pulmonary macrophage infiltration attenuated bleomycin-induced pulmonary fibrosis. In addition, as determined by flow cytometry, we discovered that the recruited macrophages in fibrotic lungs of bleomycin-treated mice were mainly M2 macrophages. In particular, we found that M2, rather than M1 macrophages, promoted myofibroblast differentiation of LR-MSCs. Moreover, we demonstrated that suppression of the Wnt/β-catenin signaling pathway could attenuate myofibroblast differentiation of LR-MSCs induced by M2 macrophages and bleomycin-induced pulmonary fibrosis. Tissue samples from IPF patients confirmed the infiltration of M2 macrophages and activation of Wnt/β-catenin signaling pathway. Conclusion In summary, this study furthered our understanding of the pulmonary fibrosis pathogenesis and highlighted M2 macrophages as a critical target for treating pulmonary fibrosis. Electronic supplementary material The online version of this article (10.1186/s12964-018-0300-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jiwei Hou
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Hankou Road 22, Nanjing, 210093, China.,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China
| | - Jingyan Shi
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Hankou Road 22, Nanjing, 210093, China.,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China
| | - Ling Chen
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Hankou Road 22, Nanjing, 210093, China.,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China
| | - Zhongyang Lv
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Hankou Road 22, Nanjing, 210093, China.,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China
| | - Xiang Chen
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Hankou Road 22, Nanjing, 210093, China.,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China
| | - Honghui Cao
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Hankou Road 22, Nanjing, 210093, China.,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China
| | - Zou Xiang
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Xiaodong Han
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Hankou Road 22, Nanjing, 210093, China. .,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China.
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8
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Qin CC, Liu YN, Hu Y, Yang Y, Chen Z. Macrophage inflammatory protein-2 as mediator of inflammation in acute liver injury. World J Gastroenterol 2017; 23:3043-3052. [PMID: 28533661 PMCID: PMC5423041 DOI: 10.3748/wjg.v23.i17.3043] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 01/11/2017] [Accepted: 02/08/2017] [Indexed: 02/06/2023] Open
Abstract
Macrophage inflammatory protein (MIP)-2 is one of the CXC chemokines and is also known as chemokine CXC ligand (CXCL2). MIP-2 affects neutrophil recruitment and activation through the p38 mitogen-activated-protein-kinase-dependent signaling pathway, by binding to its specific receptors, CXCR1 and CXCR2. MIP-2 is produced by a variety of cell types, such as macrophages, monocytes, epithelial cells, and hepatocytes, in response to infection or injury. In liver injury, activated Kupffer cells are known as the major source of MIP-2. MIP-2-recruited and activated neutrophils can accelerate liver inflammation by releasing various inflammatory mediators. Here, we give a brief introduction to the basic molecular and cellular sources of MIP-2, and focus on its physiological and pathological functions in acute liver injury induced by concanavalin A, lipopolysaccharides, irradiation, ischemia/reperfusion, alcohol, and hypoxia, and hepatectomy-induced liver regeneration and tumor colorectal metastasis. Further understanding of the regulatory mechanisms of MIP-2 secretion and activation may be helpful to develop MIP-2-targeted therapeutic strategies to prevent liver inflammation.
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9
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Zhao X, Liao YN, Huang Q. Small interfering RNA targeting receptor for advanced glycation end products protects the rats from multibacterial sepsis. Ir J Med Sci 2017; 187:225-229. [PMID: 28470354 DOI: 10.1007/s11845-017-1613-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 03/31/2017] [Indexed: 11/24/2022]
Abstract
BACKGROUND Sepsis is a major challenge in clinical medicine, and treatment options are limited. Recently, the receptor for advanced glycation end products (RAGE) appears to be an excellent target for new therapeutic agents. AIMS The objective of this study is to investigate the effect of small interfering RNA (siRNA) targeting RAGE on the outcome of multibacterial sepsis induced by cecal ligation and puncture (CLP) in a rat model. METHODS A vector-based RAGE-targeted siRNA expression system (Psilencer-siRNA) was constructed and injected into rats via the jugular vein catheter after CLP injury. The RAGE expression in livers, survival rate, and plasma cytokine levels after CLP were compared between Psilencer-siRNA treated and control rats. RESULTS The expression of RAGE in livers which was upregulated after CLP injury was greatly curtailed by Psilencer-siRNA administration. Compared to control rats, the Psilencer-siRNA-treated rats had significantly higher survival rate (p < 0.05) and markedly decreased plasma cytokine levels (p < 0.001) after CLP. CONCLUSIONS Targeting RAGE by siRNA might attenuate hyperinflammation, improve survival rate, and offer new therapeutic options for sepsis.
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Affiliation(s)
- X Zhao
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, No.305, East Zhongshan Road, Xuanwu District, Nanjing, China
| | - Y N Liao
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, No.305, East Zhongshan Road, Xuanwu District, Nanjing, China
| | - Q Huang
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, No.305, East Zhongshan Road, Xuanwu District, Nanjing, China.
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Fujita Y, Taguchi H. Nanoparticle-Based Peptide Vaccines. MICRO AND NANOTECHNOLOGY IN VACCINE DEVELOPMENT 2017. [PMCID: PMC7152328 DOI: 10.1016/b978-0-323-39981-4.00008-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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11
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Takaoka Y, Takahashi M, Kurauchi Y, Hisatsune A, Seki T, Shudo K, Katsuki H. Retinoic acid receptor agonist Am80 inhibits CXCL2 production from microglial BV-2 cells via attenuation of NF-κB signaling. Int Immunopharmacol 2016; 38:367-76. [PMID: 27351827 DOI: 10.1016/j.intimp.2016.06.025] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 05/28/2016] [Accepted: 06/21/2016] [Indexed: 11/28/2022]
Abstract
Accumulating lines of evidence suggest that retinoic acid receptor agonists such as Am80 exerts anti-inflammatory actions in the central nervous system, although detailed mechanisms of the action remain largely unknown. Our previous findings suggest that Am80 provides therapeutic effect on intracerebral hemorrhage in mice via suppression of expression of chemokine (C-X-C motif) ligand 2 (CXCL2). Here we investigated the mechanisms of inhibitory action of Am80 on expression of CXCL2 and other pro-inflammatory factors in microglial BV-2 cells. Pretreatment with Am80 markedly suppressed lipopolysaccharide (LPS)-induced expression of CXCL2 mRNA and release of CXCL2 protein. Am80 had no effect on LPS-induced activation of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase. On the other hand, Am80 prevented LPS-induced nuclear translocation of p65 subunit of NF-κB complex. In addition, total expression levels of p65 and IκBα proteins, as well as of mRNAs encoding p65 and IκBα, were lowered by Am80. Dependence of CXCL2 expression on NF-κB was confirmed by the effect of an NF-κB inhibitor caffeic acid phenethyl ester that abolished LPS-induced CXCL2 expression. Caffeic acid phenethyl ester also abolished LPS-induced expression of inducible nitric oxide synthase, interleukin-1β and tumor necrosis factor α, which may be relevant to the inhibitory effect of Am80 on expression of these pro-inflammatory factors. We additionally found that Am80 attenuated LPS-induced up-regulation of CD14, a co-receptor for Toll-like receptor 4 (TLR4). These results suggest that inhibitory effect on TLR4 signaling mediated by NF-κB pathway underlies the anti-inflammatory action of retinoic acid receptor agonists in microglia.
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Affiliation(s)
- Yuichiro Takaoka
- Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Moeka Takahashi
- Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuki Kurauchi
- Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Akinori Hisatsune
- Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto, Japan; Program for Leading Graduate Schools "HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program", Kumamoto University, Kumamoto, Japan
| | - Takahiro Seki
- Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Koichi Shudo
- Research Foundation Itsuu Laboratory, Tokyo, Japan
| | - Hiroshi Katsuki
- Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
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Chen H, Jiao H, Cheng Y, Xu K, Jia X, Shi Q, Guo S, Wang M, Du L, Wang F. In VitroandIn VivoImmunomodulatory Activity of Okra (Abelmoschus esculentus L.) Polysaccharides. J Med Food 2016; 19:253-65. [DOI: 10.1089/jmf.2015.3513] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Affiliation(s)
- Huricha Chen
- College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Animal Genetic Engineering Key Lab of Haikou, Haikou, People's Republic of China
| | - Hanwei Jiao
- College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Animal Genetic Engineering Key Lab of Haikou, Haikou, People's Republic of China
| | - Ying Cheng
- College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Animal Genetic Engineering Key Lab of Haikou, Haikou, People's Republic of China
| | - Kailian Xu
- College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Animal Genetic Engineering Key Lab of Haikou, Haikou, People's Republic of China
| | - Xiaoxiao Jia
- College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Animal Genetic Engineering Key Lab of Haikou, Haikou, People's Republic of China
| | - Qiaoyun Shi
- College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Animal Genetic Engineering Key Lab of Haikou, Haikou, People's Republic of China
| | - Shiyu Guo
- College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Animal Genetic Engineering Key Lab of Haikou, Haikou, People's Republic of China
| | - Manchuriga Wang
- College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Animal Genetic Engineering Key Lab of Haikou, Haikou, People's Republic of China
| | - Li Du
- College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Animal Genetic Engineering Key Lab of Haikou, Haikou, People's Republic of China
| | - Fengyang Wang
- College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Animal Genetic Engineering Key Lab of Haikou, Haikou, People's Republic of China
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Jiao HW, Jia XX, Zhao TJ, Rong H, Zhang JN, Cheng Y, Zhu HP, Xu KL, Guo SY, Shi QY, Zhang H, Wang FY, Chen CF, Du L. Up-regulation of TDAG51 is a dependent factor of LPS-induced RAW264.7 macrophages proliferation and cell cycle progression. Immunopharmacol Immunotoxicol 2016; 38:124-30. [PMID: 26873343 DOI: 10.3109/08923973.2016.1138968] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
CONTEXT As a component of the outer membrane in Gram-negative bacteria, lipopolysaccharide (LPS)-induced proliferation and cell cycle progression of monocytes/macrophages. It has been suggested that the proapoptotic T-cell death-associated gene 51 (TDAG51) might be associated with cell proliferation and cell cycle progression; however, its role in the interaction between LPS and macrophages remains unclear. OBJECTIVE We attempted to elucidate the role(s) of TDAG51 played in the interaction between LPS and macrophages. MATERIALS AND METHODS We investigated TDAG51 expression in RAW264.7 cells stimulated with LPS and examined the effects of RNA interference-mediated TDAG51 down-regulation. We used CCK-8 assay and flow cytometry analysis to evaluate the interaction between TDAG51 and LPS-induced proliferation and cell cycle progression in RAW264.7 cells. RESULTS Our findings indicate that TDAG51 is up-regulated in LPS-stimulated RAW264.7 cells, the TDAG51 siRNA effectively reduced TDAG51 protein up-regulation following LPS stimulation in RAW264.7 cells, the significant changes of the proliferation and cell cycle progression of RAW264.7 cells in TDAG51 Knockdown RAW264.7 cells treated with LPS were observed. CONCLUSION These findings suggested that TDAG51 up-regulation is a dependent event during LPS-mediated proliferation and cell cycle progression, and which increase our understanding of the interaction mechanism between LPS and macrophages.
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Affiliation(s)
- Han-Wei Jiao
- a College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Animal Genetic Engineering Key Lab of Haikou , Haidian Island , Haikou , People's Republic of China and
| | - Xiao-Xiao Jia
- a College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Animal Genetic Engineering Key Lab of Haikou , Haidian Island , Haikou , People's Republic of China and
| | - Tian-Jing Zhao
- a College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Animal Genetic Engineering Key Lab of Haikou , Haidian Island , Haikou , People's Republic of China and
| | - Hui Rong
- a College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Animal Genetic Engineering Key Lab of Haikou , Haidian Island , Haikou , People's Republic of China and
| | - Jia-Ning Zhang
- a College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Animal Genetic Engineering Key Lab of Haikou , Haidian Island , Haikou , People's Republic of China and
| | - Ying Cheng
- a College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Animal Genetic Engineering Key Lab of Haikou , Haidian Island , Haikou , People's Republic of China and
| | - Hua-Pei Zhu
- a College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Animal Genetic Engineering Key Lab of Haikou , Haidian Island , Haikou , People's Republic of China and
| | - Kai-Lian Xu
- a College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Animal Genetic Engineering Key Lab of Haikou , Haidian Island , Haikou , People's Republic of China and
| | - Shi-Yu Guo
- a College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Animal Genetic Engineering Key Lab of Haikou , Haidian Island , Haikou , People's Republic of China and
| | - Qiao-Yun Shi
- a College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Animal Genetic Engineering Key Lab of Haikou , Haidian Island , Haikou , People's Republic of China and
| | - Hui Zhang
- b College of Animal Science and Technology, Shihezi University , North 4th Road, Shihezi , People's Republic of China
| | - Feng-Yang Wang
- a College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Animal Genetic Engineering Key Lab of Haikou , Haidian Island , Haikou , People's Republic of China and
| | - Chuang-Fu Chen
- b College of Animal Science and Technology, Shihezi University , North 4th Road, Shihezi , People's Republic of China
| | - Li Du
- a College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Animal Genetic Engineering Key Lab of Haikou , Haidian Island , Haikou , People's Republic of China and
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Antimicrobial Peptide CMA3 Derived from the CA-MA Hybrid Peptide: Antibacterial and Anti-inflammatory Activities with Low Cytotoxicity and Mechanism of Action in Escherichia coli. Antimicrob Agents Chemother 2015; 60:495-506. [PMID: 26552969 DOI: 10.1128/aac.01998-15] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 10/28/2015] [Indexed: 12/20/2022] Open
Abstract
CA-MA is a hybrid antimicrobial peptide (AMP) derived from two naturally occurring AMPs, cecropin A and magainin 2. CA-MA shows strong antimicrobial activity against Gram-negative and Gram-positive bacteria but also exhibits cytotoxicity toward mammalian cells. Our objective was to identify CA-MA analogues with reduced cytotoxicity by systematic replacement of amino acids with positively charged R groups (His and Lys), aliphatic R groups (Leu), or polar R groups (Glu). Among the CA-MA analogues studied (CMA1 to -6), CMA3 showed the strongest antimicrobial activity, including against drug-resistant Escherichia coli and Pseudomonas aeruginosa strains isolated from hospital patients. CMA3 appeared to act by inducing pore formation (toroidal model) in the bacterial membrane. In cytotoxicity assays, CMA3 showed little cytotoxicity toward human red blood cells (hRBCs) or HaCaT cells. Additionally, no fluorescence was released from small or giant unilamellar vesicles exposed to 60 μM CMA3 for 80 s, whereas fluorescence was released within 35 s upon exposure to CA-MA. CMA3 also exerted strong lipopolysaccharide (LPS)-neutralizing activity in RAW 264.7 cells, and BALB/c mice exposed to LPS after infection by Escherichia coli showed improved survival after administration of one 0.5-mg/kg of body weight or 1-mg/kg dose of CMA3. Finally, in a mouse model of septic shock, CMA3 reduced the levels of proinflammatory factors, including both nitric oxide and white blood cells, and correspondingly reduced lung tissue damage. This study suggests that CMA3 is an antimicrobial/antiendotoxin peptide that could serve as the basis for the development of anti-inflammatory and/or antimicrobial agents with low cytotoxicity.
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15
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Mmu-miR-27a-5p-Dependent Upregulation of MCPIP1 Inhibits the Inflammatory Response in LPS-Induced RAW264.7 Macrophage Cells. BIOMED RESEARCH INTERNATIONAL 2015; 2015:607692. [PMID: 26295043 PMCID: PMC4534598 DOI: 10.1155/2015/607692] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/21/2015] [Revised: 06/18/2015] [Accepted: 07/07/2015] [Indexed: 02/07/2023]
Abstract
Lipopolysaccharide (LPS) stimulates macrophages to release proinflammatory cytokines. MicroRNAs (miRNAs) are short noncoding RNAs that are involved in inflammatory reaction. Our previously study identified the downregulated expression of mmu-miR-27a-5p in RAW267.4 cells treated with LPS. To dissect the mechanism that mmu-miR-27a-5p regulates target genes and affects proinflammatory cytokine secretion more clearly, based on previous bioinformatics prediction data, one of the potential target genes, MCPIP1 was observed to be upregulated with qRT-PCR and western blot. Luciferase reporter assays were performed to further confirm in silico prediction and determine that MCPIP1 is the target of mmu-miR-27-5p. The results suggested that mmu-miR-27a-5p directly targeted the 3′-UTR of MCPIP1 and the interaction between mmu-miR-27-5p and the 3′-UTR of MCPIP1 is sequence-specific. MCPIP1 overexpression decreased the secretion of IL-6, IL-1β, and IL-10 in macrophage cells stimulated with LPS. Our findings may provide the important information for the precise roles of mmu-miR-27a-5p in the macrophage inflammatory response to LPS stimulation in the future.
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16
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Li X, Li M, Huang S, Qiao S, Qin Z, Kang C, Shi D. The effect of buffalo CD14 shRNA on the gene expression of TLR4 signal pathway in buffalo monocyte/macrophages. Cell Mol Biol Lett 2014; 19:623-37. [PMID: 25355240 PMCID: PMC6275898 DOI: 10.2478/s11658-014-0217-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 10/24/2014] [Indexed: 11/25/2022] Open
Abstract
CD14 plays a crucial role in the inflammatory response to lipopolysaccharide (LPS), which interacts with TLR4 and MD-2 to enable cell activation, resulting in inflammation. Upstream inhibition of the inflammation pathway mediated by bacterial LPS, toll-like receptor 4 (TLR4) and cluster of differentiation antigen 14 (CD14) was proven to be an effective therapeutic approach for attenuating harmful immune activation. To explore the effect of CD14 downregulation on the expression of TLR4 signaling pathway-related genes after LPS stimulation in buffalo (Bubalus bubalis) monocyte/macrophages, effective CD14 shRNA sequences were screened using qRT-PCR and FACS analysis with buffalo CD14 shRNA lentiviral recombinant plasmids (pSicoRGFP-shRNA) and buffalo CD14 fusion expression plasmids (pDsRed-N1-buffalo CD14) co-transfected into HEK293T cells via liposomes. Of the tested shRNAs, shRNA-1041 revealed the highest knockdown efficiency (p < 0.01). When buffalo peripheral blood monocyte/macrophages were infected with shRNA-1041 lentivirus and stimulated with LPS, the expression of endogenous CD14 was significantly decreased by CD14 shRNA (p < 0.01), and the mRNA expression levels of TLR4, IL-6 and TNF-α were also significantly downregulated compared to the control groups (p < 0.01). These results demonstrated that the knockdown of endogenous CD14 had clear regulatory effects on the signal transduction of TLR4 after stimulation with LPS. These results may provide a better understanding of the molecular mechanisms of CD14 regulation in the development of several buffalo diseases.
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Affiliation(s)
- Xiangping Li
- State Key Laboratory of Subtropical Bioresource Conservation and Utilization at Guangxi University, Nanning, Guangxi, China
| | - Meiqing Li
- State Key Laboratory of Subtropical Bioresource Conservation and Utilization at Guangxi University, Nanning, Guangxi, China
| | - Shihai Huang
- College of life science and technology, Guangxi University, Nanning, Guangxi, China
| | - Shuye Qiao
- State Key Laboratory of Subtropical Bioresource Conservation and Utilization at Guangxi University, Nanning, Guangxi, China
| | - Zhaoxian Qin
- Guangxi Institute of Animal Science, Nanning, Guangxi, China
| | - Chao Kang
- College of life science and technology, Guangxi University, Nanning, Guangxi, China
| | - Deshun Shi
- State Key Laboratory of Subtropical Bioresource Conservation and Utilization at Guangxi University, Nanning, Guangxi, China
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17
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Griet M, Zelaya H, Mateos MV, Salva S, Juarez GE, de Valdez GF, Villena J, Salvador GA, Rodriguez AV. Soluble factors from Lactobacillus reuteri CRL1098 have anti-inflammatory effects in acute lung injury induced by lipopolysaccharide in mice. PLoS One 2014; 9:e110027. [PMID: 25329163 PMCID: PMC4201513 DOI: 10.1371/journal.pone.0110027] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Accepted: 09/09/2014] [Indexed: 12/12/2022] Open
Abstract
We have previously demonstrated that Lactobacillus reuteri CRL1098 soluble factors were able to reduce TNF-α production by human peripheral blood mononuclear cells. The aims of this study were to determine whether L. reuteri CRL1098 soluble factors were able to modulate in vitro the inflammatory response triggered by LPS in murine macrophages, to gain insight into the molecular mechanisms involved in the immunoregulatory effect, and to evaluate in vivo its capacity to exert anti-inflammatory actions in acute lung injury induced by LPS in mice. In vitro assays demonstrated that L. reuteri CRL1098 soluble factors significantly reduced the production of pro-inflammatory mediators (NO, COX-2, and Hsp70) and pro-inflammatory cytokines (TNF-α, and IL-6) caused by the stimulation of macrophages with LPS. NF-kB and PI3K inhibition by L. reuteri CRL1098 soluble factors contributed to these inhibitory effects. Inhibition of PI3K/Akt pathway and the diminished expression of CD14 could be involved in the immunoregulatory effect. In addition, our in vivo data proved that the LPS-induced secretion of the pro-inflammatory cytokines, inflammatory cells recruitment to the airways and inflammatory lung tissue damage were reduced in L. reuteri CRL1098 soluble factors treated mice, providing a new way to reduce excessive pulmonary inflammation.
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Affiliation(s)
- Milagros Griet
- Centro de Referencia para Lactobacilos (CERELA-CONICET), San Miguel de Tucumán, Tucumán, Argentina
| | - Hortensia Zelaya
- Centro de Referencia para Lactobacilos (CERELA-CONICET), San Miguel de Tucumán, Tucumán, Argentina
| | - Melina Valeria Mateos
- Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Bahía Blanca, Buenos Aires, Argentina
| | - Susana Salva
- Centro de Referencia para Lactobacilos (CERELA-CONICET), San Miguel de Tucumán, Tucumán, Argentina
| | - Guillermo Esteban Juarez
- Centro de Referencia para Lactobacilos (CERELA-CONICET), San Miguel de Tucumán, Tucumán, Argentina
| | - Graciela Font de Valdez
- Centro de Referencia para Lactobacilos (CERELA-CONICET), San Miguel de Tucumán, Tucumán, Argentina
| | - Julio Villena
- Centro de Referencia para Lactobacilos (CERELA-CONICET), San Miguel de Tucumán, Tucumán, Argentina
| | | | - Ana Virginia Rodriguez
- Centro de Referencia para Lactobacilos (CERELA-CONICET), San Miguel de Tucumán, Tucumán, Argentina
- * E-mail:
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18
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Immunogenicity of coiled-coil based drug-free macromolecular therapeutics. Biomaterials 2014; 35:5886-96. [PMID: 24767787 DOI: 10.1016/j.biomaterials.2014.03.063] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2014] [Accepted: 03/22/2014] [Indexed: 01/13/2023]
Abstract
A two-component CD20 (non-internalizing) receptor crosslinking system based on the biorecognition of complementary coiled-coil forming peptides was evaluated. Exposure of B cells to Fab'-peptide1 conjugate decorates the cell surface with peptide1; further exposure of the decorated cells to P-(peptide2)x (P is the N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer backbone) results in the formation of coiled-coil heterodimers at the cell surface with concomitant induction of apoptosis. The aim of this study was to determine the potential immunogenicity of this therapeutic system that does not contain low molecular weight drugs. Enantiomeric peptides (L- and D-CCE and L- and D-CCK), HPMA copolymer-peptide conjugates, and Fab' fragment-peptide conjugates were synthesized and the immunological properties of peptide conjugates evaluated in vitro on RAW264.7 macrophages and in vivo on immunocompetent BALB/c mice. HPMA copolymer did not induce immune response in vitro and in vivo. Administration of P-peptide conjugates with strong adjuvant resulted in antibody response directed to the peptide. Fab' was responsible for macrophage activation of Fab'-peptide conjugates and a major factor in the antibody induction following i.v. administration of Fab'-conjugates. There was no substantial difference in the ability of conjugates of D-peptides and conjugates of L-peptides to induce Ab response.
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19
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Thorgersen EB, Pischke SE, Barratt-Due A, Fure H, Lindstad JK, Pharo A, Hellerud BC, Mollnes TE. Systemic CD14 inhibition attenuates organ inflammation in porcine Escherichia coli sepsis. Infect Immun 2013; 81:3173-81. [PMID: 23774598 PMCID: PMC3754210 DOI: 10.1128/iai.00390-13] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2013] [Accepted: 06/10/2013] [Indexed: 12/30/2022] Open
Abstract
Sepsis is an infection-induced systemic inflammatory response syndrome. Upstream recognition molecules, like CD14, play key roles in the pathogenesis. The aim of the present study was to investigate the effect of systemic CD14 inhibition on local inflammatory responses in organs from septic pigs. Pigs (n = 34) receiving Escherichia coli-bacteria or E. coli-lipopolysaccharide (LPS) were treated with an anti-CD14 monoclonal antibody or an isotype-matched control. Lungs, liver, spleen, and kidneys were examined for bacteria and inflammatory biomarkers. E. coli and LPS were found in large amounts in the lungs compared to the liver, spleen, and kidneys. Notably, the bacterial load did not predict the respective organ inflammatory response. There was a marked variation in biomarker induction in the organs and in the effect of anti-CD14. Generally, the spleen produced the most cytokines per weight unit, whereas the liver contributed the most to the total load. All cytokines were significantly inhibited in the spleen. Interleukin-6 (IL-6) was significantly inhibited in all organs, IL-1β and IP-10 were significantly inhibited in liver, spleen, and kidneys, and tumor necrosis factor, IL-8, and PAI-1 were inhibited only in the spleen. ICAM-1 and VCAM-1 was significantly inhibited in the kidneys. Systemic CD14-inhibition efficiently, though organ dependent, attenuated local inflammatory responses. Detailed knowledge on how the different organs respond to systemic inflammation in vivo, beyond the information gained by blood examination, is important for our understanding of the nature of systemic inflammation and is required for future mediator-directed therapy in sepsis. Inhibition of CD14 seems to be a good candidate for such treatment.
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Affiliation(s)
- Ebbe Billmann Thorgersen
- Institute of Immunology, Oslo University Hospital Rikshospitalet and University of Oslo, Oslo, Norway.
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20
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Badiei A, Rivers-Auty J, Ang AD, Bhatia M. Inhibition of hydrogen sulfide production by gene silencing attenuates inflammatory activity of LPS-activated RAW264.7 cells. Appl Microbiol Biotechnol 2013; 97:7845-7852. [PMID: 23838794 DOI: 10.1007/s00253-013-5080-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2013] [Revised: 06/19/2013] [Accepted: 06/20/2013] [Indexed: 12/11/2022]
Abstract
Hydrogen sulfide is an inflammatory mediator and is produced by the activity of the enzyme cystathionine γ-lyase (CSE) in macrophages. Previously, pharmacological inhibition of CSE has been reported to have conflicting results, and this may be due to the lack of specificity of the pharmacological agents. Therefore, this study used a very specific approach of small interfering RNA (siRNA) to inhibit the production of the CSE in an in vitro setting. We found that the activation of macrophages by lipopolysaccharide (LPS) resulted in higher levels of CSE mRNA and protein as well as the increased production of proinflammatory cytokines and nitric oxide (NO). We successfully used siRNA to specifically reduce the levels of CSE mRNA and protein in activated macrophages. Furthermore, the levels of proinflammatory cytokines in LPS-activated macrophages were significantly lower in siRNA-transfected cells compared to those in untransfected controls. However, the production levels of NO by the transfected cells were higher, suggesting that CSE activity has an inhibitory effect on NO production. These findings suggest that the CSE enzyme has a crucial role in the activation of macrophages, and its activity has an inhibitory effect on NO production by these cells.
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Affiliation(s)
- Alireza Badiei
- Department of Pathology, University of Otago, PO Box 4345, Christchurch, 8140, New Zealand
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21
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Du B, Luo W, Li R, Tan B, Han H, Lu X, Li D, Qian M, Zhang D, Zhao Y, Liu M. Lgr4/Gpr48 negatively regulates TLR2/4-associated pattern recognition and innate immunity by targeting CD14 expression. J Biol Chem 2013; 288:15131-41. [PMID: 23589304 DOI: 10.1074/jbc.m113.455535] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) is pivotal in both innate and adaptive immune responses. Here we demonstrate that deletion of Lgr4/Gpr48 (G-protein-coupled receptor 48), a seven-transmembrane glycoprotein hormone receptor, potentiates TLR2/4-associated cytokine production and attenuates mouse resistance to septic shock. The expression of CD14, a co-receptor for TLR2/4-associated pathogen-associated molecular patterns, is increased significantly in Lgr4-deficient macrophages, which is consistent with the increased immune response, whereas the binding activity of cAMP-response element-binding protein is decreased significantly in Lgr4-deficient macrophages, which up-regulate the expression of CD14 at the transcriptional level. Together, our data demonstrate that Lgr4/Gpr48 plays a critical role in modulating the TLR2/4 signaling pathway and represents a useful therapeutic approach of targeting Lgr4/Gpr48 in TLR2/4-associated septic shock and autoimmune diseases.
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Affiliation(s)
- Bing Du
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China
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22
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Cheng Y, Du L, Shi Q, Jiao H, Zhang X, Hao Y, Rong H, Zhang J, Jia X, Guo S, Kuang W, Zhang H, Chen C, Wang F. Identification of miR-221 and -222 as important regulators in genotype IV swine hepatitis E virus ORF3-expressing HEK 293 cells. Virus Genes 2013; 47:49-55. [PMID: 23579640 DOI: 10.1007/s11262-013-0912-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2013] [Accepted: 04/04/2013] [Indexed: 11/30/2022]
Abstract
Hepatitis E virus (HEV) has emerged as an important cause of epidemic and sporadic acute viral hepatitis worldwide, which is a major public health challenge. A better understanding of the interaction between the virus and the host cell would be very helpful for its therapy. Swine HEV (SHEV) open reading frame 3 (ORF3) is a regulatory protein that alters the activity of selected transcription factors and cytoplasmic signaling pathways. MicroRNAs (miRNAs) are potent post-transcriptional regulators of protein-coding genes and represent an interesting lead to study SHEV infection and to identify new therapeutic targets. To explore how SHEV ORF3 affects miRNAs in host cells, we used miRNA array analysis to compare the expression patterns of miRNAs in stable cell lines that expressed or did not express SHEV ORF3. We found a significant down-regulation of miR-221 and -222 in ORF3 expressing human embryonic kidney 293 cell line. Among the 116 candidate targets genes of miR-221 and -222 that we detected in silico, we demonstrated that the expression of the cyclin-dependent kinase inhibitor 1B, also named p27(kip1), was directly regulated by these miRNAs. We hypothesize that SHEV ORF3-induced miR-221/222 downregulation enhances p27(kip1) expression in HEK293 cells. This provides new avenues for future exploration of the precise roles of miRNAs in SHEV infection.
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Affiliation(s)
- Ying Cheng
- College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research, Haidian Island, Haikou 570228, People's Republic of China
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23
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McCarthy J, O'Neill MJ, Bourre L, Walsh D, Quinlan A, Hurley G, Ogier J, Shanahan F, Melgar S, Darcy R, O'Driscoll CM. Gene silencing of TNF-alpha in a murine model of acute colitis using a modified cyclodextrin delivery system. J Control Release 2013; 168:28-34. [PMID: 23500058 DOI: 10.1016/j.jconrel.2013.03.004] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Revised: 02/26/2013] [Accepted: 03/04/2013] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic relapsing inflammation of the gastrointestinal tract. The cytokine TNF-alpha (TNF-α) plays a pivotal role in mediating this inflammatory response. RNA interference (RNAi) holds great promise for the specific and selective silencing of aberrantly expressed genes, such as TNF-α in IBD. The aim of this study was to investigate the efficacy of an amphiphilic cationic cyclodextrin (CD) vector for effective TNF-α siRNA delivery to macrophage cells and to mice with induced acute-colitis. The stability of CD.siRNA was examined by gel electrophoresis in biorelevant media reflecting colonic fluids. RAW264.7 cells were transfected with CD.TNF-α siRNA, stimulated with lipopolysaccharide (LPS) and TNF-α and IL-6 responses were measured by PCR and ELISA. Female C57BL/6 mice were exposed to dextran sodium sulphate (DSS) and treated by intrarectal administration with either CD.siRNA TNF-α or a control solution. In vitro, siRNA in CD nanocomplexes remained intact and stable in both fed and fasted simulated colonic fluids. RAW264.7 cells transfected with CD.TNF-α siRNA and stimulated with LPS displayed a significant reduction in both gene and protein levels of TNF-α and IL-6. CD.TNF-α siRNA-treated mice revealed a mild amelioration in clinical signs of colitis, but significant reductions in total colon weight and colonic mRNA expression of TNF-α and IL-6 compared to DSS-control mice were detected. This data indicates the clinical potential of a local CD-based TNF-α siRNA delivery system for the treatment of IBD.
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Affiliation(s)
- J McCarthy
- Pharmacodelivery Group, School of Pharmacy, University College Cork, Cork, Ireland
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24
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Cheng Y, Kuang W, Hao Y, Zhang D, Lei M, Du L, Jiao H, Zhang X, Wang F. Downregulation of miR-27a* and miR-532-5p and upregulation of miR-146a and miR-155 in LPS-induced RAW264.7 macrophage cells. Inflammation 2013; 35:1308-13. [PMID: 22415194 DOI: 10.1007/s10753-012-9443-8] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs that are involved in the epigenetic regulation of cellular processes. To identify more miRNAs which are involved in the macrophage inflammatory response to lipopolysaccharide (LPS) stimulation and dissect the mechanisms more clearly, microRNA profiling of LPS-treated RAW264.7 macrophage cells was performed by initial high-throughput array-based screen and further real-time RT-PCR validation; bioinformatics approaches were used to analyze the target genes of the differentially expressed miRNAs. Compared to the untreated control, two microRNAs (miR-146a and miR-155) with more than twofold higher expression and two microRNAs (miR-27a* and miR-532-5p) with twofold lower expression were detected by array-based screen, which can be validated by qRT-PCR, and more than 1,000 candidate target genes were detected by at least of one of four different algorithms (TargetScan, PicTar, miRDB, and microRNA.org); with gene ontology classification, we were able to correlate the upregulation and downregulation of miRNA to the differential expression of inflammation-related candidate target gene during LPS-induced inflammation. Our findings may provide the basic information for the precise roles of miRNAs in the macrophage inflammatory response to LPS stimulation in the future.
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Affiliation(s)
- Ying Cheng
- College of Agriculture, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research (Construction Period), Animal Genetic Engineering Key Lab of Haikou, Hainan University, Haidian Island, Haikou, 570228, People's Republic of China
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25
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Komatsu H, Shimose A, Shimizu T, Mukai Y, Kobayashi J, Ohama T, Sato K. Trypsin inhibits lipopolysaccharide signaling in macrophages via toll-like receptor 4 accessory molecules. Life Sci 2012; 91:143-50. [PMID: 22771700 DOI: 10.1016/j.lfs.2012.06.030] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Accepted: 06/23/2012] [Indexed: 12/21/2022]
Abstract
AIMS To examine the role of trypsin in the immune response of macrophages and to determine whether protease-activated receptors (PARs) are involved in the effects of trypsin. MAIN METHODS We used RAW264.7 cells and peritoneal macrophages isolated from C57BL/6 wild-type mice, PAR2 knockout mice, and ddY mice. Macrophages were stimulated with lipopolysaccharide (LPS) in the presence or absence of trypsin, thrombin, and PAR subtype-specific agonists (PARs-AP). Activation of macrophages was quantified by nitric oxide production and expression of inflammatory mediators, such as inducible nitric oxide synthase, interleukin-1β, and interleukin-6. To clarify the effect of trypsin on LPS receptors, we also investigated the expression of toll-like receptor 4 (TLR4), soluble MD-2 (sMD-2), membrane-bound MD-2 (mMD-2), soluble CD14 (sCD14), and membrane-bound CD14 (mCD14). To directly investigate the effect of trypsin on CD14 protein, we expressed recombinant CD14 protein. KEY FINDINGS Trypsin inhibited LPS-induced nitric oxide production and expression of inducible nitric oxide synthase, interleukin-1β, and interleukin-6. The same inhibitory effects of trypsin were observed in wild-type macrophages and in PAR2 knockout macrophages. Furthermore, the other PAR agonists, thrombin, PAR1-AP, PAR2-AP, and PAR4-AP, did not mimic the effect of trypsin. Although trypsin did not affect TLR4 or mMD-2 expression, sCD14, mCD14, and sMD-2 expressions were decreased by trypsin. Furthermore, trypsin also degraded recombinant CD14 protein. SIGNIFICANCE Trypsin inhibited LPS signaling PAR-independently via degradation of TLR4 accessory molecules. This observation provides a better understanding of the complicated immune response in acute pancreatitis.
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Affiliation(s)
- Hiroyuki Komatsu
- Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Japan
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26
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Lei M, Du L, Jiao H, Cheng Y, Zhang D, Hao Y, Li G, Qiu W, Fan Q, Li C, Chen C, Wang F. Inhibition of mCD14 inhibits TNFα secretion and NO production in RAW264.7 cells stimulated by Brucella melitensis infection. Vet Microbiol 2012; 160:362-8. [PMID: 22770519 DOI: 10.1016/j.vetmic.2012.05.039] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2011] [Revised: 05/24/2012] [Accepted: 05/25/2012] [Indexed: 01/31/2023]
Abstract
Brucellosis, caused by Brucella spp., is an important disease affecting not only human health, but also a number of animal species around the world. A receptor for LPS of Brucella and important innate immune molecule, CD14, has been implicated in the initiation of the inflammatory response to sepsis. Evidence indicates that upstream inhibition of the LPS initiated inflammatory pathway is an effective therapeutic approach for attenuating damaging immune activation. The aim of this study was to explore the possibility of using RNA interference (RNAi) targeting mCD14 as a strategy for inhibiting the secretion of tumor necrosis factor alpha (TNFα) and the production of nitric oxide (NO) from Brucella-stimulated RAW264.7 cells and attenuating damaging immune activation. The current study stably incorporated mCD14-shRNA-224 into the RAW264.7 cell line by lentiviral gene transfer to successfully knockdown mCD14, and was then challenged with Brucella melitensis M5-90. The secretion of TNFα, interleukin (IL)-12, CXCL1/KC, and inducible nitric oxide synthase (iNOS) protein expression, and NO production were evaluated. The mCD14-shRNA-224 knockdown was shown to effectively inhibit B. melitensis M5-90-stimulated TNFα release, iNOS protein expression, and NO production, but no significant differences were observed for IL-12 and CXCL1/KC. These findings provide the basis for the development of RNAi-based prophylaxis and therapy for B. melitensis induced inflammatory disease.
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Affiliation(s)
- Ming Lei
- College of Agriculture, Hainan University, Hainan Key Lab of Tropical Animal Reproduction & Breeding and Epidemic Disease Research (Construction Period), Animal Genetic Engineering Key Lab of Haikou, Haidian Island, Haikou 570228, People's Republic of China
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27
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Kálai T, Borza E, Antus C, Radnai B, Gulyás-Fekete G, Fehér A, Sümegi B, Hideg K. Synthesis and study of new paramagnetic resveratrol analogues. Bioorg Med Chem 2011; 19:7311-7. [PMID: 22088309 DOI: 10.1016/j.bmc.2011.10.066] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2011] [Revised: 10/20/2011] [Accepted: 10/21/2011] [Indexed: 10/15/2022]
Abstract
New resveratrol analogues containing five- and six-membered nitroxides and isoindoline nitroxides were synthesized. These new compounds were compared to resveratrol based on their ABTS radical scavenging ability as well on their capacity to suppress inflammatory process in macrophages induced by lipopolysaccharides. The ABTS and ROS scavenging activities of new molecules were the same or weaker than that of resveratrol, but some of paramagnetic resveratrol derivatives suppressed nitrite and TNFα production more efficiently than resveratrol. Based on these results the new nitroxide and phenol containing hybrid molecules can be considered as new antioxidant and anti-inflammatory agents.
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Affiliation(s)
- Tamás Kálai
- Institute of Organic and Medicinal Chemistry, University of Pécs, H-7602 Pécs, PO Box 99, Hungary
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