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Bicer M, Fidan O. Can mesenchymal stem/stromal cells and their secretomes combat bacterial persisters? World J Microbiol Biotechnol 2023; 39:276. [PMID: 37567959 DOI: 10.1007/s11274-023-03725-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 08/07/2023] [Indexed: 08/13/2023]
Abstract
The increasing number of life-threatening infections caused by persister bacteria is associated with various issues, including antimicrobial resistance and biofilm formation. Infections due to persister cells are often difficult to suppress without the use of last-resort antibiotics. Throughout the world, bacterial persistence and resistance create an unmet clinical demand for the exploration of newly introduced therapeutic approaches. Mesenchymal stem / stromal cells (MSCs) have an antimicrobial activity to protect against bacterial infections, including those caused by bacterial persisters. MSCs have substantial potential to secrete antimicrobial peptides (AMPs), including cathelicidin, beta-defensins, lipocalin-2, hepcidin, indoleamine 2,3-dioxygenase (IDO), cysteine proteases, and inducible nitric oxide synthases (iNOS). MSCs possess the potential to contribute to innate immunity by regulating the immune response. Recently, MSCs and their secreted components have been reported to improve antimicrobial activity. Bactericidal activity by MSCs and their secretomes has been shown to be mediated in part by the secretion of AMPs. Even though they were discovered more than 80 years ago, therapeutic options for persisters are restricted, and there is an urgent need for alternative treatment regimens. Hence, this review intends to critically assess the current literature on the effects of MSCs and their secretomes on persister bacteria. MSCs and their secretome-based therapies could be preferred as an up-and-coming approach to reinforce the antimicrobial efficiency in persister infections.
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Affiliation(s)
- Mesude Bicer
- Department of Bioengineering, Faculty of Life and Natural Sciences, Abdullah Gul University, Kayseri, 38080, Turkey.
| | - Ozkan Fidan
- Department of Bioengineering, Faculty of Life and Natural Sciences, Abdullah Gul University, Kayseri, 38080, Turkey
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2
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Liu T, Sun Z, Yang Z, Qiao X. Microbiota-derived short-chain fatty acids and modulation of host-derived peptides formation: Focused on host defense peptides. Biomed Pharmacother 2023; 162:114586. [PMID: 36989711 DOI: 10.1016/j.biopha.2023.114586] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 03/12/2023] [Accepted: 03/21/2023] [Indexed: 03/29/2023] Open
Abstract
The byproducts of bacterial fermentation known as short-chain fatty acids (SCFAs) are chemically comprised of a carboxylic acid component and a short hydrocarbon chain. Recent investigations have demonstrated that SCFAs can affect intestinal immunity by inducing endogenous host defense peptides (HDPs) and their beneficial effects on barrier integrity, gut health, energy supply, and inflammation. HDPs, which include defensins, cathelicidins, and C-type lectins, perform a significant function in innate immunity in gastrointestinal mucosal membranes. SCFAs have been demonstrated to stimulate HDP synthesis by intestinal epithelial cells via interactions with G protein-coupled receptor 43 (GPR43), activation of the Jun N-terminal kinase (JNK) and Mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways, and the cell growth pathways. Furthermore, SCFA butyrate has been demonstrated to enhance the number of HDPs released from macrophages. SCFAs promote monocyte-to-macrophage development and stimulate HDP synthesis in macrophages by inhibiting histone deacetylase (HDAC). Understanding the etiology of many common disorders might be facilitated by studies into the function of microbial metabolites, such as SCFAs, in the molecular regulatory processes of immune responses (e.g., HDP production). This review will focus on the current knowledge of the role and mechanism of microbiota-derived SCFAs in influencing the synthesis of host-derived peptides, particularly HDPs.
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Morio KA, Sternowski RH, Brogden KA. Induction of Endogenous Antimicrobial Peptides to Prevent or Treat Oral Infection and Inflammation. Antibiotics (Basel) 2023; 12:antibiotics12020361. [PMID: 36830272 PMCID: PMC9952314 DOI: 10.3390/antibiotics12020361] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/03/2023] [Accepted: 02/05/2023] [Indexed: 02/11/2023] Open
Abstract
Antibiotics are often used to treat oral infections. Unfortunately, excessive antibiotic use can adversely alter oral microbiomes and promote the development of antibiotic-resistant microorganisms, which can be difficult to treat. An alternate approach could be to induce the local transcription and expression of endogenous oral antimicrobial peptides (AMPs). To assess the feasibility and benefits of this approach, we conducted literature searches to identify (i) the AMPs expressed in the oral cavity; (ii) the methods used to induce endogenous AMP expression; and (iii) the roles that expressed AMPs may have in regulating oral inflammation, immunity, healing, and pain. Search results identified human neutrophil peptides (HNP), human beta defensins (HBD), and cathelicidin AMP (CAMP) gene product LL-37 as prominent AMPs expressed by oral cells and tissues. HNP, HBD, and LL-37 expression can be induced by micronutrients (trace elements, elements, and vitamins), nutrients, macronutrients (mono-, di-, and polysaccharides, amino acids, pyropeptides, proteins, and fatty acids), proinflammatory agonists, thyroid hormones, and exposure to ultraviolet (UV) irradiation, red light, or near infrared radiation (NIR). Localized AMP expression can help reduce infection, inflammation, and pain and help oral tissues heal. The use of a specific inducer depends upon the overall objective. Inducing the expression of AMPs through beneficial foods would be suitable for long-term health protection. Additionally, the specialized metabolites or concentrated extracts that are utilized as dosage forms would maintain the oral and intestinal microbiome composition and control oral and intestinal infections. Inducing AMP expression using irradiation methodologies would be applicable to a specific oral treatment area in addition to controlling local infections while regulating inflammatory and healing processes.
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Affiliation(s)
| | | | - Kim A. Brogden
- College of Dentistry, The University of Iowa, Iowa City, IA 52242, USA
- Correspondence:
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Baindara P, Ganguli S, Chakraborty R, Mandal SM. Preventing Respiratory Viral Diseases with Antimicrobial Peptide Master Regulators in the Lung Airway Habitat. Clin Pract 2023; 13:125-147. [PMID: 36648852 PMCID: PMC9844411 DOI: 10.3390/clinpract13010012] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/22/2022] [Accepted: 12/28/2022] [Indexed: 01/18/2023] Open
Abstract
The vast surface area of the respiratory system acts as an initial site of contact for microbes and foreign particles. The whole respiratory epithelium is covered with a thin layer of the airway and alveolar secretions. Respiratory secretions contain host defense peptides (HDPs), such as defensins and cathelicidins, which are the best-studied antimicrobial components expressed in the respiratory tract. HDPs have an important role in the human body's initial line of defense against pathogenic microbes. Epithelial and immunological cells produce HDPs in the surface fluids of the lungs, which act as endogenous antibiotics in the respiratory tract. The production and action of these antimicrobial peptides (AMPs) are critical in the host's defense against respiratory infections. In this study, we have described all the HDPs secreted in the respiratory tract as well as how their expression is regulated during respiratory disorders. We focused on the transcriptional expression and regulation mechanisms of respiratory tract HDPs. Understanding how HDPs are controlled throughout infections might provide an alternative to relying on the host's innate immunity to combat respiratory viral infections.
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Affiliation(s)
- Piyush Baindara
- Department of Radiation Oncology, University of Missouri, Columbia, MO 65211, USA
| | - Sriradha Ganguli
- OMICS Laboratory, Department of Biotechnology, University of North Bengal, P.O. NBU, Siliguri 734013, West Bengal, India
| | - Ranadhir Chakraborty
- OMICS Laboratory, Department of Biotechnology, University of North Bengal, P.O. NBU, Siliguri 734013, West Bengal, India
| | - Santi M. Mandal
- Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India
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5
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Huang FC, Huang SC. The Pivotal Role of Aryl Hydrocarbon Receptor-Regulated Tight Junction Proteins and Innate Immunity on the Synergistic Effects of Postbiotic Butyrate and Active Vitamin D3 to Defense against Microbial Invasion in Salmonella Colitis. Nutrients 2023; 15:305. [PMID: 36678175 PMCID: PMC9860786 DOI: 10.3390/nu15020305] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 12/23/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
Our recent report illustrated the unitedly advantageous effects of postbiotic butyrate on active vitamin D3 (VD3)-orchestrated innate immunity in Salmonella colitis. There is growing awareness that aryl hydrocarbon receptor (AhR) can regulate intestinal immunity and barrier function, through modulating cecal inflammation and junction proteins expression. Hence, we researched the participation of AhR-regulated tight junction functions on the united effects of butyrate and VD3 on intestinal defense to Salmonella infection. Salmonella colitis model were elicited by oral gavage with 1 × 108 CFU of a S. typhimurium wild-type strain SL1344 in C57BL/6 mice. Before and after the colitis generation, mice were fed with butyrate and/or VD3 by oral gavage in the absence or presence of intraperitoneal injection of AhR inhibitor for 4 and 7 days, respectively. We observed that butyrate and VD3 could concert together to reduce the invasion of Salmonella in colitis mice by enhancing cecal cytokines and antimicrobial peptides expression and reducing zonulin and claudin-2 protein expressions in mucosal stain, compared to single treatment, which were counteracted by AhR inhibitor. It implies that AhR is involved in the united effects of butyrate and VD3 on the intestinal defense to Salmonella infection in colitis mice. This study discloses the promising alternative therapy of combining postbiotic and VD3 for invasive Salmonellosis and the pivotal role of AhR pathway.
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Affiliation(s)
- Fu-Chen Huang
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Shun-Chen Huang
- Department of Anatomic Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
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The interaction among gut microbes, the intestinal barrier and short chain fatty acids. ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2022; 9:159-174. [PMID: 35573092 PMCID: PMC9079705 DOI: 10.1016/j.aninu.2021.09.012] [Citation(s) in RCA: 118] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 09/08/2021] [Accepted: 09/09/2021] [Indexed: 12/15/2022]
Abstract
The mammalian gut is inhabited by a massive and complicated microbial community, in which the host achieves a stable symbiotic environment through the interdependence, coordination, reciprocal constraints and participation in an immune response. The interaction between the host gut and the microbiota is essential for maintaining and achieving the homeostasis of the organism. Consequently, gut homeostasis is pivotal in safeguarding the growth and development and potential productive performance of the host. As metabolites of microorganisms, short chain fatty acids are not only the preferred energy metabolic feedstock for host intestinal epithelial cells, but also exert vital effects on antioxidants and the regulation of intestinal community homeostasis. Herein, we summarize the effects of intestinal microorganisms on the host gut and the mechanisms of action of short chain fatty acids on the four intestinal barriers of the organism, which will shed light on the manipulation of the intestinal community to achieve precise nutrition for specific individuals and provide a novel perspective for the prevention and treatment of diseases.
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7
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Gubatan J, Holman DR, Puntasecca CJ, Polevoi D, Rubin SJS, Rogalla S. Antimicrobial peptides and the gut microbiome in inflammatory bowel disease. World J Gastroenterol 2021; 27:7402-7422. [PMID: 34887639 PMCID: PMC8613745 DOI: 10.3748/wjg.v27.i43.7402] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/13/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Antimicrobial peptides (AMP) are highly diverse and dynamic molecules that are expressed by specific intestinal epithelial cells, Paneth cells, as well as immune cells in the gastrointestinal (GI) tract. They play critical roles in maintaining tolerance to gut microbiota and protecting against enteric infections. Given that disruptions in tolerance to commensal microbiota and loss of barrier function play major roles in the pathogenesis of inflammatory bowel disease (IBD) and converge on the function of AMP, the significance of AMP as potential biomarkers and novel therapeutic targets in IBD have been increasingly recognized in recent years. In this frontier article, we discuss the function and mechanisms of AMP in the GI tract, examine the interaction of AMP with the gut microbiome, explore the role of AMP in the pathogenesis of IBD, and review translational applications of AMP in patients with IBD.
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Affiliation(s)
- John Gubatan
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Redwood City, CA 94063, United States
| | - Derek R Holman
- Department of Radiology, Molecular Imaging Program at Stanford , Stanford University, Stanford , CA 94305, United States
| | | | - Danielle Polevoi
- Stanford University School of Medicine, Stanford University, Stanford, CA 94063, United States
| | - Samuel JS Rubin
- Stanford University School of Medicine, Stanford University, Stanford, CA 94063, United States
| | - Stephan Rogalla
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Redwood City, CA 94063, United States
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Jiang Y, Liao H, Zhang X, Cao S, Hu X, Yang Z, Fang Y, Wang H. IL-33 synergistically promotes the proliferation of lung cancer cells in vitro by inducing antibacterial peptide LL-37 and proinflammatory cytokines in macrophages. Immunobiology 2020; 225:152025. [PMID: 33190003 DOI: 10.1016/j.imbio.2020.152025] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 08/30/2020] [Accepted: 10/18/2020] [Indexed: 02/07/2023]
Abstract
Lung cancer is the primary cause of cancer-related deaths, and the persistent inflammation is inextricably linked with the lung cancer tumorigenesis. Pro-inflammatory cytokine interleukin-33 (IL-33) is able to serve as a potent modulator of cancer. Mounting evidence indicates IL-33 has significant effect on lung cancer progression by regulating host immune response, but the current opinions about the function and mechanism of IL-33 in lung cancer are still controversial. Meanwhile, antibacterial peptide LL-37 also exerts a momentous effect on immune responses to lung cancer. LL-37 is regarded as versatile, including antimicrobial activities, chemotaxis and immunoregulation. However, the immunomodulatory mechanism of IL-33 and LL-37 in lung cancer remains thoroughly not defined. Here, we determined the secretion of LL-37 was up-regulated in lung cancer serum samples. Similarly, the expression of CRAMP was enhancive in macrophages after co-cultured with lung cancer cells. Moreover, we expounded that IL-33 could up-regulate LL-37 secretion in macrophages, resulting in the massive releases of IL-6 and IL-1β. Additionally, LL-37 cooperated with IL-33 to increase the phosphorylation of p38 MAPK and NF-κB p65 pathways, and augmented IL-6 and IL-1β secretion, which resulting in the proliferation of lung cancer cells in vitro. In conclusion, our study identified that IL-33 aggravated the inflammation of lung cancer by increasing LL-37 expression in macrophages, thereby promoting lung cancer cell proliferation in vitro. It is contributed to our present understanding of the immunomodulatory relationship between pro-inflammatory cytokines and antibacterial peptides in the tumor immune response, and offer a novel perspective for controlling the progress of lung cancer.
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Affiliation(s)
- Yinting Jiang
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China; School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Hongyi Liao
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China; Department of Clinical Laboratory Medicine, Yongchuan Hospital, Chongqing Medical University, Chongqing, China
| | - Xuemei Zhang
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China; School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Sijia Cao
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China; School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Xuexue Hu
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China; School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Zihan Yang
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China; School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Yuting Fang
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China; School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Hong Wang
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China; School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China.
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9
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Chen J, Zhai Z, Long H, Yang G, Deng B, Deng J. Inducible expression of defensins and cathelicidins by nutrients and associated regulatory mechanisms. Peptides 2020; 123:170177. [PMID: 31704211 DOI: 10.1016/j.peptides.2019.170177] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Revised: 10/16/2019] [Accepted: 10/17/2019] [Indexed: 02/07/2023]
Abstract
Host defense peptides (HDPs) are crucial components of the body's first line of defense that protect organisms from infections and mediate immune responses. Defensins and cathelicidins are the two most important families of HDPs in mammals. In this review, we summarize the nutrients that are involved in inducible expression of endogenous defensins and cathelicidins. In addition, the mitogen-activated protein kinases (MAPK), nuclear factor kappa B (NF-κB) and histone deacetylase (HDAC) signaling pathways that play vital roles in the induction of defensin and cathelicidin expression are highlighted. Endogenous defensins and cathelicidins induced by nutrients may be potential alternatives to antibiotic treatments against infection and diseases. This review mainly focuses on the inducible expression and regulatory mechanisms of defensins and cathelicidins in multiple species by different nutrients and the potential applications of defensin- and cathelicidin-inducing nutrients.
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Affiliation(s)
- Jialuo Chen
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, Subtropical Institute of Animal Nutrition and Feed, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Zhenya Zhai
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, Subtropical Institute of Animal Nutrition and Feed, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Hongrong Long
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, Subtropical Institute of Animal Nutrition and Feed, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Guangming Yang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, Subtropical Institute of Animal Nutrition and Feed, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Baichuan Deng
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, Subtropical Institute of Animal Nutrition and Feed, College of Animal Science, South China Agricultural University, Guangzhou, China.
| | - Jinping Deng
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, Subtropical Institute of Animal Nutrition and Feed, College of Animal Science, South China Agricultural University, Guangzhou, China.
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10
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Effects of Intestinal Microbial⁻Elaborated Butyrate on Oncogenic Signaling Pathways. Nutrients 2019; 11:nu11051026. [PMID: 31067776 PMCID: PMC6566851 DOI: 10.3390/nu11051026] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 04/29/2019] [Accepted: 05/05/2019] [Indexed: 12/12/2022] Open
Abstract
The intestinal microbiota is well known to have multiple benefits on human health, including cancer prevention and treatment. The effects are partially mediated by microbiota-produced short chain fatty acids (SCFAs) such as butyrate, propionate and acetate. The anti-cancer effect of butyrate has been demonstrated in cancer cell cultures and animal models of cancer. Butyrate, as a signaling molecule, has effects on multiple signaling pathways. The most studied effect is its inhibition on histone deacetylase (HDAC), which leads to alterations of several important oncogenic signaling pathways such as JAK2/STAT3, VEGF. Butyrate can interfere with both mitochondrial apoptotic and extrinsic apoptotic pathways. In addition, butyrate also reduces gut inflammation by promoting T-regulatory cell differentiation with decreased activities of the NF-κB and STAT3 pathways. Through PKC and Wnt pathways, butyrate increases cancer cell differentiation. Furthermore, butyrate regulates oncogenic signaling molecules through microRNAs and methylation. Therefore, butyrate has the potential to be incorporated into cancer prevention and treatment regimens. In this review we summarize recent progress in butyrate research and discuss the future development of butyrate as an anti-cancer agent with emphasis on its effects on oncogenic signaling pathways. The low bioavailability of butyrate is a problem, which precludes clinical application. The disadvantage of butyrate for medicinal applications may be overcome by several approaches including nano-delivery, analogue development and combination use with other anti-cancer agents or phytochemicals.
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11
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Dietary modulation of endogenous host defense peptide synthesis as an alternative approach to in-feed antibiotics. ACTA ACUST UNITED AC 2018; 4:160-169. [PMID: 30140755 PMCID: PMC6104571 DOI: 10.1016/j.aninu.2018.01.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2017] [Revised: 01/01/2018] [Accepted: 01/06/2018] [Indexed: 12/11/2022]
Abstract
Traditionally, antibiotics are included in animal feed at subtherapeutic levels for growth promotion and disease prevention. However, recent links between in-feed antibiotics and a rise in antibiotic-resistant pathogens have led to a ban of all antibiotics in livestock production by the European Union in January 2006 and a removal of medically important antibiotics in animal feeds in the United States in January 2017. An urgent need arises for antibiotic alternatives capable of maintaining animal health and productivity without triggering antimicrobial resistance. Host defense peptides (HDP) are a critical component of the animal innate immune system with direct antimicrobial and immunomodulatory activities. While in-feed supplementation of recombinant or synthetic HDP appears to be effective in maintaining animal performance and alleviating clinical symptoms in the context of disease, dietary modulation of the synthesis of endogenous host defense peptides has emerged as a cost-effective, antibiotic-alternative approach to disease control and prevention. Several different classes of small-molecule compounds have been found capable of promoting HDP synthesis. Among the most efficacious compounds are butyrate and vitamin D. Moreover, butyrate and vitamin D synergize with each other in enhancing HDP synthesis. This review will focus on the regulation of HDP synthesis by butyrate and vitamin D in humans, chickens, pigs, and cattle and argue for potential application of HDP-inducing compounds in antibiotic-free livestock production.
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12
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Ta A, Thakur BK, Dutta P, Sinha R, Koley H, Das S. Double-stranded RNA induces cathelicidin expression in the intestinal epithelial cells through phosphatidylinositol 3-kinase-protein kinase Cζ-Sp1 pathway and ameliorates shigellosis in mice. Cell Signal 2017; 35:140-153. [DOI: 10.1016/j.cellsig.2017.03.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Revised: 02/21/2017] [Accepted: 03/23/2017] [Indexed: 02/06/2023]
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Liu X, Cao G, Wang Q, Yao X, Fang B. The effect of Bacillus coagulans-fermented and nonfermented Ginkgo biloba on the immunity status of broiler chickens. J Anim Sci 2016; 93:3384-94. [PMID: 26440007 DOI: 10.2527/jas.2015-8902] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
To evaluate and compare the effects of Bacillus coagulans-fermented Ginkgo biloba (FG) and nonfermented Ginkgo biloba (NFG) on the immunity status of broiler chickens, 180 1-d-old female Arbor Acres chicks were divided into 3 groups and fed either a basal diet, a basal diet supplemented with 0.3% NFG, or a basal diet supplemented with 0.3% FG. Blood samples were taken on the seventh (before vaccination), 14th, 21st, 28th and 35th day for the assessment of serum IL-18 and interferon γ (IFN-γ) levels by ELISA. In addition, Newcastle disease antibody titer analysis was made via hemagglutination and hemagglutination inhibition test methods. On d 35, 6 chickens from each group were sacrificed and the thymus, liver, spleen, small intestine (jejunum segment), cecum, and bursa of Fabricius from each chicken were removed for analysis. RNA was isolated for defensin expression detection by real-time PCR (q-PCR). The results showed that serum IL-18 and IFN-γ levels decreased after treatment with NFG and FG compared with untreated control chickens. The ND antibody titers did not differ significantly between the 3 groups on the seventh, 14th, 21st and 28th day; however, on the 35th day, the ND antibody titers of the NFG and FG chickens were both significantly higher than those of control group chickens. Defensin RNA expression levels were inhibited by NFG; however, they were induced by FG. In conclusion, fermentation of Ginkgo biloba with Bacillus coagulans can promote the beneficial effect of Gingko biloba on the immunity status of broiler chickens.
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Xiong H, Guo B, Gan Z, Song D, Lu Z, Yi H, Wu Y, Wang Y, Du H. Butyrate upregulates endogenous host defense peptides to enhance disease resistance in piglets via histone deacetylase inhibition. Sci Rep 2016; 6:27070. [PMID: 27230284 PMCID: PMC4882515 DOI: 10.1038/srep27070] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 05/15/2016] [Indexed: 01/05/2023] Open
Abstract
Butyrate has been used to treat different inflammatory disease with positive outcomes, the mechanisms by which butyrate exerts its anti-inflammatory effects remain largely undefined. Here we proposed a new mechanism that butyrate manipulate endogenous host defense peptides (HDPs) which contributes to the elimination of Escherichia coli O157:H7, and thus affects the alleviation of inflammation. An experiment in piglets treated with butyrate (0.2% of diets) 2 days before E. coli O157:H7 challenge was designed to investigate porcine HDP expression, inflammation and E. coli O157:H7 load in feces. The mechanisms underlying butyrate-induced HDP gene expression and the antibacterial activity and bacterial clearance of macrophage 3D4/2 cells in vitro were examined. Butyrate treatment (i) alleviated the clinical symptoms of E. coli O157:H7-induced hemolytic uremic syndrome (HUS) and the severity of intestinal inflammation; (ii) reduced the E. coli O157:H7 load in feces; (iii) significantly upregulated multiple, but not all, HDPs in vitro and in vivo via histone deacetylase (HDAC) inhibition; and (iv) enhanced the antibacterial activity and bacterial clearance of 3D4/2 cells. Our findings indicate that butyrate enhances disease resistance, promotes the clearance of E. coli O157:H7, and alleviates the clinical symptoms of HUS and inflammation, partially, by affecting HDP expression via HDAC inhibition.
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Affiliation(s)
- Haitao Xiong
- Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, P.R. China
| | - Bingxiu Guo
- Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, P.R. China
| | - Zhenshun Gan
- Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, P.R. China
| | - Deguang Song
- Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, P.R. China
| | - Zeqing Lu
- Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, P.R. China
| | - Hongbo Yi
- Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, P.R. China
| | - Yueming Wu
- Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, P.R. China
| | - Yizhen Wang
- Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, P.R. China
| | - Huahua Du
- Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, P.R. China
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15
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Zhang L, Lu L, Li S, Zhang G, Ouyang L, Robinson K, Tang Y, Zhu Q, Li D, Hu Y, Liu Y. 1,25-Dihydroxyvitamin-D3 Induces Avian β-Defensin Gene Expression in Chickens. PLoS One 2016; 11:e0154546. [PMID: 27135828 PMCID: PMC4852925 DOI: 10.1371/journal.pone.0154546] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2016] [Accepted: 04/14/2016] [Indexed: 02/07/2023] Open
Abstract
Host defense peptides (HDPs) play a critical role in innate immunity. Specific modulation of endogenous HDP synthesis by dietary compounds has been regarded as a novel approach to boost immunity and disease resistance in animal production. 1,25-dihydroxy vitamin D3 (1,25D3) is well known as a powerful HDP inducer in humans, but limited information about the effect of 1,25D3 on HDPs in poultry is available. Here, we sought to examine whether 1,25D3 could stimulate avian β-defensin (AvBD) expression in chickens. We used chicken embryo intestinal epithelial cells (CEIEPCs) and peripheral blood mononuclear cells (PBMCs) to study the effect of 1,25D3 on the expression of AvBDs. We observed that 1,25D3 is able to up-regulate the expression of several AvBDs in CEIEPCs and PBMCs, whereas it increased the amounts of AvBD4 mRNA in CEIEPCs only in the presence of lipopolysaccharide (LPS). On the other hand, LPS treatment not only inhibited the expression of CYP24A1 but also altered the expression pattern of VDR in CEIEPCs. Furthermore, AvBDs were not directly regulated by 1,25D3, as cycloheximide completely blocked 1,25D3-induced expression of AvBDs. Our observations suggest that 1,25D3 is capable of inducing AvBD gene expression and is a potential antibiotic alternative through augmentation of host innate immunity as well as disease control in chickens.
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Affiliation(s)
- Long Zhang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, 611130, P. R. China
| | - Lu Lu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, 611130, P. R. China
| | - Siming Li
- Institute of Animal Husbandry and Veterinary, Jiangxi Academy of Agricultural Science, Nanchang, 330200, P. R. China
| | - Guolong Zhang
- Department of Animal Science, Oklahoma State University, Stillwater, Oklahoma, 74078, United States of America
| | - Linghua Ouyang
- Institute of Animal Husbandry and Veterinary, Jiangxi Academy of Agricultural Science, Nanchang, 330200, P. R. China
| | - Kelsy Robinson
- Department of Animal Science, Oklahoma State University, Stillwater, Oklahoma, 74078, United States of America
| | - Yanqiang Tang
- Institute of Animal Husbandry and Veterinary, Jiangxi Academy of Agricultural Science, Nanchang, 330200, P. R. China
| | - Qing Zhu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, 611130, P. R. China
| | - Diyan Li
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, 611130, P. R. China
| | - Yaodong Hu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, 611130, P. R. China
| | - Yiping Liu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, 611130, P. R. China
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16
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The human cathelicidin LL-37 — A pore-forming antibacterial peptide and host-cell modulator. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2016; 1858:546-66. [DOI: 10.1016/j.bbamem.2015.11.003] [Citation(s) in RCA: 255] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 10/30/2015] [Accepted: 11/05/2015] [Indexed: 01/12/2023]
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The activation of the TLR2/p38 pathway by sodium butyrate in bovine mammary epithelial cells is involved in the reduction of Staphylococcus aureus internalization. Mol Immunol 2015; 68:445-55. [PMID: 26471700 DOI: 10.1016/j.molimm.2015.09.025] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2015] [Revised: 09/26/2015] [Accepted: 09/29/2015] [Indexed: 01/31/2023]
Abstract
Staphylococcus aureus is an etiological agent of human and animal diseases, and it is able to internalize into non-professional phagocytic cells (i.e. bovine mammary epithelial cells, bMECs), which is an event that is related to chronic and recurrent infections. bMECs contribute to host innate immune responses (IIR) through TLR pathogen recognition, whereby TLR2 is the most relevant for S. aureus. In a previous report, we showed that sodium butyrate (NaB, 0.5mM), which is a short chain fatty acid (SCFA), reduced S. aureus internalization into bMECs by modulating their IIR. However, the molecular mechanism of this process has not been described, which was the aim of this study. The results showed that the TLR2 membrane abundance (MA) and mRNA expression were induced by 0.5mM NaB ∼1.6-fold and ∼1.7-fold, respectively. Additionally, 0.5mM NaB induced p38 phosphorylation, but not JNK1/2 or ERK1/2 phosphorylation in bMECs, which reached the baseline when the bMECs were S. aureus-challenged. Additionally, bMECs that were treated with 0.5mM NaB (24h) showed activation of 8 transcriptional factors (AP-1, E2F-1, FAST-1, MEF-1, EGR, PPAR, ER and CBF), which were partially reverted when the bMECs were S. aureus-challenged. Additionally, 0.5mM NaB (24h) up-regulated mRNA expression of the antimicrobial peptides, TAP (∼4.8-fold), BNBD5 (∼3.2-fold) and BNBD10 (∼2.6-fold). Notably, NaB-treated and S. aureus-challenged bMECs increased the mRNA expression of all of the antimicrobial peptides that were evaluated, and this was evident for LAP and BNBD5. In the NaB-treated bMECs, we did not detect significant expression changes for IL-1β and IL-6 and only TNF-α, IL-10 and IL-8 were induced. Interestingly, the NaB-treated and S. aureus-challenged bMECs maintained the anti-inflammatory response that was induced by this SCFA. In conclusion, our results suggest that 0.5mM NaB activates bMECs via TLR2/p38, which leads to improved antimicrobial defense before/after pathogen invasion, and NaB may exert anti-inflammatory effects during infection.
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18
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Bactericidal Activity of Ceragenin CSA-13 in Cell Culture and in an Animal Model of Peritoneal Infection. Antimicrob Agents Chemother 2015; 59:6274-82. [PMID: 26248361 DOI: 10.1128/aac.00653-15] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2015] [Accepted: 07/20/2015] [Indexed: 12/11/2022] Open
Abstract
Ceragenins constitute a novel family of cationic antibiotics characterized by a broad spectrum of antimicrobial activities, which have mostly been assessed in vitro. Using a polarized human lung epithelial cell culture system, we evaluated the antibacterial activities of the ceragenin CSA-13 against two strains of Pseudomonas aeruginosa (PAO1 and Xen5). Additionally, the biodistribution and bactericidal activity of a CSA-13-IRDye 800CW derivate were assessed using an animal model of peritoneal infection after PAO1 challenge. In cell culture, CSA-13 bactericidal activities against PAO1 and Xen5 were higher than the activities of the human cathelicidin peptide LL-37. Increased CSA-13 activity was observed in polarized human lung epithelial cell cultures subjected to butyric acid treatment, which is known to increase endogenous LL-37 production. Eight hours after intravenous or intraperitoneal injection, the greatest CSA-13-IRDye 800CW accumulation was observed in mouse liver and kidneys. CSA-13-IRDye 800CW administration resulted in decreased bacterial outgrowth from abdominal fluid collected from animals subjected to intraperitoneal PAO1 infection. These observations indicate that CSA-13 may synergistically interact with antibacterial factors that are naturally present at mucosal surfaces and it maintains its antibacterial activity in the infected abdominal cavity. Cationic lipids such as CSA-13 represent excellent candidates for the development of new antibacterial compounds.
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19
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Current and potential applications of host-defense peptides and proteins in urology. BIOMED RESEARCH INTERNATIONAL 2015; 2015:189016. [PMID: 25815308 PMCID: PMC4359858 DOI: 10.1155/2015/189016] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2014] [Revised: 10/21/2014] [Accepted: 10/24/2014] [Indexed: 12/02/2022]
Abstract
The use of antibiotics has become increasingly disfavored as more multidrug resistant pathogens are on the rise. A promising alternative to the use of these conventional drugs includes antimicrobial peptides or host-defense peptides. These peptides typically consist of short amino acid chains with a net cationic charge and a substantial portion of hydrophobic residues. They mainly target the bacterial cell membrane but are also capable of translocating through the membrane and target intracellular components, making it difficult for bacteria to gain resistance as multiple essential cellular processes are being targeted. The use of these peptides in the field of biomedical therapies has been examined, and the different approaches to using them under various settings are constantly being discovered. In this review, we discuss the current and potential applications of these host-defense peptides in the field of urology. Besides the use of these peptides as antimicrobial agents, the value of these biological molecules has recently been expanded to their use as antitumor and anti-kidney-stone agents.
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20
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Complexity of antimicrobial peptide regulation during pathogen-host interactions. Int J Antimicrob Agents 2014; 45:447-54. [PMID: 25532742 DOI: 10.1016/j.ijantimicag.2014.11.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 10/10/2014] [Accepted: 11/07/2014] [Indexed: 12/16/2022]
Abstract
Antimicrobial peptides (AMPs) are a key component of the immune system and are expressed by a large variety of organisms. AMPs are capable of eliminating a broad range of micro-organisms, illustrated by murine models where lack of AMP expression resulted in enhanced susceptibility to infection. Despite the importance of AMPs in immune defences, it is not clear whether a change in AMP expression is pathogen-specific or reflects a general response to groups of pathogens. Furthermore, it is unclear how the evoked change in AMP expression affects the host. To fully exploit the therapeutic potential of AMPs - by direct application of peptides or by using AMP-inducers - it is crucial to gain an insight into the complexity involved in pathogen-mediated regulation of AMP expression. This review summarises current knowledge on how AMP expression is affected by pathogens. In addition, the relevance and specificity of these changes in AMPs during infection will be discussed.
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21
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Steppe M, Van Nieuwerburgh F, Vercauteren G, Boyen F, Eeckhaut V, Deforce D, Haesebrouck F, Ducatelle R, Van Immerseel F. Safety assessment of the butyrate-producing Butyricicoccus pullicaecorum strain 25-3(T), a potential probiotic for patients with inflammatory bowel disease, based on oral toxicity tests and whole genome sequencing. Food Chem Toxicol 2014; 72:129-37. [PMID: 25007784 DOI: 10.1016/j.fct.2014.06.024] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2013] [Revised: 06/18/2014] [Accepted: 06/26/2014] [Indexed: 02/09/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammation of the digestive tract, characterized by dysbiosis of the intestinal microbiota. Probiotics have been suggested as a strategy to reduce active disease or extend remission. We isolated and characterized the butyrate-producing strain Butyricicoccus pullicaecorum 25-3(T) and identified it as a potential probiotic for patients with IBD. To evaluate the safety of 25-3(T) for use in humans, we conducted a standard acute oral toxicity test and a 28-day repeated oral dose toxicity test. The complete genome of B. pullicaecorum 25-3(T) was sequenced to search for virulence factors and antibiotic resistance determinants. The minimum inhibitory concentration (MIC) of 21 antimicrobials was determined. Results showed no adverse effects in the oral toxicity tests. B. pullicaecorum 25-3(T) is resistant against aminoglycosides and trimethoprim. The genome of 25-3(T) contains no virulence factors, one gene related to harmful metabolites and 52 sequences with high similarity to antimicrobial and toxic compound resistance genes, that did not correspond with a resistant phenotype. This first report of a safety assessment of a butyrate-producing strain from Clostridium cluster IV shows that B. pullicaecorum 25-3(T) is a non-pathogenic strain, but carries antibiotic resistance genes with the risk of transfer, that need further investigation.
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Affiliation(s)
- Marjan Steppe
- Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium.
| | - Filip Van Nieuwerburgh
- Laboratory of Pharmaceutical Biotechnology, Ghent University, Harelbekestraat 72, Ghent, Belgium
| | - Griet Vercauteren
- Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium
| | - Filip Boyen
- Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium
| | - Venessa Eeckhaut
- Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium
| | - Dieter Deforce
- Laboratory of Pharmaceutical Biotechnology, Ghent University, Harelbekestraat 72, Ghent, Belgium
| | - Freddy Haesebrouck
- Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium
| | - Richard Ducatelle
- Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium
| | - Filip Van Immerseel
- Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium
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22
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Jiang W, Sunkara LT, Zeng X, Deng Z, Myers SM, Zhang G. Differential regulation of human cathelicidin LL-37 by free fatty acids and their analogs. Peptides 2013; 50:129-38. [PMID: 24140860 DOI: 10.1016/j.peptides.2013.10.008] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2013] [Revised: 10/08/2013] [Accepted: 10/09/2013] [Indexed: 11/19/2022]
Abstract
LL-37 is the single cathelicidin host defense peptide in humans with direct antimicrobial and immunomodulatory activities. Specific regulation of LL-37 synthesis has emerged as a novel non-antibiotic approach to disease control and prevention. Short-chain fatty acids, and butyrate in particular, were found recently to be strong inducers of LL-37 gene expression without causing inflammation. Here, we further evaluated the LL-37-inducing efficiency of a broad range of saturated free fatty acids and their derivatives in human HT-29 colonic epithelial cells and U-937 monocytic cells by real-time RT-PCR. Surprisingly, we revealed that valerate, hexanoate, and heptanoate with 5-7 carbons are more potent than 4-carbon butyrate in promoting LL-37 gene expression in both cell types. Free fatty acids with longer than 7 or shorter than 4 carbons showed only a marginal effect on LL-37 expression. Studies with a series of fatty acid derivatives with modifications in the aliphatic chain or carboxylic acid group yielded several analogs such as benzyl butyrate, trans-cinnamyl butyrate, glyceryl tributyrate, and phenethyl butyrate with a comparable LL-37-inducing activity to sodium butyrate. On the other hand, although reactive, the anhydride derivatives of short- and medium-chain fatty acids are as potent as their corresponding free acid forms in LL-37 induction. Thus, these newly identified free fatty acids and their analogs with a strong capacity to augment LL-37 synthesis may hold promise as immune boosting dietary supplements for antimicrobial therapy.
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Affiliation(s)
- Weiyu Jiang
- Department of Animal Science, Oklahoma State University, Stillwater, OK 74048, USA
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23
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Sunkara LT, Zeng X, Curtis AR, Zhang G. Cyclic AMP synergizes with butyrate in promoting β-defensin 9 expression in chickens. Mol Immunol 2013; 57:171-80. [PMID: 24141182 DOI: 10.1016/j.molimm.2013.09.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Revised: 09/19/2013] [Accepted: 09/21/2013] [Indexed: 10/26/2022]
Abstract
Host defense peptides (HDP) have both microbicidal and immunomodulatory properties. Specific induction of endogenous HDP synthesis has emerged as a novel approach to antimicrobial therapy. Cyclic adenosine monophosphate (cAMP) and butyrate have been implicated in HDP induction in humans. However, the role of cAMP signaling and the possible interactions between cAMP and butyrate in regulating HDP expression in other species remain unknown. Here we report that activation of cAMP signaling induces HDP gene expression in chickens as exemplified by β-defensin 9 (AvBD9). We further showed that, albeit being weak inducers, cAMP agonists synergize strongly with butyrate or butyrate analogs in AvBD9 induction in macrophages and primary jejunal explants. Additionally, oral supplementation of forskolin, an adenylyl cyclase agonist in the form of a Coleus forskohlii extract, was found to induce AvBD9 expression in the crop of chickens. Furthermore, feeding with both forskolin and butyrate showed an obvious synergy in triggering AvBD9 expression in the crop and jejunum of chickens. Surprisingly, inhibition of the MEK-ERK mitogen-activated protein kinase (MAPK) pathway augmented the butyrate-FSK synergy, whereas blocking JNK or p38 MAPK pathway significantly diminished AvBD9 induction in chicken macrophages and jejunal explants in response to butyrate and FSK individually or in combination. Collectively, these results suggest the potential for concomitant use of butyrate and cAMP signaling activators in enhancing HDP expression, innate immunity, and disease resistance in both animals and humans.
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Affiliation(s)
- Lakshmi T Sunkara
- Department of Animal Science, Oklahoma State University, Stillwater, OK 74078, USA
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24
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Zeng X, Sunkara LT, Jiang W, Bible M, Carter S, Ma X, Qiao S, Zhang G. Induction of porcine host defense peptide gene expression by short-chain fatty acids and their analogs. PLoS One 2013; 8:e72922. [PMID: 24023657 PMCID: PMC3758276 DOI: 10.1371/journal.pone.0072922] [Citation(s) in RCA: 99] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2013] [Accepted: 07/13/2013] [Indexed: 01/08/2023] Open
Abstract
Dietary modulation of the synthesis of endogenous host defense peptides (HDPs) represents a novel antimicrobial approach for disease control and prevention, particularly against antibiotic-resistant infections. However, HDP regulation by dietary compounds such as butyrate is species-dependent. To examine whether butyrate could induce HDP expression in pigs, we evaluated the expressions of a panel of porcine HDPs in IPEC-J2 intestinal epithelial cells, 3D4/31 macrophages, and primary monocytes in response to sodium butyrate treatment by real-time PCR. We revealed that butyrate is a potent inducer of multiple, but not all, HDP genes. Porcine β-defensin 2 (pBD2), pBD3, epididymis protein 2 splicing variant C (pEP2C), and protegrins were induced markedly in response to butyrate, whereas pBD1 expression remained largely unaltered in any cell type. Additionally, a comparison of the HDP-inducing efficacy among saturated free fatty acids of different aliphatic chain lengths revealed that fatty acids containing 3–8 carbons showed an obvious induction of HDP expression in IPEC-J2 cells, with butyrate being the most potent and long-chain fatty acids having only a marginal effect. We further investigated a panel of butyrate analogs for their efficacy in HDP induction, and found glyceryl tributyrate, benzyl butyrate, and 4-phenylbutyrate to be comparable with butyrate. Identification of butyrate and several analogs with a strong capacity to induce HDP gene expression in pigs provides attractive candidates for further evaluation of their potential as novel alternatives to antibiotics in augmenting innate immunity and disease resistance of pigs.
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Affiliation(s)
- Xiangfang Zeng
- Department of Animal Science, Oklahoma State University, Stillwater, Oklahoma, United States of America
- State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China
| | - Lakshmi T. Sunkara
- Department of Animal Science, Oklahoma State University, Stillwater, Oklahoma, United States of America
| | - Weiyu Jiang
- Department of Animal Science, Oklahoma State University, Stillwater, Oklahoma, United States of America
| | - Megan Bible
- Department of Animal Science, Oklahoma State University, Stillwater, Oklahoma, United States of America
| | - Scott Carter
- Department of Animal Science, Oklahoma State University, Stillwater, Oklahoma, United States of America
| | - Xi Ma
- State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China
| | - Shiyan Qiao
- State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China
| | - Guolong Zhang
- Department of Animal Science, Oklahoma State University, Stillwater, Oklahoma, United States of America
- Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, Oklahoma, United States of America
- Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma, United States of America
- * E-mail:
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25
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Broekman DC, Guðmundsson GH, Maier VH. Differential regulation of cathelicidin in salmon and cod. FISH & SHELLFISH IMMUNOLOGY 2013; 35:532-538. [PMID: 23727282 DOI: 10.1016/j.fsi.2013.05.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2012] [Revised: 04/29/2013] [Accepted: 05/06/2013] [Indexed: 06/02/2023]
Abstract
Antimicrobial peptides (AMPs) are an important component of innate immunity in vertebrates. The cathelicidin family of AMPs is well characterized in mammals and has also been reported in several fish species. In this study we investigated the regulation of cathelicidin expression in a gadoid and a salmonid cell-line in order to dissect the signalling pathways involved. For this, fish cells were treated with microbial lysates, purified microbial components and commercial signalling inhibitors and expression of cathelicidin was assessed with quantitative real-time PCR (qPCR). We found that cathelicidin expression was induced in both cell lines in response to microbial stimuli, but the response patterns differed in these evolutionary distant fish species. Our data suggest that in salmonids, pattern recognition receptors such as TLR5 may be involved in the stimulation of cathelicidin expression and that the signalling cascade can include PI3-kinase and cellular trafficking compartments. A detailed knowledge of the regulating factors involved in AMP-related defence responses, including cathelicidin, could help in developing strategies to enhance the immune defence of fish.
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Affiliation(s)
- Daniela C Broekman
- Institute of Biology, University of Iceland, Sturlagata 7, 101 Reykjavik, Iceland
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26
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Méndez-Samperio P. Recent advances in the field of antimicrobial peptides in inflammatory diseases. Adv Biomed Res 2013; 2:50. [PMID: 24516850 PMCID: PMC3905337 DOI: 10.4103/2277-9175.114192] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2012] [Accepted: 08/23/2012] [Indexed: 12/31/2022] Open
Abstract
Antimicrobial peptides are cationic molecules, which participate in multiple aspects of the immune response including the control of inflammatory diseases, characteristic that make these molecules attractive as therapeutic tools. These peptides are produced in bacteria, insects, plants and vertebrates, and are classified together due to their capacity to directly inhibit the growth of microorganisms, and to regulate the immune response by inducing the secretion of chemokines and cytokines. Various families of antimicrobial peptides have been identified including the cathelicidins and defensins, the most investigated human antimicrobial peptides. This review will cover the main biological functions of antimicrobial and cell-penetrating peptides in inflammation, and describe the importance and utility of antimicrobial peptides as therapeutics for inflammatory diseases.
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Affiliation(s)
- Patricia Méndez-Samperio
- Department of Immunology, National School of Biological Sciences, National Polytechnic Institute, Mexico, D.F., Mexico
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27
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Brandenburg LO, Jansen S, Albrecht LJ, Merres J, Gerber J, Pufe T, Tauber SC. CpG oligodeoxynucleotides induce the expression of the antimicrobial peptide cathelicidin in glial cells. J Neuroimmunol 2012; 255:18-31. [PMID: 23141747 DOI: 10.1016/j.jneuroim.2012.10.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Revised: 10/18/2012] [Accepted: 10/19/2012] [Indexed: 11/26/2022]
Abstract
During bacterial infections, antimicrobial peptides are synthesised as an important part of the innate immune system. However, expression and function in the central nervous system (CNS) need further investigations. The aim of this study was to examine the involvement of the pattern-recognition-receptor toll-like receptor 9 (TLR9) in the expression of the cathelin-related antimicrobial peptide (CRAMP) and to characterise the participating signal transduction pathways. In primary TLR9 deficient and wildtype mice astrocytes as well as microglia cells, the expression of CRAMP after treatment with the TLR9 agonist unmethylated cytosine-guanine oligodeoxynucleotide motifs (CpG-DNA) was examined in vitro. In vivo CRAMP expression after intraventricular infusion of CpG-DNA in TLR9 deficient and wildtype mice as well as in mice with pneumococcal meningitis localised in glial cells was determined. Furthermore, the regulation of different signal transduction pathways involved in CpG-DNA-induced CRAMP expression in glial cells was analysed. An in vitro and in vivo CpG-DNA-induced increase of CRAMP expression in astrocytes and microglia cells using real time RT-PCR and immunofluorescence was demonstrated. Different signal transduction pathways such as mitogen-activated protein kinases and inflammatory mediated pathways are involved in the expression of CRAMP in primary glial cells. Interestingly, TLR9-deficient glial cells showed a reduced but not completely abolished CRAMP mRNA expression and ERK1/2 phosphorylation in response to CpG-DNA treatment. On the other side in vivo, TLR9 deletion did not change CRAMP expression after bacterial infection. In conclusion, our results show that TLR9 can induce the expression of antimicrobial peptides such as CRAMP in response to bacterial DNA motifs in primary glial cells. Additional findings suggest also that CpG-DNA-induced effects are not only mediated by TLR9, but also mediated by other pattern recognition receptors.
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Interleukin 13 exposure enhances vitamin D-mediated expression of the human cathelicidin antimicrobial peptide 18/LL-37 in bronchial epithelial cells. Infect Immun 2012; 80:4485-94. [PMID: 23045480 DOI: 10.1128/iai.06224-11] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Vitamin D is an important regulator of the expression of antimicrobial peptides, and vitamin D deficiency is associated with respiratory infections. Regulating expression of antimicrobial peptides, such as the human cathelicidin antimicrobial peptide 18 (hCAP18)/LL-37, by vitamin D in bronchial epithelial cells requires local conversion of 25(OH)-vitamin D(3) (25D(3)) into its bioactive metabolite, 1,25(OH)(2)-vitamin D(3) (1,25D(3)), by CYP27B1. Low circulating vitamin D levels in childhood asthma are associated with more-severe exacerbations, which are often associated with infections. Atopic asthma is accompanied by Th2-driven inflammation mediated by cytokines such as interleukin 4 (IL-4) and IL-13, and the effect of these cytokines on vitamin D metabolism and hCAP18/LL-37 expression is unknown. Therefore, we investigated this with well-differentiated bronchial epithelial cells. To this end, cells were treated with IL-13 with and without 25D(3), and expression of hCAP18/LL-37, CYP27B1, the 1,25D(3)-inactivating enzyme CYP24A1, and vitamin D receptor was assessed by quantitative PCR. We show that IL-13 enhances the ability of 25D(3) to increase expression of hCAP18/LL-37 and CYP24A1. In addition, exposure to IL-13 resulted in increased CYP27B1 expression, whereas vitamin D receptor (VDR) expression was not significantly affected. The enhancing effect of IL-13 on 25D(3)-mediated expression of hCAP18/LL-37 was further confirmed using SDS-PAGE Western blotting and immunofluorescence staining. In conclusion, we demonstrate that IL-13 induces vitamin D-dependent hCAP18/LL-37 expression, most likely by increasing CYP27B1. These data suggest that Th2 cytokines regulate the vitamin D metabolic pathway in bronchial epithelial cells.
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Bentley-Hewitt KL, Blatchford PA, Parkar SG, Ansell J, Pernthaner A. Digested and fermented green kiwifruit increases human β-defensin 1 and 2 production in vitro. PLANT FOODS FOR HUMAN NUTRITION (DORDRECHT, NETHERLANDS) 2012; 67:208-214. [PMID: 22872469 DOI: 10.1007/s11130-012-0305-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
The intestinal mucosa is constantly exposed to a variety of microbial species including commensals and pathogens, the latter leaving the host susceptible to infection. Antimicrobial peptides (AMP) are an important part of the first line of defense at mucosal surfaces. Human β-defensins (HBD) are AMP expressed by colonic epithelial cells, which act as broad spectrum antimicrobials. This study explored the direct and indirect effects of green kiwifruit (KF) on human β-defensin 1 and 2 (HBD-1 and 2) production by epithelial cells. In vitro digestion of KF pulp consisted of a simulated gastric and duodenal digestion, followed by colonic microbial fermentation using nine human faecal donors. Fermenta from individual donors was sterile filtered and independently added to epithelial cells prior to analysis of HBD protein production. KF products obtained from the gastric and duodenal digestion had no effect on the production of HBD-1 or 2 by epithelial cells, demonstrating that KF does not contain substances that directly modulate defensin production. However, when the digested KF products were further subjected to in vitro colonic fermentation, the fermentation products significantly up-regulated HBD-1 and 2 production by the same epithelial cells. We propose that this effect was predominantly mediated by the presence of short-chain fatty acids (SCFA) in the fermenta. Exposure of cells to purified SCFA confirmed this and HBD-1 and 2 production was up-regulated with acetate, propionate and butyrate. In conclusion, in vitro colonic fermentation of green kiwifruit digest appears to prime defense mechanisms in gut cells by enhancing the production of antimicrobial defensins.
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Affiliation(s)
- Kerry L Bentley-Hewitt
- Food and Nutrition, The New Zealand Institute for Plant & Food Research Ltd., Palmerston North, New Zealand.
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Rieder F, Karrasch T, Ben-Horin S, Schirbel A, Ehehalt R, Wehkamp J, de Haar C, Velin D, Latella G, Scaldaferri F, Rogler G, Higgins P, Sans M. Results of the 2nd scientific workshop of the ECCO (III): basic mechanisms of intestinal healing. J Crohns Colitis 2012; 6:373-85. [PMID: 22405177 DOI: 10.1016/j.crohns.2011.11.009] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2011] [Accepted: 11/13/2011] [Indexed: 02/08/2023]
Abstract
The second scientific workshop of the European Crohn's and Colitis Organization (ECCO) focused on the relevance of intestinal healing for the disease course of inflammatory bowel disease (IBD). The objective was to better understand basic mechanisms, markers for disease prediction, detection and monitoring of intestinal healing, impact of intestinal healing on the disease course of IBD as well as therapeutic strategies. The results of this workshop are presented in four separate manuscripts. This section describes basic mechanisms of intestinal healing, identifies open questions in the field and provides a framework for future studies.
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Affiliation(s)
- Florian Rieder
- Department of Gastroenterology & Hepatology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, USA.
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31
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Sarker P, Ahmed S, Tiash S, Rekha RS, Stromberg R, Andersson J, Bergman P, Gudmundsson GH, Agerberth B, Raqib R. Phenylbutyrate counteracts Shigella mediated downregulation of cathelicidin in rabbit lung and intestinal epithelia: a potential therapeutic strategy. PLoS One 2011; 6:e20637. [PMID: 21673991 PMCID: PMC3108617 DOI: 10.1371/journal.pone.0020637] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2010] [Accepted: 05/06/2011] [Indexed: 12/16/2022] Open
Abstract
Background Cathelicidins and defensins are endogenous antimicrobial peptides (AMPs) that are downregulated in the mucosal epithelia of the large intestine in shigellosis. Oral treatment of Shigella infected rabbits with sodium butyrate (NaB) reduces clinical severity and counteracts the downregulation of cathelicidin (CAP-18) in the large intestinal epithelia. Aims To develop novel regimen for treating infectious diseases by inducing innate immunity, we selected sodium 4-phenylbutyrate (PB), a registered drug for a metabolic disorder as a potential therapeutic candidate in a rabbit model of shigellosis. Since acute respiratory infections often cause secondary complications during shigellosis, the systemic effect of PB and NaB on CAP-18 expression in respiratory epithelia was also evaluated. Methods The readouts were clinical outcomes, CAP-18 expression in mucosa of colon, rectum, lung and trachea (immunohistochemistry and real-time PCR) and release of the CAP-18 peptide/protein in stool (Western blot). Principal findings Significant downregulation of CAP-18 expression in the epithelia of rectum and colon, the site of Shigella infection was confirmed. Interestingly, reduced expression of CAP-18 was also noticed in the epithelia of lung and trachea, indicating a systemic effect of the infection. This suggests a causative link to acute respiratory infections during shigellosis. Oral treatment with PB resulted in reduced clinical illness and upregulation of CAP-18 in the epithelium of rectum. Both PB and NaB counteracted the downregulation of CAP-18 in lung epithelium. The drug effect is suggested to be systemic as intravenous administration of NaB could also upregulate CAP-18 in the epithelia of lung, rectum and colon. Conclusion Our results suggest that PB has treatment potential in human shigellosis. Enhancement of CAP-18 in the mucosal epithelia of the respiratory tract by PB or NaB is a novel discovery. This could mediate protection from secondary respiratory infections that frequently are the lethal causes in dysentery.
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Affiliation(s)
- Protim Sarker
- International Centre for Diarrheal Disease Research, Bangladesh, Dhaka, Bangladesh
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Sultan Ahmed
- International Centre for Diarrheal Disease Research, Bangladesh, Dhaka, Bangladesh
| | - Snigdha Tiash
- International Centre for Diarrheal Disease Research, Bangladesh, Dhaka, Bangladesh
| | - Rokeya Sultana Rekha
- International Centre for Diarrheal Disease Research, Bangladesh, Dhaka, Bangladesh
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Roger Stromberg
- Department of Biosciences and Nutrition, Center for Infectious Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Jan Andersson
- Department of Medicine, Center for Infectious Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Peter Bergman
- Department of Medicine, Center for Infectious Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden
| | | | - Birgitta Agerberth
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Rubhana Raqib
- International Centre for Diarrheal Disease Research, Bangladesh, Dhaka, Bangladesh
- * E-mail:
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Abstract
In the preantibiotic era, TB of the skin was treated successfully with UV light. By the 1920s, pulmonary TB was being treated with regular sun exposure. During the last decade, basic laboratory research into the antimicrobial actions of vitamin D has provided new insights into these historical observations. Vitamin D has a critical role in the innate immune system through the production of antimicrobial peptides - particularly cathelicidin. Vitamin D would appear to have an important role in respiratory tract, skin and potentially gut health. A number of autoimmune diseases, including multiple sclerosis, Type I diabetes, systemic lupus erythematosus and rheumatoid arthritis, are associated with vitamin D deficiency. Vitamin D could have an important role in the prevention and possible treatment of these conditions; however, much of the current evidence relates to basic science and epidemiological research. In many situations, appropriate double-blind, randomized controlled trial data to guide clinicians treating infectious and autoimmune disease is still lacking.
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Affiliation(s)
- Jim Bartley
- Department of Otolaryngology-Head and Neck Surgery, Counties-Manukau District Health Board, Auckland, New Zealand.
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Dhaliwal W, Shawa T, Khanam M, Jagatiya P, Simuyandi M, Ndulo N, Bevins CL, Sanderson IR, Kelly P. Intestinal antimicrobial gene expression: impact of micronutrients in malnourished adults during a randomized trial. J Infect Dis 2010; 202:971-8. [PMID: 20695797 PMCID: PMC3374852 DOI: 10.1086/655903] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND Because both micronutrients and antimicrobial peptides protect against diarrhea, we looked for an effect on intestinal antimicrobial peptide gene expression during a randomized controlled trial of multiple micronutrient (MM) supplementation. METHODS Consenting adults (n=287) in Lusaka, Zambia, were randomized to receive a daily MM supplement or placebo and were followed up for 3.3 years, with a crossover after 2 years. Intestinal biopsy samples were obtained at annual intervals, and messenger RNA of the intestinal antimicrobial peptides human alpha defensin (HD) 5, HD6, human beta-defensin (hBD) 1, hBD2, and LL-37 were quantified by real-time reverse-transcriptase polymerase chain reaction. Samples were also obtained during diarrhea episodes and after convalescence. RESULTS There was no effect overall of treatment allocation. However, in malnourished adults (body mass index < or =18.5), HD5 mRNA was increased by 0.8 log transcripts/microg total RNA in MM recipients, compared with HD5 mRNA in placebo recipients (P=.007). During diarrhea, HD5 expression was reduced by 0.8 log transcripts in placebo recipients (P=.02) but was not reduced in MM recipients, nor was it reduced after the crossover. Correlations between HD5 and nutritional status were found that were sex-specific but not explained by serum leptin or adiponectin concentrations. CONCLUSIONS Micronutrient supplementation was associated with up-regulation of HD5 only in malnourished adults. Interactions between antimicrobial gene expression and nutritional status may help to explain the increased risk of infection in individuals with malnutrition.
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Affiliation(s)
- Winnie Dhaliwal
- Institute of Cell and Molecular Science, Barts & The London School of Medicine, Queen Mary University of London, UK
| | - Tamara Shawa
- Tropical Gastroenterology & Nutrition group, University of Zambia School of Medicine, Lusaka, Zambia
| | - Moriam Khanam
- Institute of Cell and Molecular Science, Barts & The London School of Medicine, Queen Mary University of London, UK
| | - Poonam Jagatiya
- Institute of Cell and Molecular Science, Barts & The London School of Medicine, Queen Mary University of London, UK
| | - Michelo Simuyandi
- Tropical Gastroenterology & Nutrition group, University of Zambia School of Medicine, Lusaka, Zambia
| | - Namwiinga Ndulo
- Tropical Gastroenterology & Nutrition group, University of Zambia School of Medicine, Lusaka, Zambia
| | - Charles L Bevins
- Department of Immunology, University of California at Davis, Davis, California, USA
| | - Ian R Sanderson
- Institute of Cell and Molecular Science, Barts & The London School of Medicine, Queen Mary University of London, UK
| | - Paul Kelly
- Institute of Cell and Molecular Science, Barts & The London School of Medicine, Queen Mary University of London, UK
- Tropical Gastroenterology & Nutrition group, University of Zambia School of Medicine, Lusaka, Zambia
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Wu S, Liao AP, Xia Y, Li YC, Li JD, Sartor RB, Sun J. Vitamin D receptor negatively regulates bacterial-stimulated NF-kappaB activity in intestine. THE AMERICAN JOURNAL OF PATHOLOGY 2010; 177:686-97. [PMID: 20566739 PMCID: PMC2913341 DOI: 10.2353/ajpath.2010.090998] [Citation(s) in RCA: 195] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Accepted: 04/02/2010] [Indexed: 12/13/2022]
Abstract
Vitamin D receptor (VDR) plays an essential role in gastrointestinal inflammation. Most investigations have focused on the immune response; however, how bacteria regulate VDR and how VDR modulates the nuclear factor (NF)-kappaB pathway in intestinal epithelial cells remain unexplored. This study investigated the effects of VDR ablation on NF-kappaB activation in intestinal epithelia and the role of enteric bacteria on VDR expression. We found that VDR(-/-) mice exhibited a pro-inflammatory bias. After Salmonella infection, VDR(-/-) mice had increased bacterial burden and mortality. Serum interleukin-6 in noninfected VDR(+/+) mice was undetectable, but was easily detectable in VDR(-/-) mice. NF-kappaB p65 formed a complex with VDR in noninfected wild-type mouse intestine. In contrast, deletion of VDR abolished VDR/P65 binding. P65 nuclear translocation occurred in colonic epithelial cells of untreated VDR(-/-) mice. VDR deletion also elevated NF-kappaB activity in intestinal epithelia. VDR was localized to the surface epithelia of germ-free mice, but to crypt epithelial cells in conventionalized mice. VDR expression, distribution, transcriptional activity, and target genes were regulated by Salmonella stimulation, independent of 1,25-dihydroxyvitamin D3. Our study demonstrates that commensal and pathogenic bacteria directly regulate colonic epithelial VDR expression and location in vivo. VDR negatively regulates bacterial-induced intestinal NF-kappaB activation and attenuates response to infection. Therefore, VDR is an important contributor to intestinal homeostasis and host protection from bacterial invasion and infection.
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Affiliation(s)
- Shaoping Wu
- Gastroenterology & Hepatology Division, Department of Medicine, University of Rochester, Rochester, New York, USA
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Thibault R, Blachier F, Darcy-Vrillon B, de Coppet P, Bourreille A, Segain JP. Butyrate utilization by the colonic mucosa in inflammatory bowel diseases: a transport deficiency. Inflamm Bowel Dis 2010; 16:684-95. [PMID: 19774643 DOI: 10.1002/ibd.21108] [Citation(s) in RCA: 184] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The short-chain fatty acid butyrate, which is mainly produced in the lumen of the large intestine by the fermentation of dietary fibers, plays a major role in the physiology of the colonic mucosa. It is also the major energy source for the colonocyte. Numerous studies have reported that butyrate metabolism is impaired in intestinal inflamed mucosa of patients with inflammatory bowel disease (IBD). The data of butyrate oxidation in normal and inflamed colonic tissues depend on several factors, such as the methodology or the models used or the intensity of inflammation. The putative mechanisms involved in butyrate oxidation impairment may include a defect in beta oxidation, luminal compounds interfering with butyrate metabolism, changes in luminal butyrate concentrations or pH, and a defect in butyrate transport. Recent data show that butyrate deficiency results from the reduction of butyrate uptake by the inflamed mucosa through downregulation of the monocarboxylate transporter MCT1. The concomitant induction of the glucose transporter GLUT1 suggests that inflammation could induce a metabolic switch from butyrate to glucose oxidation. Butyrate transport deficiency is expected to have clinical consequences. Particularly, the reduction of the intracellular availability of butyrate in colonocytes may decrease its protective effects toward cancer in IBD patients.
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Affiliation(s)
- Ronan Thibault
- UMR 1280 Physiologie des Adaptations Nutritionnelles, INRA, Université de Nantes, CHU Nantes, Nantes, France.
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36
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Zhang Y, Zhou L, Bao YL, Wu Y, Yu CL, Huang YX, Sun Y, Zheng LH, Li YX. Butyrate induces cell apoptosis through activation of JNK MAP kinase pathway in human colon cancer RKO cells. Chem Biol Interact 2010; 185:174-81. [PMID: 20346929 DOI: 10.1016/j.cbi.2010.03.035] [Citation(s) in RCA: 105] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2010] [Revised: 03/17/2010] [Accepted: 03/18/2010] [Indexed: 02/07/2023]
Abstract
Butyrate has been shown to display anti-cancer activity through the induction of apoptosis in various cancer cells. However, the underlying mechanism involved in butyrate-induced apoptosis is still not fully understood. Here, we investigated the cytotoxicity mechanism of butyrate in human colon cancer RKO cells. The results showed that butyrate induced a strong growth inhibitory effect against RKO cells. Butyrate also effectively induced apoptosis in RKO cells, which was characterized by DNA fragmentation, nuclear staining of DAPI, and the activation of caspase-9 and caspase-3. The expression of anti-apoptotic protein Bcl-2 decreased, whereas the apoptotic protein Bax increased in a dose-dependent manner during butyrate-induced apoptosis. Moreover, treatment of RKO cells with butyrate induced a sustained activation of the phosphorylation of c-jun N-terminal kinase (JNK) in a dose- and time-dependent manner, and the pharmacological inhibition of JNK MAPK by SP600125 significantly abolished the butyrate-induced apoptosis in RKO cells. These results suggest that butyrate acts on RKO cells via the JNK but not the p38 pathway. Butyrate triggered the caspase apoptotic pathway, indicated by an enhanced Bax-to-Bcl-2 expression ratio and caspase cascade reaction, which was blocked by SP600125. Taken together, our data indicate that butyrate induces apoptosis through JNK MAPK activation in colon cancer RKO cells.
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Affiliation(s)
- Yu Zhang
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China
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37
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Gombart AF. The vitamin D-antimicrobial peptide pathway and its role in protection against infection. Future Microbiol 2010; 4:1151-65. [PMID: 19895218 DOI: 10.2217/fmb.09.87] [Citation(s) in RCA: 300] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Vitamin D deficiency has been correlated with increased rates of infection. Since the early 19th century, both environmental (i.e., sunlight) and dietary sources (cod liver) of vitamin D have been identified as treatments for TB. The recent discovery that vitamin D induces antimicrobial peptide gene expression explains, in part, the 'antibiotic' effect of vitamin D and has greatly renewed interest in the ability of vitamin D to improve immune function. Subsequent work indicates that this regulation is biologically important for the response of the innate immune system to wounds and infection and that deficiency may lead to suboptimal responses toward bacterial and viral infections. The regulation of the cathelicidin antimicrobial peptide gene is a human/primate-specific adaptation and is not conserved in other mammals. The capacity of the vitamin D receptor to act as a high-affinity receptor for vitamin D and a low-affinity receptor for secondary bile acids and potentially other novel nutritional compounds suggests that the evolutionary selection to place the cathelicidin gene under control of the vitamin D receptor allows for its regulation under both endocrine and xenobiotic response systems. Future studies in both humans and humanized mouse models will elucidate the importance of this regulation and lead to the development of potential therapeutic applications.
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Affiliation(s)
- Adrian F Gombart
- Linus Pauling Institute, Department of Biochemisty & Biophysics, Oregon State University, Corvallis, 97331-7305, USA.
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Brandenburg LO, Varoga D, Nicolaeva N, Leib SL, Podschun R, Wruck CJ, Wilms H, Lucius R, Pufe T. Expression and regulation of antimicrobial peptide rCRAMP after bacterial infection in primary rat meningeal cells. J Neuroimmunol 2009; 217:55-64. [PMID: 19879657 DOI: 10.1016/j.jneuroim.2009.10.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2009] [Revised: 09/17/2009] [Accepted: 10/08/2009] [Indexed: 11/18/2022]
Abstract
Bacterial meningitis is characterized by an inflammation of the meninges and continues to be an important cause of mortality and morbidity. Meningeal cells cover the cerebral surface and are involved in the first interaction between pathogens and the brain. Little is known about the role of meningeal cells and the expression of antimicrobial peptides in the innate immune system. In this study we characterized the expression, secretion and bactericidal properties of rat cathelin-related antimicrobial peptide (rCRAMP), a homologue of the human LL-37, in rat meningeal cells after incubation with different bacterial supernatants and the bacterial cell wall components lipopolysaccharide (LPS) and peptidoglycan (PGN). Using an agar diffusion test, we observed that supernatants from meningeal cells incubated with bacterial supernatants, LPS and PGN showed signs of antimicrobial activity. The inhibition of rCRAMP expression using siRNA reduced the antimicrobial activity of the cell culture supernatants. The expression of rCRAMP in rat meningeal cells involved various signal transduction pathways and was induced by the inflammatory cytokines interleukin-1, -6 and tumor necrosis factor alpha. In an experimental model of meningitis, infant rats were intracisternally infected with Streptococcus pneumoniae and rCRAMP was localized in meningeal cells using immunohistochemistry. These results suggest that cathelicidins produced by meningeal cells play an important part in the innate immune response against pathogens in CNS bacterial infections.
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Abstract
Antimicrobial peptides (AMPs) are important components of our first line of defense. Induction of AMPs such as LL-37 of the cathelicidin family might provide a novel approach in treating bacterial infections. In this study we identified 4-phenylbutyrate (PBA) as a novel inducer of AMP expression and investigated affected regulatory pathways. We treated various cell lines with PBA and assessed mRNA expression by real-time reverse transcriptase PCR (RT-PCR). Cathelicidin AMP (CAMP) gene expression was found to be upregulated in all four cell lines tested. Additionally, we found that the beta-defensin 1 gene was upregulated in the lung epithelial cell line VA10 while being downregulated in the monocytic cell line U937. Further we found that PBA induced CAMP gene expression synergistically with 1,25-dihydroxyvitamin D(3) at both protein and mRNA levels. The general mechanism of induction of CAMP gene expression by PBA was found to be dependent on protein synthesis. Results from quantitative chromatin immunoprecipitation experiments challenge the common view that histone deacetylase inhibitors directly increase CAMP gene expression. Furthermore, we have demonstrated that inhibition of the mitogen-activated protein kinases MEK1/2 and c-Jun N-terminal kinase attenuate PBA-induced CAMP gene expression. Similarly, alpha-methylhydrocinnamate (ST7), an analogue of PBA, increases CAMP gene expression. Our findings contribute to understanding of the regulation of AMP expression and suggest that PBA and/or ST7 is a promising drug candidate for treatment of microbial infections by strengthening the epithelial antimicrobial barriers.
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Chakraborty K, Maity PC, Sil AK, Takeda Y, Das S. cAMP stringently regulates human cathelicidin antimicrobial peptide expression in the mucosal epithelial cells by activating cAMP-response element-binding protein, AP-1, and inducible cAMP early repressor. J Biol Chem 2009; 284:21810-21827. [PMID: 19531482 PMCID: PMC2755907 DOI: 10.1074/jbc.m109.001180] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2009] [Revised: 05/21/2009] [Indexed: 01/27/2023] Open
Abstract
Little is known about the regulation of the innate host defense peptide cathelicidin at the mucosal surfaces. Expression is believed to be transcriptionally regulated, and several cis-acting elements have been identified in the cathelicidin putative promoter. However, the trans-acting factors have not been clearly defined. We have recently reported that bacterial exotoxins suppress cathelicidin expression in sodium butyrate-differentiated intestinal epithelial cells (ECs), and this may be mediated through inducible cAMP early repressor. Here we have shown that cAMP-signaling pathways transcriptionally regulate cathelicidin expression in various ECs. cAMP-response element-binding protein (CREB) and AP-1 (activator protein-1) bind to the cathelicidin putative promoter in vitro. Additionally, transcriptional complexes containing CREB, AP-1, and cathelicidin upstream regulatory sequences are formed within ECs. We have also shown that these complexes may activate cathelicidin promoter and are required for its inducible expression in ECs. This is underscored by the fact that silencing of CREB and AP-1 results in failure of ECs to up-regulate cathelicidin, and hepatitis B virus X protein may use CREB to induce cathelicidin. On the other hand, inducible cAMP early repressor competes with CREB and AP-1 for binding to the cathelicidin promoter and represses transcription, thus functioning as a counter-regulatory mechanism. Finally, both CREB and AP-1 were shown to play major roles in the regulation of cathelicidin in sodium butyrate-differentiated HT-29 cells. This is the first report of a detailed mechanistic study of inducible cathelicidin expression in the mucosal ECs. At the same time, it describes a novel immunomodulatory function of cAMP.
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Affiliation(s)
- Krishnendu Chakraborty
- From the Department of Clinical Medicine, National Institute of Cholera and Enteric Diseases, P-33 C.I.T. Road, Scheme XM, Beliaghata, Kolkata 700010
| | - Palash Chandra Maity
- the Department of Microbiology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700019, and
| | - Alok Kumar Sil
- the Department of Microbiology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700019, and
| | - Yoshifumi Takeda
- the Collaborative Research Center of Okayama University for Infectious Diseases, National Institute of Cholera and Enteric Diseases, P-33 C.I.T. Road, Scheme XM, Beliaghata, Kolkata 700010, India
| | - Santasabuj Das
- From the Department of Clinical Medicine, National Institute of Cholera and Enteric Diseases, P-33 C.I.T. Road, Scheme XM, Beliaghata, Kolkata 700010
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41
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Li G, Domenico J, Jia Y, Lucas JJ, Gelfand EW. NF-kappaB-dependent induction of cathelicidin-related antimicrobial peptide in murine mast cells by lipopolysaccharide. Int Arch Allergy Immunol 2009; 150:122-32. [PMID: 19439978 PMCID: PMC2814151 DOI: 10.1159/000218115] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2008] [Accepted: 01/12/2009] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND An important aspect of the innate immune response to pathogens is the production of anti-microbial peptides such as cathelicidin-related antimicrobial peptide (CRAMP), the murine homologue of human cathelicidin LL-37. In this study, mechanisms regulating LPS-induction of CRAMP gene expression in mast cells were investigated. NF-kappaB and MAPK pathways were the focus of investigation. METHODS Mouse bone marrow-derived mast cells were grown in culture and stimulated with LPS. MAPKs and NF-kappaB were monitored by immunoblot analysis. ERK, JNK and p38 MAPK were inhibited using siRNAs or a pharmacological inhibitor. Accumulation of the p65 component of NF-kappaB was inhibited by siRNA and NF-kappaB activation was inhibited by overexpression of I kappaB alpha. MEKK2 or MEKK3 were overexpressed by transfection. The effects of all of these treatments on CRAMP gene expression were monitored by RT-PCR. RESULTS Inhibition of ERK, JNK or p38 MAPK had little discernible effect on LPS-inducible CRAMP gene expression. Overexpression of MEKK2 or MEKK3 likewise had little impact. However, inhibition of the accumulation of p65 NF-kappaB prevented LPS-induced CRAMP mRNA. An important role for NF-kappaB in CRAMP gene expression was confirmed by overexpression of I kappaB alpha, which reduced both basal and induced levels of CRAMP mRNA. CONCLUSIONS NF-kappaB, but not MAPKs, plays an important role in LPS-mediated induction of CRAMP gene in mast cells. Defects which inhibit NF-kappaB activity may increase susceptibility to bacterial and viral pathogens which are sensitive to cathelicidins.
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Affiliation(s)
| | | | | | | | - Erwin W. Gelfand
- Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colo., USA
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Ochoa-Zarzosa A, Villarreal-Fernández E, Cano-Camacho H, López-Meza JE. Sodium butyrate inhibits Staphylococcus aureus internalization in bovine mammary epithelial cells and induces the expression of antimicrobial peptide genes. Microb Pathog 2009; 47:1-7. [PMID: 19393738 DOI: 10.1016/j.micpath.2009.04.006] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2009] [Revised: 04/07/2009] [Accepted: 04/09/2009] [Indexed: 11/26/2022]
Abstract
A distinctive feature of bovine milk fat is the presence of butyrate, molecule with recognized antimicrobial and antiinflammatory properties. Bovine mastitis is a pathology characterized by inflammatory and infectious processes; however, the role of sodium butyrate on Staphylococcus aureus infection in mammary epithelium has not been studied. In this work we assess the role of sodium butyrate on the invasion of bovine mammary epithelial cells (bMEC) by S. aureus responsible of mastitis and on the expression of antimicrobial peptide genes. Our data show that sodium butyrate (0.25-0.5mM) reduces approximately 50% the internalization of S. aureus (ATCC 27543) into bMEC. By RT-PCR analysis, we showed that sodium butyrate is able to up-regulate the expression of tracheal antimicrobial peptide (TAP), beta-defensin and inducible nitric oxide synthase (iNOS) mRNAs, as well as nitric oxide production. Also, sodium butyrate and infection increased acetylation of histone H3 in bMEC. These results indicate that sodium butyrate could be effective to modulate innate immune gene expression in mammary gland that leads to a better defense against bacterial infection. To our knowledge, this is the first report that shows a role of sodium butyrate during the internalization of S. aureus into bMEC.
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Affiliation(s)
- Alejandra Ochoa-Zarzosa
- Facultad de Medicina Veterinaria y Zootecnia, Universidad Michoacana de San Nicolás de Hidalgo, Administración Chapultepec, Centro Multidisciplinario de Estudios en Biotecnología, Morelia, Michoacán, Mexico
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43
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Kim YS, Young MR, Bobe G, Colburn NH, Milner JA. Bioactive food components, inflammatory targets, and cancer prevention. Cancer Prev Res (Phila) 2009; 2:200-8. [PMID: 19258539 PMCID: PMC3449301 DOI: 10.1158/1940-6207.capr-08-0141] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Various dietary components may modify chronic inflammatory processes at the stage of cytokine production, amplification of nuclear factor-kappaB-mediated inflammatory gene expression, and the release of anti-inflammatory cytokine, transforming growth factor-beta. This review provides a synopsis of the strengths and weaknesses of the evidence that specific bioactive food components influence inflammation-related targets linked to cancer. A target repeatedly surfacing as a site of action for several dietary components is transforming growth factor beta. Whereas the use of dietary intervention strategies offers intriguing possibilities for maintaining normal cell function by modifying a process that is essential for cancer development and progression, more information is needed to characterize the minimum quantity of the bioactive food components required to bring about a change in inflammation-mediated cancer, the ideal time for intervention, and the importance of genetics in determining the response. Unquestionably, the societal benefits of using foods and their components to prevent chronic inflammation and associated complications, including cancer, are enormous.
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Affiliation(s)
- Young S Kim
- Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, MD, USA.
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44
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The roles of cathelicidin LL-37 in immune defences and novel clinical applications. Curr Opin Hematol 2009; 16:41-7. [PMID: 19068548 DOI: 10.1097/moh.0b013e32831ac517] [Citation(s) in RCA: 214] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
PURPOSE OF REVIEW LL-37 is the only member of the cathelicidin family of host defence peptides expressed in humans. It is primarily produced by phagocytic leucocytes and epithelial cells, and mediates a wide range of biological responses: direct killing of microorganisms, chemotaxis and chemokine induction, regulation of inflammatory responses, as well as adjuvant, angiogenic and wound healing effects. In this review we will cover the recent advances in the understanding of LL-37 biology: its activities, the mechanisms of its induction and roles in immune defence. RECENT FINDINGS Recent studies advanced our understanding of the mechanisms controlling LL-37 expression, demonstrating the key involvement of the vitamin D3 and the hypoxia response pathways, and the impacts of commensal and pathogenic microorganisms on its production. The synergistic and antagonistic interactions between LL-37 and other immune mediators have been further elucidated. Furthermore, studies in animal models and human patients further characterized the roles of cathelicidins in immunity, with roles in infectious and inflammatory conditions. The underlying properties of LL-37 have been exploited to create innate defence regulator peptides that represent a novel immunomodulatory approach to treating infections. SUMMARY The understanding of the biological properties and functions of LL-37 and other host defence peptides advances our knowledge of innate immunity, the interactions of the host with pathogens and the microflora, as well as the pathology of infectious and inflammatory diseases, creating many strategies and opportunities for therapeutic intervention.
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45
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Schwab M, Reynders V, Steinhilber D, Stein J. Combined treatment of Caco-2 cells with butyrate and mesalazine inhibits cell proliferation and reduces Survivin protein level. Cancer Lett 2009; 273:98-106. [PMID: 18774638 DOI: 10.1016/j.canlet.2008.07.027] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2008] [Revised: 07/28/2008] [Accepted: 07/28/2008] [Indexed: 01/16/2023]
Abstract
There is epidemiological evidence, that mesalazine can inhibit colon cancer development by affecting proliferation and apoptosis. Several studies suggest that supplementary intake of butyrate may yield to improved efficacy of mesalazine. However, the underlying molecular mechanisms of such interaction remain unknown. This study addressed the combinatory effect of both substances on the growth of Caco-2 cells. Challenging of cells with mesalazine and butyrate provoked a time-dependent decrease in both cell counts and proliferation. Co-treatment with the substances could further intensify these effects. The growth-inhibitory action of mesalazine and butyrate was accompanied by a significant increase in caspase-3 activity, cleavage of PARP and caspase-8, while decreasing the expression of Xiap and Survivin simultaneously. Co-incubation of both substances exaggerated effects on all examined apoptosis-regulatory proteins except for Xiap. Our data demonstrate that co-treatment of mesalazine and butyrate evoked additive effects on inhibition of cell growth and induction of apoptosis in Caco-2 cells.
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Affiliation(s)
- Markus Schwab
- First Department of Medicine-ZAFES, Division of Gastroenterology, Johann Wolfgang Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
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Role of glial cells in the functional expression of LL-37/rat cathelin-related antimicrobial peptide in meningitis. J Neuropathol Exp Neurol 2008; 67:1041-54. [PMID: 18957897 DOI: 10.1097/nen.0b013e31818b4801] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Antimicrobial peptides are intrinsic to the innate immune system in many organ systems, but little is known about their expression in the central nervous system. We examined cerebrospinal fluid (CSF) and serum from patients with active bacterial meningitis to assess antimicrobial peptides and possible bactericidal properties of the CSF. We found antimicrobial peptides (human cathelicidin LL-37) in the CSF of patients with bacterial meningitis but not in control CSF. We next characterized the expression, secretion, and bactericidal properties of rat cathelin-related antimicrobial peptide, the homologue of the human LL-37, in rat astrocytes and microglia after incubation with different bacterial components. Using real-time polymerase chain reaction and Western blotting, we determined that supernatants from both astrocytes and microglia incubated with bacterial component supernatants had antimicrobial activity. The expression of rat cathelin-related antimicrobial peptide in rat glial cells involved different signal transduction pathways and was induced by the inflammatory cytokines interleukin 1beta and tumor necrosis factor. In an experimental model of meningitis, infant rats were intracisternally infected with Streptococcus pneumoniae, and rat cathelin-related antimicrobial peptide was localized in glia, choroid plexus, and ependymal cells by immunohistochemistry. Together, these results suggest that cathelicidins produced by glia and other cells play an important part in the innate immune response against pathogens in central nervous system bacterial infections.
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47
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Schwab M, Reynders V, Loitsch S, Steinhilber D, Schröder O, Stein J. The dietary histone deacetylase inhibitor sulforaphane induces human beta-defensin-2 in intestinal epithelial cells. Immunology 2008; 125:241-251. [PMID: 18373608 PMCID: PMC2561129 DOI: 10.1111/j.1365-2567.2008.02834.x] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2007] [Revised: 02/13/2007] [Accepted: 02/15/2008] [Indexed: 12/17/2022] Open
Abstract
Antimicrobial peptides like human beta-defensin-2 (HBD-2) play an important role in the innate immune system protecting the intestinal mucosa against bacterial invasion. The dietary histone deacetylase (HDAC) inhibitors sulforaphane (SFN) and butyrate have received a great deal of attention because of their ability to simultaneously modulate multiple cellular targets involved in cellular protection. In this study the influence of SFN and butyrate on HBD-2 expression as well as the molecular pathways involved in SFN-mediated induction of HBD-2 were scrutinized. Treatment of Caco-2, HT-29 and SW480 cells with SFN led to a time- and dose-dependent upregulation of HBD-2 mRNA expression as determined by semi-quantitative reverse transcription-polymerase chain reaction. Moreover, HBD-2 protein production increased in response to SFN, measured by enzyme-linked immunosorbent assay. Induction of HBD-2 was also observed in response to butyrate. Immunofluorescence analysis revealed that the protein was localized in the cytosol. Coincubation of SFN with a vitamin D receptor (VDR), or an extracellular-regulated kinase 1/2 or a nuclear factor-kappaB inhibitor all reduced HBD-2 mRNA upregulation. In contrast, transfection of cells with a dominant-negative peroxisome proliferator-activated receptor gamma (PPARgamma) mutant vector to inhibit PPARgamma wild-type action and inhibition of p38 mitogen-activated protein kinase (MAPK) signalling did not affect SFN-mediated upregulation of HBD-2 mRNA. Moreover, SFN induced the expression of VDR, PPARgamma and phosphorylated ERK1/2 but did not affect p38 MAPK activation. The data clearly demonstrate for the first time that the dietary HDAC inhibitor SFN is able to induce antimicrobial peptides in colonocytes. In this process HBD-2 expression is regulated via VDR, mitogen-activated protein kinase kinase/extracellular-regulated kinase and nuclear factor-kappaB signalling.
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Affiliation(s)
- Markus Schwab
- First Department of Medicine-ZAFES, Johann Wolfgang Goethe-University FrankfurtFrankfurt am Main, Germany
| | - Veerle Reynders
- First Department of Medicine-ZAFES, Johann Wolfgang Goethe-University FrankfurtFrankfurt am Main, Germany
| | - Stefan Loitsch
- First Department of Medicine-ZAFES, Johann Wolfgang Goethe-University FrankfurtFrankfurt am Main, Germany
| | - Dieter Steinhilber
- Institute of Pharmaceutical Chemistry-ZAFES, Johann Wolfgang Goethe-University FrankfurtFrankfurt am Main, Germany
| | - Oliver Schröder
- First Department of Medicine-ZAFES, Johann Wolfgang Goethe-University FrankfurtFrankfurt am Main, Germany
| | - Jürgen Stein
- First Department of Medicine-ZAFES, Johann Wolfgang Goethe-University FrankfurtFrankfurt am Main, Germany
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Chakraborty K, Ghosh S, Koley H, Mukhopadhyay AK, Ramamurthy T, Saha DR, Mukhopadhyay D, Roychowdhury S, Hamabata T, Takeda Y, Das S. Bacterial exotoxins downregulate cathelicidin (hCAP-18/LL-37) and human beta-defensin 1 (HBD-1) expression in the intestinal epithelial cells. Cell Microbiol 2008; 10:2520-37. [PMID: 18717821 DOI: 10.1111/j.1462-5822.2008.01227.x] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Cathelicidin (hCAP-18/LL-37) and beta-defensin 1 (HBD-1) are human antimicrobial peptides (AMPs) with high basal expression levels, which form the first line of host defence against infections over the epithelial surfaces. The antimicrobial functions owe to their direct microbicidal effects as well as the immunomodulatory role. Pathogenic microorganisms have developed multiple modalities including transcriptional repression to combat this arm of the host immune response. The precise mechanisms and the pathogen-derived molecules responsible for transcriptional downregulation remain unknown. Here, we have shown that enteric pathogens suppress LL-37 and HBD-1 expression in the intestinal epithelial cells (IECs) with Vibrio cholerae and enterotoxigenic Escherichia coli (ETEC) exerting the most dramatic effects. Cholera toxin (CT) and labile toxin (LT), the major virulence proteins of V. cholerae and ETEC, respectively, are predominantly responsible for these effects, both in vitro and in vivo. CT transcriptionally downregulates the AMPs by activating several intracellular signalling pathways involving protein kinase A (PKA), ERK MAPKinase and Cox-2 downstream of cAMP accumulation and inducible cAMP early repressor (ICER) may mediate this role of CT, at least in part. This is the first report to show transcriptional repression of the AMPs through the activation of cellular signal transduction pathways by well-known virulence proteins of pathogenic microorganisms.
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Flatt T, Heyland A, Rus F, Porpiglia E, Sherlock C, Yamamoto R, Garbuzov A, Palli SR, Tatar M, Silverman N. Hormonal regulation of the humoral innate immune response in Drosophila melanogaster. J Exp Biol 2008; 211:2712-24. [PMID: 18689425 PMCID: PMC2522372 DOI: 10.1242/jeb.014878] [Citation(s) in RCA: 200] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Juvenile hormone (JH) and 20-hydroxy-ecdysone (20E) are highly versatile hormones, coordinating development, growth, reproduction and aging in insects. Pulses of 20E provide key signals for initiating developmental and physiological transitions, while JH promotes or inhibits these signals in a stage-specific manner. Previous evidence suggests that JH and 20E might modulate innate immunity, but whether and how these hormones interact to regulate the immune response remains unclear. Here we show that JH and 20E have antagonistic effects on the induction of antimicrobial peptide (AMP) genes in Drosophila melanogaster. 20E pretreatment of Schneider S2 cells promoted the robust induction of AMP genes, following immune stimulation. On the other hand, JH III, and its synthetic analogs (JHa) methoprene and pyriproxyfen, strongly interfered with this 20E-dependent immune potentiation, although these hormones did not inhibit other 20E-induced cellular changes. Similarly, in vivo analyses in adult flies confirmed that JH is a hormonal immuno-suppressor. RNA silencing of either partner of the ecdysone receptor heterodimer (EcR or Usp) in S2 cells prevented the 20E-induced immune potentiation. In contrast, silencing methoprene-tolerant (Met), a candidate JH receptor, did not impair immuno-suppression by JH III and JHa, indicating that in this context MET is not a necessary JH receptor. Our results suggest that 20E and JH play major roles in the regulation of gene expression in response to immune challenge.
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Affiliation(s)
- Thomas Flatt
- Brown University, Division of Biology and Medicine, Department of Ecology and Evolutionary Biology, Providence, RI
| | - Andreas Heyland
- University of Guelph, Department of Integrative Biology, Guelph, Canada
| | - Florentina Rus
- University of Massachusetts Medical School, Department of Medicine, Division of Infectious Disease, University of Massachusetts Medical School, Worcester, MA
| | - Ermelinda Porpiglia
- University of Massachusetts Medical School, Department of Medicine, Division of Infectious Disease, University of Massachusetts Medical School, Worcester, MA
| | - Chris Sherlock
- University of Massachusetts Medical School, Department of Medicine, Division of Infectious Disease, University of Massachusetts Medical School, Worcester, MA
| | - Rochele Yamamoto
- Brown University, Division of Biology and Medicine, Department of Ecology and Evolutionary Biology, Providence, RI
| | - Alina Garbuzov
- Brown University, Division of Biology and Medicine, Department of Ecology and Evolutionary Biology, Providence, RI
| | - Subba R. Palli
- University of Kentucky, Department of Entomology, Agricultural Science Center, College of Agriculture, Lexington, KY
| | - Marc Tatar
- Brown University, Division of Biology and Medicine, Department of Ecology and Evolutionary Biology, Providence, RI
| | - Neal Silverman
- University of Massachusetts Medical School, Department of Medicine, Division of Infectious Disease, University of Massachusetts Medical School, Worcester, MA
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50
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Bibliography. Current world literature. Growth and development. Curr Opin Endocrinol Diabetes Obes 2008; 15:79-101. [PMID: 18185067 DOI: 10.1097/med.0b013e3282f4f084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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