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Miao S, Liu H, Yang Q, Zhang Y, Chen T, Chen S, Mao X, Zhang Q. Cathelicidin peptide LL-37: A multifunctional peptide involved in heart disease. Pharmacol Res 2024; 210:107529. [PMID: 39615616 DOI: 10.1016/j.phrs.2024.107529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 10/30/2024] [Accepted: 11/27/2024] [Indexed: 12/07/2024]
Abstract
Heart disease is a common human disease with high morbidity and mortality. Timely and effective prevention and treatment is an urgent clinical problem. The pathogenesis of heart disease is complex and diverse, involving hypertension, diabetes, atherosclerosis, drug toxicity, thrombosis, infection and other aspects. LL-37, an endogenous peptide, is well known for its antimicrobial properties. In recent years, LL-37 has been found to have a variety of biological functions, including its role in the regulation of atherosclerosis, thrombosis, inflammatory responses, and cardiac hypertrophy. Engineered LL-37-related peptides were developed and proved to regulate the development of disease, which revealed its potential clinical application. A comprehensive review and summary of LL-37 is presented to clarify its role in heart disease and to provide a reference and direction for future research.
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Affiliation(s)
- Shuo Miao
- Department of Urology, Affiliated Hospital of Qingdao University, Qingdao, China; School of Basic Medicine, Qingdao University, Qingdao, China
| | - Houde Liu
- School of Basic Medicine, Qingdao University, Qingdao, China
| | - Qingyu Yang
- Department of Urology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yaping Zhang
- Department of Urology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Tao Chen
- Department of Urology, Affiliated Hospital of Qingdao University, Qingdao, China; Qingdao Ruipule Medical Technology Co., Ltd, China
| | - Shuai Chen
- School of Basic Medicine, Guizhou University of Traditional Chinese, China
| | - Xin Mao
- Department of Urology, Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Qingsong Zhang
- Department of Urology, Affiliated Hospital of Qingdao University, Qingdao, China.
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Wu E, Zhu J, Ma Z, Tuo B, Terai S, Mizuno K, Li T, Liu X. Gastric alarmin release: A warning signal in the development of gastric mucosal diseases. Front Immunol 2022; 13:1008047. [PMID: 36275647 PMCID: PMC9583272 DOI: 10.3389/fimmu.2022.1008047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 09/14/2022] [Indexed: 11/13/2022] Open
Abstract
Alarmins exist outside cells and are early warning signals to the immune system; as such, alarmin receptors are widely distributed on various immune cells. Alarmins, proinflammatory molecular patterns associated with tissue damage, are usually released into the extracellular space, where they induce immune responses and participate in the damage and repair processes of mucosal diseases.In the stomach, gastric alarmin release has been shown to be involved in gastric mucosal inflammation, antibacterial defense, adaptive immunity, and wound healing; moreover, this release causes damage and results in the development of gastric mucosal diseases, including various types of gastritis, ulcers, and gastric cancer. Therefore, it is necessary to understand the role of alarmins in gastric mucosal diseases. This review focuses on the contribution of alarmins, including IL33, HMGB1, defensins and cathelicidins, to the gastric mucosal barrier and their role in gastric mucosal diseases. Here, we offer a new perspective on the prevention and treatment of gastric mucosal diseases.
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Affiliation(s)
- Enqin Wu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jiaxing Zhu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Zhiyuan Ma
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Biguang Tuo
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Shuji Terai
- Division of Gastroenterology & Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Kenichi Mizuno
- Division of Gastroenterology & Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Taolang Li
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Xuemei Liu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
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Su G, Luo Y, Chen D, Yu B, He J. NF-κB-dependent induction of porcine β-defensin 114 regulates intestinal epithelium homeostasis. Int J Biol Macromol 2021; 192:241-249. [PMID: 34619281 DOI: 10.1016/j.ijbiomac.2021.09.163] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 09/24/2021] [Accepted: 09/24/2021] [Indexed: 11/29/2022]
Abstract
Intestinal epithelial cells (IECs) offer a primary physical barrier against commensal and pathogenic microorganisms in the gastrointestine. However, the influence of IECs on the development and regulation of mucosal immunity to infection is unknown. Here, we show that the porcine β-defensin 114 (PBD114) is an endotoxin-responsive gene expressed in IECs. Analysis on expression profiling of PBD114 gene using an infected porcine model and IPEC-J2 cells unveiled a pattern of induction in response to stimulation of various toll-like receptors (TLRs). By means of promoter analysis, PBD114 was found to be a NF-κB-dependent gene. Importantly, PBD114 suppresses endotoxin-induced inflammation and apoptosis in IECs through downregulation of two critical inflammation-associated signaling proteins, NF-kappa-B inhibitor alpha (IkB-α) and extracellular signal-regulated kinase1/2 (ERK1/2). PBD114 also suppresses inflammation and IEC apoptosis in mice exposed to bacterial endotoxins. Thus, we propose that TLR-activated NF-kB rapidly increases the expression of PBD114 that operates a feedback control of the NF-kB-dependent inflammation. The NF-kB-dependent induction of PBD114 may be a key event through which the mammalian host maintains intestinal epithelium homeostasis in response to various infections or diseases.
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Affiliation(s)
- Guoqi Su
- Institute of Animal Nutrition, Sichuan Agricultural University, Sichuan Province, Chengdu 611130, PR China; Chongqing Academy of Animal Sciences, Chongqing 402460, PR China
| | - Yuheng Luo
- Institute of Animal Nutrition, Sichuan Agricultural University, Sichuan Province, Chengdu 611130, PR China; Key Laboratory of Animal Disease-resistant Nutrition, Sichuan Province, Chengdu 611130, PR China
| | - Daiwen Chen
- Institute of Animal Nutrition, Sichuan Agricultural University, Sichuan Province, Chengdu 611130, PR China; Key Laboratory of Animal Disease-resistant Nutrition, Sichuan Province, Chengdu 611130, PR China
| | - Bing Yu
- Institute of Animal Nutrition, Sichuan Agricultural University, Sichuan Province, Chengdu 611130, PR China; Key Laboratory of Animal Disease-resistant Nutrition, Sichuan Province, Chengdu 611130, PR China
| | - Jun He
- Institute of Animal Nutrition, Sichuan Agricultural University, Sichuan Province, Chengdu 611130, PR China; Key Laboratory of Animal Disease-resistant Nutrition, Sichuan Province, Chengdu 611130, PR China.
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Host defense peptide LL-37 is involved in the regulation of cell proliferation and production of pro-inflammatory cytokines in hepatocellular carcinoma cells. Amino Acids 2021; 53:471-484. [PMID: 33675414 DOI: 10.1007/s00726-021-02966-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 02/26/2021] [Indexed: 11/12/2022]
Abstract
Recent studies on the roles and mechanisms of LL-37 have demonstrated that LL-37 can either serve as a tumor promoter or a tumor suppressor in different cancers. The expression and function of LL-37 in hepatocellular carcinoma (HCC), however, remain unclear. In the present study, we confirmed the down-regulation of LL-37 in HCC tissues and the synthetic LL-37 peptide reduced the viability of HCC cells in a dose-dependent manner. Furthermore, we demonstrated that LL-37 peptide significantly delayed G1-S transition in Huh7 but not in HepG2 cells by suppressing CyclinD1-CDK4-p21 checkpoint signaling pathway. However, LL-37 caused no obvious apoptosis both in Huh7 and HepG2 cells, though the expression of apoptosis-related genes was strongly changed through qRT-PCR analysis, hinting at the possibility that LL-37 participates in regulating the apoptosis of HCC cells, but may not the only mechanism. Besides, we also identified that LL-37 treatment strongly inhibited the mRNA expression of TLR4 both in Huh7 and HepG2 cells, accompanied with the reduced expression of genes responsible for pro-inflammatory cytokines, including IL-8 and IL-6. In conclusion, our research suggested that LL-37 may be associated with the development of HCC.
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Combinational therapy with antibiotics and antibiotic-loaded adipose-derived stem cells reduce abscess formation in implant-related infection in rats. Sci Rep 2020; 10:11182. [PMID: 32636453 PMCID: PMC7341734 DOI: 10.1038/s41598-020-68184-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 06/19/2020] [Indexed: 02/06/2023] Open
Abstract
Implant-related infection is difficult to treat without extended antibiotic courses. However, the long-term use of antibiotics has led to the development of multidrug- and methicillin-resistant Staphylococcusaureus. Thus, alternatives to conventional antibiotic therapy are needed. Recently, mesenchymal stem cells have been shown to have antimicrobial properties. This study aimed to evaluate the antimicrobial activity and therapeutic effect of local treatment with antibiotic-loaded adipose-derived stem cells (ADSCs) plus an antibiotic in a rat implant-associated infection model. Liquid chromatography/tandem mass spectrometry revealed that ADSCs cultured in the presence of ciprofloxacin for 24 h showed time-dependent antibiotic loading. Next, we studied the therapeutic effects of ADSCs and ciprofloxacin alone or in combination in an implant-related infection rat model. The therapeutic effects of ADSCs plus antibiotics, antibiotics, and ADSCs were compared with no treatment as a control. Rats treated with ADSCs plus ciprofloxacin had the lowest modified osteomyelitis scores, abscess formation, and bacterial burden on the implant among all groups (P < 0.05). Thus, local treatment with ADSCs plus an antibiotic has an antimicrobial effect in implant-related infection and decrease abscess formation. Thus, our findings indicate that local administration of ADSCs with antibiotics represents a novel treatment strategy for implant-associated osteomyelitis.
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Huynh E, Akhtar N, Li J. Efficient Production of Recombinant Protegrin-1 From Pichia pastoris, and Its Antimicrobial and in vitro Cell Migration Activity. Front Microbiol 2018; 9:2300. [PMID: 30319593 PMCID: PMC6170612 DOI: 10.3389/fmicb.2018.02300] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Accepted: 09/10/2018] [Indexed: 01/08/2023] Open
Abstract
Protegrin (PG) belongs to the antimicrobial peptide cathelicidin family. To date, five protegrin sequences have been identified in pigs, PG-1 to PG-5. Of these, PG-1 exhibits potent antimicrobial activity against a broad range of antibiotic-resistant microorganisms as well as viruses. However, the other potential role(s) of PG beyond antimicrobial has largely been unexplored. The aim of this study was to use nonpathogenic yeast Pichia pastoris to express antimicrobially active recombinant protegrin (rPG-1). Additionally, the effect of PG-1 on cell migration and proliferation was also examined in vitro using pig intestinal epithelial cells as a model. Highest level of rPG-1 (104 ± 11 μg/mL) was detected at 24 h in fermentation culture medium. Similar to rPG-1, 0.8 ± 0.10 g/L of proform PG-1 (rProPG-1) and 0.2 ± 0.02 g/L of the PG-1 cathelin domain (rCath) was detected in fermentation culture medium. Resulting recombinant PG-1 and cleaved rProPG-1 exerted antimicrobial activity against Escherichia coli DH5α at the same level as chemically synthesized PG-1. Enhanced cell migration was observed (p < 0.05) in groups treated with rProPG-1, rCath, and rPG-1 compared to the control. Furthermore, rPG-1 was stable at temperatures ranging from 25°C to 80°C. In summary, biologically active recombinant protegrin in its pro-, cathelin-, and mature- forms were successfully expressed in P. pastoris suggesting potential feasibility for future therapeutic applications.
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Affiliation(s)
- Evanna Huynh
- Department of Animal Biosciences, University of Guelph, Guelph, ON, Canada
| | - Nadeem Akhtar
- Department of Animal Biosciences, University of Guelph, Guelph, ON, Canada
| | - Julang Li
- Department of Animal Biosciences, University of Guelph, Guelph, ON, Canada
- College of Life Science and Engineering, Foshan University, Foshan, China
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van Harten RM, van Woudenbergh E, van Dijk A, Haagsman HP. Cathelicidins: Immunomodulatory Antimicrobials. Vaccines (Basel) 2018; 6:vaccines6030063. [PMID: 30223448 PMCID: PMC6161271 DOI: 10.3390/vaccines6030063] [Citation(s) in RCA: 169] [Impact Index Per Article: 24.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 08/30/2018] [Accepted: 09/12/2018] [Indexed: 12/20/2022] Open
Abstract
Cathelicidins are host defense peptides with antimicrobial and immunomodulatory functions. These effector molecules of the innate immune system of many vertebrates are diverse in their amino acid sequence but share physicochemical characteristics like positive charge and amphipathicity. Besides being antimicrobial, cathelicidins have a wide variety in immunomodulatory functions, both boosting and inhibiting inflammation, directing chemotaxis, and effecting cell differentiation, primarily towards type 1 immune responses. In this review, we will examine the biology and various functions of cathelicidins, focusing on putting in vitro results in the context of in vivo situations. The pro-inflammatory and anti-inflammatory functions are highlighted, as well both direct and indirect effects on chemotaxis and cell differentiation. Additionally, we will discuss the potential and limitations of using cathelicidins as immunomodulatory or antimicrobial drugs.
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Affiliation(s)
- Roel M van Harten
- Division Molecular Host Defence, Dept. Infectious diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands.
| | - Esther van Woudenbergh
- Division Molecular Host Defence, Dept. Infectious diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands.
| | - Albert van Dijk
- Division Molecular Host Defence, Dept. Infectious diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands.
| | - Henk P Haagsman
- Division Molecular Host Defence, Dept. Infectious diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands.
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Effects of LL-37 on Gingival Fibroblasts: A Role in Periodontal Tissue Remodeling? Vaccines (Basel) 2018; 6:vaccines6030044. [PMID: 30041453 PMCID: PMC6161023 DOI: 10.3390/vaccines6030044] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 07/16/2018] [Accepted: 07/18/2018] [Indexed: 11/16/2022] Open
Abstract
Mounting evidence suggests that the host defence peptide, LL-37, plays a role in both inflammation and in wound healing; however, the role of this peptide in the remodeling and maintenance of oral tissues is not yet fully understood. Fibroblasts are the most abundant cell type within the periodontal tissues, and gingival fibroblasts play an important role in maintaining and repairing the gingival tissues which are constantly exposed to external insults. In this study we examined the direct effects of LL-37 treatment on gingival fibroblasts and found that LL-37 significantly increased secretion of both interleukin 8 (IL-8) and IL-6 from these cells. LL-37 tended to decrease matrix metalloproteinase (MMP) activity in gingival fibroblasts, but this decrease did not reach statistical significance. LL-37 significantly increased tissue inhibitor of metalloproteinase-1 (TIMP-1) production by gingival fibroblasts, but had no significant effect on TIMP-2 levels. LL-37 was also shown to significantly increase production of basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and keratinocyte growth factor (KGF) in gingival fibroblasts. Taken together, these results suggest an important role for the host defence peptide, LL-37, in modulating the fibroblast response to remodeling in periodontal tissues.
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Shen J, Xiao Z. Cathelicidin in Gastrointestinal Disorders. ANTIMICROBIAL PEPTIDES IN GASTROINTESTINAL DISEASES 2018:61-76. [DOI: 10.1016/b978-0-12-814319-3.00004-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Zhang H, Zhang B, Zhang X, Wang X, Wu K, Guan Q. Effects of cathelicidin-derived peptide from reptiles on lipopolysaccharide-induced intestinal inflammation in weaned piglets. Vet Immunol Immunopathol 2017; 192:41-53. [PMID: 29042014 DOI: 10.1016/j.vetimm.2017.09.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 09/16/2017] [Accepted: 09/20/2017] [Indexed: 12/15/2022]
Abstract
Cathelicidins are the largest family of antimicrobial peptides. C-BF, which is short for Cathelicidin-Bungarus Fasciatus, was isolated from snake venom. C-BF was found to be the most potential substitutes for antibiotics. In this study, we analyzed the effects of cathelicidin-derived peptide C-BF, on lipopolysaccharide (LPS)-induced intestinal damage in weaned piglets, to evaluate the therapeutic effect of C-BF on infectious disease of piglets. Twenty-four piglets were randomly assigned into four groups: control, C-BF, LPS, and C-BF+LPS. The LPS and C-BF+LPS groups were intraperitoneally injected with LPS at fixed timepoints, while the control and C-BF groups were injected with equal volumes of saline. The C-BF and C-BF+LPS groups were then intraperitoneally injected with antimicrobial peptide C-BF, while the control and LPS groups were injected with equal volumes of saline. All piglets were observed for 15days and then sacrificed for analysis. The results showed that C-BF significantly improved the growth performance of weaned piglets compared with LPS-treated animals (P<0.05), and that C-BF could ameliorate the structural and developmental damage to the small intestine caused by LPS treatment. Further, the level of apoptosis in the LPS group was significantly higher than in the other three groups (P<0.05), as was the invasion of inflammatory cells into the intestinal mucosa of the jejunum (P<0.05), leading to increased secretion of pro-inflammatory cytokines. In conclusion, the study indicates that C-BF treatment may be a potential therapy for LPS/pathogen-induced intestinal injury in piglets.
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Affiliation(s)
- Haiwen Zhang
- Key Laboratory of Tropical Animal Breeding and Epidemic Disease Research of Hainan Province, Hainan University, Haikou, Hainan, 570228, People's Republic of China; Laboratory of Tropical Animal Breeding, Reproduction and Nutrition, Hainan University, Haikou, Hainan, 570228, People's Republic of China.
| | - Bingxi Zhang
- Key Laboratory of Tropical Animal Breeding and Epidemic Disease Research of Hainan Province, Hainan University, Haikou, Hainan, 570228, People's Republic of China.
| | - Xiaomeng Zhang
- Key Laboratory of Tropical Animal Breeding and Epidemic Disease Research of Hainan Province, Hainan University, Haikou, Hainan, 570228, People's Republic of China.
| | - Xuemei Wang
- Key Laboratory of Tropical Animal Breeding and Epidemic Disease Research of Hainan Province, Hainan University, Haikou, Hainan, 570228, People's Republic of China; Laboratory of Tropical Animal Breeding, Reproduction and Nutrition, Hainan University, Haikou, Hainan, 570228, People's Republic of China.
| | - Kebang Wu
- Key Laboratory of Tropical Animal Breeding and Epidemic Disease Research of Hainan Province, Hainan University, Haikou, Hainan, 570228, People's Republic of China; Laboratory of Tropical Animal Breeding, Reproduction and Nutrition, Hainan University, Haikou, Hainan, 570228, People's Republic of China.
| | - Qingfeng Guan
- Key Laboratory of Tropical Animal Breeding and Epidemic Disease Research of Hainan Province, Hainan University, Haikou, Hainan, 570228, People's Republic of China; Laboratory of Tropical Animal Breeding, Reproduction and Nutrition, Hainan University, Haikou, Hainan, 570228, People's Republic of China.
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Wong CCM, Zhang L, Wu WKK, Shen J, Chan RLY, Lu L, Hu W, Li MX, Li LF, Ren SX, Li YF, Li J, Cho CH. Cathelicidin-encoding Lactococcus lactis promotes mucosal repair in murine experimental colitis. J Gastroenterol Hepatol 2017; 32:609-619. [PMID: 27470075 DOI: 10.1111/jgh.13499] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Revised: 06/22/2016] [Accepted: 07/08/2016] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIM The preventive effect of intrarectal administration of mouse cathelicidin (mCRAMP) and oral administration of mCRAMP-encoding Lactococcus lactis (N4I) has been shown in murine experimental colitis. It is pivotal to understand the ability of N4I whether it can promote mucosal repair in existing colitis. METHODS Mice with dextran sulfate sodium-induced ulcerative colitis (UC) were treated orally with L. lactis or its transformed strain with or without nisin induction. The body weight, clinical symptoms, and histological changes of colonic tissues were determined. Sulfasalazine was used as a reference drug. Young adult mouse colon cells were used to further elucidate the direct action and possible mechanisms of mCRAMP to promote colonic wound repair. RESULTS Results showed that N4I could improve the clinical symptoms, maintain crypt integrity and preserve mucus-secreting layer in colitis animals. The preparation also could prevent cell death and promote cell proliferation. In contrast, effective dose of sulfasalazine only alleviated clinical symptoms but not the mucosal damage and repair in the colon. In vitro study further showed that mCRAMP could directly promote wound repair by accelerating cell migration but not cell proliferation through the GPCR/MAPK pathway. CONCLUSIONS mCRAMP-encoding L. lactis could be a potential therapeutic preparation better than the traditional anti-inflammatory agent in the treatment of UC.
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Affiliation(s)
- Clover C M Wong
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Lin Zhang
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - William K K Wu
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Ruby L Y Chan
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Lan Lu
- Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, China
| | - Wei Hu
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Ming X Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Long F Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Shun X Ren
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Yi F Li
- Central Laboratory, Affiliated Nanshan Hospital, Guangdong Medical College, Shenzhen, Guangdong, 518052, China
| | - Jiang Li
- Department of Clinical Laboratory, Affiliated Nanshan Hospital, Guangdong Medical College, Shenzhen, Guangdong, 518052, China
| | - Chi H Cho
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
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12
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Zatorski H. Pathophysiology and Risk Factors in Peptic Ulcer Disease. INTRODUCTION TO GASTROINTESTINAL DISEASES VOL. 2 2017:7-20. [DOI: 10.1007/978-3-319-59885-7_2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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13
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Verjans ET, Zels S, Luyten W, Landuyt B, Schoofs L. Molecular mechanisms of LL-37-induced receptor activation: An overview. Peptides 2016; 85:16-26. [PMID: 27609777 DOI: 10.1016/j.peptides.2016.09.002] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 09/01/2016] [Accepted: 09/03/2016] [Indexed: 12/30/2022]
Abstract
The human cathelicidin peptide LL-37 plays a crucial role in the immune system on many levels, from the first line of defense in epithelial cells to restoring the tissue after infection. On host cells, the majority of the LL-37-induced effects are mediated via the direct or indirect activation of several structurally unrelated cell surface receptors or intracellular targets. How LL-37 is able to affect multiple receptors is currently not well understood. So far, the mechanistic details underlying receptor activation are poorly investigated and evidence for a conventional ligand/receptor interaction is scarce. Over the past few decades, a large number of studies have reported on the activation of a receptor and/or components of the downstream signal transduction pathway induced by LL-37. This review summarizes the current knowledge on molecular mechanisms underlying LL-37-induced receptor activation.
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Affiliation(s)
- Eddy-Tim Verjans
- KU Leuven, Department of Biology, Division of Neurobiology and Animal Physiology, Naamsestraat 59, 3000 Leuven, Belgium.
| | - Sven Zels
- KU Leuven, Department of Biology, Division of Neurobiology and Animal Physiology, Naamsestraat 59, 3000 Leuven, Belgium
| | - Walter Luyten
- KU Leuven, Department of Biology, Division of Neurobiology and Animal Physiology, Naamsestraat 59, 3000 Leuven, Belgium
| | - Bart Landuyt
- KU Leuven, Department of Biology, Division of Neurobiology and Animal Physiology, Naamsestraat 59, 3000 Leuven, Belgium
| | - Liliane Schoofs
- KU Leuven, Department of Biology, Division of Neurobiology and Animal Physiology, Naamsestraat 59, 3000 Leuven, Belgium
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Pound LD, Patrick C, Eberhard CE, Mottawea W, Wang GS, Abujamel T, Vandenbeek R, Stintzi A, Scott FW. Cathelicidin Antimicrobial Peptide: A Novel Regulator of Islet Function, Islet Regeneration, and Selected Gut Bacteria. Diabetes 2015; 64:4135-47. [PMID: 26370175 DOI: 10.2337/db15-0788] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 08/22/2015] [Indexed: 11/13/2022]
Abstract
Cathelicidin antimicrobial peptide (CAMP) is a naturally occurring secreted peptide that is expressed in several organs with pleiotropic roles in immunomodulation, wound healing, and cell growth. We previously demonstrated that gut Camp expression is upregulated when type 1 diabetes-prone rats are protected from diabetes development. Unexpectedly, we have also identified novel CAMP expression in the pancreatic β-cells of rats, mice, and humans. CAMP was present even in sterile rat embryo islets, germ-free adult rat islets, and neogenic tubular complexes. Camp gene expression was downregulated in young BBdp rat islets before the onset of insulitis compared with control BBc rats. CAMP treatment of dispersed islets resulted in a significant increase in intracellular calcium mobilization, an effect that was both delayed and blunted in the absence of extracellular calcium. Additionally, CAMP treatment promoted insulin and glucagon secretion from isolated rat islets. Thus, CAMP is a promoter of islet paracrine signaling that enhances islet function and glucoregulation. Finally, daily treatment with the CAMP/LL-37 peptide in vivo in BBdp rats resulted in enhanced β-cell neogenesis and upregulation of potentially beneficial gut microbes. In particular, CAMP/LL-37 treatment shifted the abundance of specific bacterial populations, mitigating the gut dysbiosis observed in the BBdp rat. Taken together, these findings indicate a novel functional role for CAMP/LL-37 in islet biology and modification of gut microbiota.
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Affiliation(s)
- Lynley D Pound
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Christopher Patrick
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Chandra E Eberhard
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Walid Mottawea
- Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Gen-Sheng Wang
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Turki Abujamel
- Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
| | - Roxanne Vandenbeek
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Alain Stintzi
- Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
| | - Fraser W Scott
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
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15
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Sun J, Xu M, Ortsäter H, Lundeberg E, Juntti-Berggren L, Chen YQ, Haeggström JZ, Gudmundsson GH, Diana J, Agerberth B. Cathelicidins positively regulate pancreatic β-cell functions. FASEB J 2015; 30:884-94. [PMID: 26527065 DOI: 10.1096/fj.15-275826] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Accepted: 10/19/2015] [Indexed: 12/18/2022]
Abstract
Cathelicidins are pleiotropic antimicrobial peptides largely described for innate antimicrobial defenses and, more recently, immunomodulation. They are shown to modulate a variety of immune or nonimmune host cell responses. However, how cathelicidins are expressed by β cells and modulate β-cell functions under steady-state or proinflammatory conditions are unknown. We find that cathelicidin-related antimicrobial peptide (CRAMP) is constitutively expressed by rat insulinoma β-cell clone INS-1 832/13. CRAMP expression is inducible by butyrate or phenylbutyric acid and its secretion triggered upon inflammatory challenges by IL-1β or LPS. CRAMP promotes β-cell survival in vitro via the epidermal growth factor receptor (EGFR) and by modulating expression of antiapoptotic Bcl-2 family proteins: p-Bad, Bcl-2, and Bcl-xL. Also via EGFR, CRAMP stimulates glucose-stimulated insulin secretion ex vivo by rat islets. A similar effect is observed in diabetes-prone nonobese diabetic (NOD) mice. Additional investigation under inflammatory conditions reveals that CRAMP modulates inflammatory responses and β-cell apoptosis, as measured by prostaglandin E2 production, cyclooxygenases (COXs), and caspase activation. Finally, CRAMP-deficient cnlp(-/-) mice exhibit defective insulin secretion, and administration of CRAMP to prediabetic NOD mice improves blood glucose clearance upon glucose challenge. Our finding suggests that cathelicidins positively regulate β-cell functions and may be potentially used for intervening β-cell dysfunction-associated diseases.
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Affiliation(s)
- Jia Sun
- *State Key Laboratory of Food Science and Technology, School of Food Science and Technology and Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, China; Biomedical Centre, Uppsala University, Uppsala, Sweden; Diabetes Research Unit, Department of Clinical Science and Education, Department of Physiology and Pharmacology, and The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden; Biomedical Center, University of Iceland, Reykjavik, Iceland; Institut National de la Santé et de la Recherche Médicale, Institute Necker-Enfants Malades, Centre National de la Recherche Scientifique, Paris, France; **Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Meng Xu
- *State Key Laboratory of Food Science and Technology, School of Food Science and Technology and Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, China; Biomedical Centre, Uppsala University, Uppsala, Sweden; Diabetes Research Unit, Department of Clinical Science and Education, Department of Physiology and Pharmacology, and The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden; Biomedical Center, University of Iceland, Reykjavik, Iceland; Institut National de la Santé et de la Recherche Médicale, Institute Necker-Enfants Malades, Centre National de la Recherche Scientifique, Paris, France; **Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Henrik Ortsäter
- *State Key Laboratory of Food Science and Technology, School of Food Science and Technology and Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, China; Biomedical Centre, Uppsala University, Uppsala, Sweden; Diabetes Research Unit, Department of Clinical Science and Education, Department of Physiology and Pharmacology, and The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden; Biomedical Center, University of Iceland, Reykjavik, Iceland; Institut National de la Santé et de la Recherche Médicale, Institute Necker-Enfants Malades, Centre National de la Recherche Scientifique, Paris, France; **Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Erik Lundeberg
- *State Key Laboratory of Food Science and Technology, School of Food Science and Technology and Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, China; Biomedical Centre, Uppsala University, Uppsala, Sweden; Diabetes Research Unit, Department of Clinical Science and Education, Department of Physiology and Pharmacology, and The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden; Biomedical Center, University of Iceland, Reykjavik, Iceland; Institut National de la Santé et de la Recherche Médicale, Institute Necker-Enfants Malades, Centre National de la Recherche Scientifique, Paris, France; **Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Lisa Juntti-Berggren
- *State Key Laboratory of Food Science and Technology, School of Food Science and Technology and Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, China; Biomedical Centre, Uppsala University, Uppsala, Sweden; Diabetes Research Unit, Department of Clinical Science and Education, Department of Physiology and Pharmacology, and The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden; Biomedical Center, University of Iceland, Reykjavik, Iceland; Institut National de la Santé et de la Recherche Médicale, Institute Necker-Enfants Malades, Centre National de la Recherche Scientifique, Paris, France; **Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Yong Q Chen
- *State Key Laboratory of Food Science and Technology, School of Food Science and Technology and Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, China; Biomedical Centre, Uppsala University, Uppsala, Sweden; Diabetes Research Unit, Department of Clinical Science and Education, Department of Physiology and Pharmacology, and The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden; Biomedical Center, University of Iceland, Reykjavik, Iceland; Institut National de la Santé et de la Recherche Médicale, Institute Necker-Enfants Malades, Centre National de la Recherche Scientifique, Paris, France; **Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Jesper Z Haeggström
- *State Key Laboratory of Food Science and Technology, School of Food Science and Technology and Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, China; Biomedical Centre, Uppsala University, Uppsala, Sweden; Diabetes Research Unit, Department of Clinical Science and Education, Department of Physiology and Pharmacology, and The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden; Biomedical Center, University of Iceland, Reykjavik, Iceland; Institut National de la Santé et de la Recherche Médicale, Institute Necker-Enfants Malades, Centre National de la Recherche Scientifique, Paris, France; **Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Gudmundur H Gudmundsson
- *State Key Laboratory of Food Science and Technology, School of Food Science and Technology and Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, China; Biomedical Centre, Uppsala University, Uppsala, Sweden; Diabetes Research Unit, Department of Clinical Science and Education, Department of Physiology and Pharmacology, and The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden; Biomedical Center, University of Iceland, Reykjavik, Iceland; Institut National de la Santé et de la Recherche Médicale, Institute Necker-Enfants Malades, Centre National de la Recherche Scientifique, Paris, France; **Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Julien Diana
- *State Key Laboratory of Food Science and Technology, School of Food Science and Technology and Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, China; Biomedical Centre, Uppsala University, Uppsala, Sweden; Diabetes Research Unit, Department of Clinical Science and Education, Department of Physiology and Pharmacology, and The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden; Biomedical Center, University of Iceland, Reykjavik, Iceland; Institut National de la Santé et de la Recherche Médicale, Institute Necker-Enfants Malades, Centre National de la Recherche Scientifique, Paris, France; **Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Birgitta Agerberth
- *State Key Laboratory of Food Science and Technology, School of Food Science and Technology and Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, China; Biomedical Centre, Uppsala University, Uppsala, Sweden; Diabetes Research Unit, Department of Clinical Science and Education, Department of Physiology and Pharmacology, and The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden; Biomedical Center, University of Iceland, Reykjavik, Iceland; Institut National de la Santé et de la Recherche Médicale, Institute Necker-Enfants Malades, Centre National de la Recherche Scientifique, Paris, France; **Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
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16
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Zhang H, Xia X, Han F, Jiang Q, Rong Y, Song D, Wang Y. Cathelicidin-BF, a Novel Antimicrobial Peptide from Bungarus fasciatus, Attenuates Disease in a Dextran Sulfate Sodium Model of Colitis. Mol Pharm 2015; 12:1648-61. [PMID: 25807257 DOI: 10.1021/acs.molpharmaceut.5b00069] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Antimicrobial peptides are molecules of innate immunity. Cathelicidin-BF is the first cathelicidin peptide found in reptiles. However, the immunoregulatory and epithelial barrier protective properties of C-BF have not been reported. Inflammatory bowel diseases, including ulcerative colitis and Crohn's disease, can lead to colon cancer, the third most common malignant tumor. The objective is to develop the new found cathelicidin-BF as a therapeutic to patients of ulcerative colitis. The morphology of the colon epithelium was observed by H&E staining; apoptosis index and infiltration of inflammatory cells in colonic epithelium were measured by TUNEL and immunohistochemistry; the expression level of endogenous mCRAMP was analyzed by immunofluorescence; and phosphorylation of the transcription factors c-jun and NF-κB in colon were analyzed by Western blot. Our results showed that the morphology of the colon epithelium in the C-BF+DSS group was improved compared with the DSS group. Apoptosis and infiltration of inflammatory cells in colonic epithelium were also significantly attenuated in the C-BF+DSS group compared with the DSS group, and the expression level of endogenous mCRAMP in the DSS group was significantly higher than other groups. DSS-induced phosphorylation level of c-jun and NF-κB while C-BF effectively inhibited phosphorylation of NF-κB (p65). The barrier protective effect of C-BF was still excellent. In conclusion, C-BF effectively attenuated inflammation and improved disrupted barrier function. Notably, this is the first report to demonstrate that C-BF attenuates DSS-induced UC both through the regulation of intestinal immune and retention of barrier function, and the exact pathway was through NF-κB.
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Affiliation(s)
- Haiwen Zhang
- Key Laboratory of Animal Nutrition and Feed Science (Hua Dong), Ministry of Agriculture College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Xi Xia
- Key Laboratory of Animal Nutrition and Feed Science (Hua Dong), Ministry of Agriculture College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Feifei Han
- Key Laboratory of Animal Nutrition and Feed Science (Hua Dong), Ministry of Agriculture College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Qin Jiang
- Key Laboratory of Animal Nutrition and Feed Science (Hua Dong), Ministry of Agriculture College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Yili Rong
- Key Laboratory of Animal Nutrition and Feed Science (Hua Dong), Ministry of Agriculture College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Deguang Song
- Key Laboratory of Animal Nutrition and Feed Science (Hua Dong), Ministry of Agriculture College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Yizhen Wang
- Key Laboratory of Animal Nutrition and Feed Science (Hua Dong), Ministry of Agriculture College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
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17
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Choi KYG, Napper S, Mookherjee N. Human cathelicidin LL-37 and its derivative IG-19 regulate interleukin-32-induced inflammation. Immunology 2014; 143:68-80. [PMID: 24666281 DOI: 10.1111/imm.12291] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Revised: 03/20/2014] [Accepted: 03/21/2014] [Indexed: 12/18/2022] Open
Abstract
Human cathelicidin LL-37 protects against infections and endotoxin-induced inflammation. In a recent study we have shown that IG-19, an LL-37-derived peptide, protects in a murine model of arthritis. Cytokine interleukin-32 (IL-32) is elevated and directly associated with the disease severity of inflammatory arthritis. Therefore, in this study we examined the effects of LL-37 and IG-19 on IL-32-induced responses in human peripheral blood-derived mononuclear cells (PBMC) and macrophages. We showed that CD14(+) monocytes are the primary cells that produce pro-inflammatory tumour necrosis factor-α (TNF-α) following stimulation of PBMC with IL-32. We demonstrated that LL-37 and IG-19 significantly suppress IL-32-induced production of pro-inflammatory cytokines, e.g. TNF-α and IL-1β, without altering chemokine production. In contrast, LL-37 and IG-19 enhance the production of the anti-inflammatory cytokine IL-1RA. Further mechanistic studies revealed that LL-37 and IG-19 suppress IL-32-mediated phosphorylation of Fyn (Y420) Src kinase. In contrast, IL-32-mediated phosphorylation of AKT-1 (T308) and MKP-1 (S359) is not suppressed by the peptides. LL-37 and IG-19 alone induce the phosphorylation of MKP-1 (S359), which is a known negative regulator of inflammation. Furthermore, the peptides induce the activity of p44/42 mitogen-activated protein kinase, which is known to phosphorylate MKP-1 (S359). This is the first study to demonstrate the regulation of IL-32-induced inflammation by LL-37 and its derivative peptide IG-19. The mechanistic results from this study suggest that regulation of immune-mediated inflammation by these peptides may be controlled by the dual phosphatase MKP-1. We speculate that LL-37 and its derivatives may contribute to the control of immune-mediated inflammatory diseases.
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Affiliation(s)
- Ka-Yee G Choi
- Department of Internal Medicine, Manitoba Centre for Proteomics and Systems Biology, University of Manitoba, Winnipeg, MB, Canada; Department of Immunology, University of Manitoba, Winnipeg, MB, Canada
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18
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Chow JYC, Li ZJ, Kei WK, Cho CH. Cathelicidin a potential therapeutic peptide for gastrointestinal inflammation and cancer. World J Gastroenterol 2013; 19:2731-2735. [PMID: 23687409 PMCID: PMC3653146 DOI: 10.3748/wjg.v19.i18.2731] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2013] [Accepted: 04/04/2013] [Indexed: 02/06/2023] Open
Abstract
Cathelicidins, are host defense peptides synthesized and stored in circulating leukocytes and numerous types of epithelial tissues in particular the gastrointestinal (GI) tract and skin. They have been known for their antimicrobial activities against a variety of microbes. Recently it was discovered that they have other significant biological functions and produce appealing pharmacological actions against inflammation and cancer in the GI tract through defined mechanisms. Experimental evidence shows that these actions could be tissue and disease specific and concentration dependent. This article reviews some of the physiological functions of cathelicidins and also their therapeutic potential in the treatment of inflammation and cancer and also the delivery system for this peptide as targeted therapy for various disorders in the GI tract both in animals and humans.
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19
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To KKW, Ren SX, Wong CCM, Cho CH. Reversal of ABCG2-mediated multidrug resistance by human cathelicidin and its analogs in cancer cells. Peptides 2013; 40:13-21. [PMID: 23274176 DOI: 10.1016/j.peptides.2012.12.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2012] [Revised: 12/17/2012] [Accepted: 12/18/2012] [Indexed: 01/16/2023]
Abstract
Multidrug resistance (MDR) of cancer cells to a wide spectrum of anticancer drugs is a major obstacle to successful chemotherapy. It is usually mediated by the overexpression of one of the three major ABC transporters actively pumping cytotoxic drugs out of the cells. There has been great interest in the search for inhibitors toward these transporters with an aim to circumvent resistance. This is usually achieved by screening from natural product library and the subsequent structural modifications. This study reported the reversal of ABCG2-mediated MDR in drug-selected resistant cancer cell lines by a class of host defense antimicrobial peptides, the human cathelicidin LL37 and its fragments. The effective human cathelicidin peptides (LL17-32 and LL13-37) were found to increase the accumulation of mitoxantrone in cancer cell lines with ABCG2 overexpression, thereby circumventing resistance to mitoxantrone. At the effective concentrations of the cathelicidin peptides, cell proliferation of the parental cells without elevated ABCG2 expression was not affected. Result from drug efflux and ATPase assays suggested that both LL17-32 and LL13-37 interact with ABCG2 and inhibit its transport activity in an uncompetitive manner. The peptides were also found to downregulate ABCG2 protein expression in the resistant cells, probably through a lysosomal degradation pathway. Our data suggest that the human cathelicidin may be further developed for sensitizing resistant cancer cells to chemotherapy.
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Affiliation(s)
- Kenneth K W To
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Room 801N, Lo Kwee-Seong Integrated Biomedical Sciences Building, Area 39, Shatin, New Territories, Hong Kong, China.
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20
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Zhang L, Yu J, Wong CCM, Ling TKW, Li ZJ, Chan KM, Ren SX, Shen J, Chan RLY, Lee CC, Li MSM, Cheng ASL, To KF, Gallo RL, Sung JJY, Wu WKK, Cho CH. Cathelicidin protects against Helicobacter pylori colonization and the associated gastritis in mice. Gene Ther 2012; 20:751-60. [PMID: 23254369 DOI: 10.1038/gt.2012.92] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2012] [Revised: 08/31/2012] [Accepted: 10/08/2012] [Indexed: 12/29/2022]
Abstract
Cathelicidin, an antimicrobial peptide of the innate immune system, has been shown to modulate microbial growth, wound healing and inflammation. However, whether cathelicidin controls Helicobacter pylori infection in vivo remains unexplored. This study sought to elucidate the role of endogenous and exogenous mouse cathelicidin (CRAMP) in the protection against H. pylori infection and the associated gastritis in mice. Results showed that genetic ablation of CRAMP in mice significantly increased the susceptibility of H. pylori colonization and the associated gastritis as compared with the wild-type control. Furthermore, replenishment with exogenous CRAMP, delivered via a bioengineered CRAMP-secreting strain of Lactococcus lactis, reduced H. pylori density in the stomach as well as the associated inflammatory cell infiltration and cytokine production. Collectively, these findings indicate that cathelicidin protects against H. pylori infection and its associated gastritis in vivo. Our study also demonstrates the feasibility of using the transformed food-grade bacteria to deliver cathelicidin, which may have potential clinical applications in the treatment of H. pylori infection in humans.
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Affiliation(s)
- L Zhang
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
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21
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Ren SX, Cheng ASL, To KF, Tong JHM, Li MS, Shen J, Shen J, Wong CCM, Zhang L, Chan RLY, Wang XJ, Ng SSM, Chiu LCM, Marquez VE, Gallo RL, Chan FKL, Yu J, Sung JJY, Wu WKK, Cho CH. Host immune defense peptide LL-37 activates caspase-independent apoptosis and suppresses colon cancer. Cancer Res 2012; 72:6512-23. [PMID: 23100468 DOI: 10.1158/0008-5472.can-12-2359] [Citation(s) in RCA: 111] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Cathelicidins are a family of bacteriocidal polypeptides secreted by macrophages and polymorphonuclear leukocytes (PMN). LL-37, the only human cathelicidin, has been implicated in tumorigenesis, but there has been limited investigation of its expression and function in cancer. Here, we report that LL-37 activates a p53-mediated, caspase-independent apoptotic cascade that contributes to suppression of colon cancer. LL-37 was expressed strongly in normal colon mucosa but downregulated in colon cancer tissues, where in both settings its expression correlated with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive apoptotic cells. Exposure of colon cancer cells to LL-37 induced phosphatidylserine externalization and DNA fragmentation in a manner independent of caspase activation. Apoptogenic function was mediated by nuclear translocation of the proapoptotic factors, apoptosis-inducing factor (AIF) and endonuclease G (EndoG), through p53-dependent upregulation of Bax and Bak and downregulation of Bcl-2 via a pertussis toxin-sensitive G-protein-coupled receptor (GPCR) pathway. Correspondingly, colonic mucosa of cathelicidin-deficient mice exhibited reduced expression of p53, Bax, and Bak and increased expression of Bcl-2 together with a lower basal level of apoptosis. Cathelicidin-deficient mice exhibited an increased susceptibility to azoxymethane-induced colon tumorigenesis, establishing pathophysiologic relevance in colon cancer. Collectively, our findings show that LL-37 activates a GPCR-p53-Bax/Bak/Bcl-2 signaling cascade that triggers AIF/EndoG-mediated apoptosis in colon cancer cells.
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Affiliation(s)
- Shun X Ren
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong
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22
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Wong CCM, Zhang L, Li ZJ, Wu WKK, Ren SX, Chen YC, Ng TB, Cho CH. Protective effects of cathelicidin-encoding Lactococcus lactis in murine ulcerative colitis. J Gastroenterol Hepatol 2012; 27:1205-12. [PMID: 22507188 DOI: 10.1111/j.1440-1746.2012.07158.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Intrarectal administration of mouse cathelin-related antimicrobial peptide (mCRAMP) reduced intestinal inflammation in mice. In the current study, we examined whether mCRAMP-transformed Lactococcus lactis given orally attained similar protective effects. METHOD mCRAMP was produced and secreted from the transformed L. lactis. Murine colitis was induced by ingestion of 3% dextran sulfate sodium (DSS) for 7 days. Eight or 10 log colony forming unit (cfu) L. lactis or the transformed strains with or without nisin induction were given orally as a parallel treatment with DSS. The body weight, fecal microbiota populations, clinical symptoms and histological examinations of colonic tissues were determined. Myeloperoxidase (MPO) activity and malondialdehyde (MDA) level were also evaluated to reflect the degree of inflammation. A prototype anti-inflammatory drug sulfasalazine was used as a reference drug to compare the efficacy and mechanisms of action for ulcerative colitis (UC). RESULT Compared with the control group with colitis, cathelicidin-transformed L. lactis could improve the clinical symptoms, maintain crypt integrity and preserve mucus content (P < 0.01). The number of apoptotic cells, MPO activity and MDA level were also significantly reduced (P < 0.05). The increases of fecal microbiota in colitis animals were markedly prevented (P < 0.001). Unlike mCRAMP-encoding L. lactis, effective doses of sulfasalazine only alleviated the clinical symptoms (P < 0.01) but not the mucosal damage in the colon. CONCLUSION mCRAMP-transformed L. lactis has been shown to produce mCRAMP, effectively preventing murine UC. Oral administration of this biological preparation is better than sulfasalazine for the treatment of UC.
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Affiliation(s)
- Clover Ching Man Wong
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
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23
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Lee E, Sidoryk-Wegrzynowicz M, Yin Z, Webb A, Son DS, Aschner M. Transforming growth factor-α mediates estrogen-induced upregulation of glutamate transporter GLT-1 in rat primary astrocytes. Glia 2012; 60:1024-36. [PMID: 22488924 PMCID: PMC3353324 DOI: 10.1002/glia.22329] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2011] [Accepted: 02/28/2012] [Indexed: 01/02/2023]
Abstract
Glutamate transporter-1 (GLT-1) plays a central role in preventing excitotoxicity by removing excess glutamate from the synaptic clefts. 17β-Estradiol (E2) and tamoxifen (TX), a selective estrogen receptor (ER) modulator, afford neuroprotection in a range of experimental models. However, the mechanisms that mediate E2 and TX neuroprotection have yet to be elucidated. We tested the hypothesis that E2 and TX enhance GLT-1 function by increasing transforming growth factor (TGF)-α expression and, thus, attenuate manganese (Mn)-induced impairment in astrocytic GLT-1 expression and glutamate uptake in rat neonatal primary astrocytes. The results showed that E2 (10 nM) and TX (1 μM) increased GLT-1 expression and reversed the Mn-induced reduction in GLT-1, both at the mRNA and protein levels. E2/TX also concomitantly reversed the Mn-induced inhibition of astrocytic glutamate uptake. E2/TX activated the GLT-1 promoter and attenuated the Mn-induced repression of the GLT-1 promoter in astrocytes. TGF-α knockdown (siRNA) abolished the E2/TX effect on GLT-1 expression, and inhibition of epidermal growth factor receptor (TGF-α receptor) suppressed the effect of E2/TX on GLT-1 expression and GLT-1 promoter activity. E2/TX also increased TGF-α mRNA and protein levels with a concomitant increase in astrocytic glutamate uptake. All ERs (ER-α, ER-β, and G protein-coupled receptor 30) were involved in mediating E2 effects on the regulation of TGF-α, GLT-1, and glutamate uptake. These results indicate that E2/TX increases GLT-1 expression in astrocytes via TGF-α signaling, thus offering an important putative target for the development of novel therapeutics for neurological disorders.
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Affiliation(s)
- Eunsook Lee
- Department of Physiology, Meharry Medical College, Nashville, TN 37208, USA.
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Miyamoto H, Baba S, Nakajima S, Mine T, Yoshikawa N, Fumoto S, Nishida K. Pretreatment with epidermal growth factor enhances naked plasmid DNA transfer onto gastric serosal surface in mice. Biol Pharm Bull 2012; 35:903-8. [PMID: 22687482 DOI: 10.1248/bpb.35.903] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We have developed a simple administration method, which is gastric serosal surface instillation of naked plasmid DNA (pDNA) in experimental animals. The purpose of this study was to improve gastric gene transfer efficiency by pre-treatment with a macropinocytosis enhancer, such as fetuin or epidermal growth factor (EGF), in mice. A series of concentrations of fetuin were instilled onto gastric serosal surface prior to instillation of naked pDNA in mice; however, fetuin did not improve transgene expression in the stomach 6 h after administration of pDNA. EGF also did not affect transgene expression in the stomach when pDNA was instilled immediately after EGF instillation. On the other hand, when pDNA was instilled onto gastric serosal surface 24 h after EGF treatment, transgene expression in the stomach was significantly improved by 2.6-fold. In addition, transgene-positive cells were increased 5.3-fold by EGF pre-treatment. High transgene expression in the stomach lasted for 48 h in the EGF pre-treatment group in comparison with that in the no pre-treatment group. These findings are valuable to develop an effective method of in vivo gene transfer to the stomach.
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Choi KY, Chow LNY, Mookherjee N. Cationic host defence peptides: multifaceted role in immune modulation and inflammation. J Innate Immun 2012; 4:361-70. [PMID: 22739631 DOI: 10.1159/000336630] [Citation(s) in RCA: 155] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2011] [Accepted: 01/18/2012] [Indexed: 12/21/2022] Open
Abstract
Host defence peptides (HDPs) are innate immune effector molecules found in diverse species. HDPs exhibit a wide range of functions ranging from direct antimicrobial properties to immunomodulatory effects. Research in the last decade has demonstrated that HDPs are critical effectors of both innate and adaptive immunity. Various studies have hypothesized that the antimicrobial property of certain HDPs may be largely due to their immunomodulatory functions. Mechanistic studies revealed that the role of HDPs in immunity is very complex and involves various receptors, signalling pathways and transcription factors. This review will focus on the multiple functions of HDPs in immunity and inflammation, with special reference to cathelicidins, e.g. LL-37, certain defensins and novel synthetic innate defence regulator peptides. We also discuss emerging concepts of specific HDPs in immune-mediated inflammatory diseases, including the potential use of cationic peptides as therapeutics for immune-mediated inflammatory disorders.
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Affiliation(s)
- Ka-Yee Choi
- Manitoba Centre for Proteomics and Systems Biology, Departments of Internal Medicine and Immunology, University of Manitoba, Winnipeg, Man., Canada
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Mine T, Ishii H, Nakajima S, Yoshikawa N, Miyamoto H, Nakashima M, Nakamura J, Fumoto S, Nishida K. Rubbing gastric serosal surface enhances naked plasmid DNA transfer in rats and mice. Biol Pharm Bull 2011; 34:1514-7. [PMID: 21881243 DOI: 10.1248/bpb.34.1514] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We have developed in vivo gene transfer to mesothelial cells on the peritoneal organs, including the stomach. Simple instillation of naked plasmid DNA onto the gastric serosal surface in mice resulted in effective but transient transgene expression. Here, we developed a simple method to improve not only the transfection efficiency but also the duration of transgene expression. Rubbing the gastric serosal surface using a medical spoon immediately after instillation of naked plasmid DNA onto the gastric serosal surface resulted in 59-fold higher transgene expression 24 h after administration in rats. Without rubbing, transgene expression decreased under the detection limit 7 d after administration. On the other hand, rubbing the gastric serosal surface with a medical spoon after instillation of plasmid DNA prolonged transgene expression for one month. Mechanistic study in mice revealed that improved transfection should not be due to stimulation of cell function such as macropinocytosis by rubbing because rubbing before instillation of plasmid DNA did not improve transfection. Plasmid DNA should enter effectively into cells during rubbing. These findings are valuable to develop an effective method of in vivo gene transfer into peritoneal organs.
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Affiliation(s)
- Toyoharu Mine
- Graduate School of Biomedical Sciences, Nagasaki University, Japan
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27
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Yang YH, Zhou H, Binmadi NO, Proia P, Basile JR. Plexin-B1 activates NF-κB and IL-8 to promote a pro-angiogenic response in endothelial cells. PLoS One 2011; 6:e25826. [PMID: 22028792 PMCID: PMC3196529 DOI: 10.1371/journal.pone.0025826] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2011] [Accepted: 09/11/2011] [Indexed: 12/13/2022] Open
Abstract
Background The semaphorins and their receptors, the plexins, are proteins related to c-Met and the scatter factors that have been implicated in an expanding signal transduction network involving co-receptors, RhoA and Ras activation and deactivation, and phosphorylation events. Our previous work has demonstrated that Semaphorin 4D (Sema4D) acts through its receptor, Plexin-B1, on endothelial cells to promote angiogenesis in a RhoA and Akt-dependent manner. Since NF-κB has been linked to promotion of angiogenesis and can be activated by Akt in some contexts, we wanted to examine NF-κB in Sema4D treated cells to determine if there was biological significance for the pro-angiogenic phenotype observed in endothelium. Methods/Principal Findings Using RNA interference techniques, gel shifts and NF-κB reporter assays, we demonstrated NF-κB translocation to the nucleus in Sema4D treated endothelial cells occurring downstream of Plexin-B1. This response was necessary for endothelial cell migration and capillary tube formation and protected endothelial cells against apoptosis as well, but had no effect on cell proliferation. We dissected Plexin-B1 signaling with chimeric receptor constructs and discovered that the ability to activate NF-κB was dependent upon Plexin-B1 acting through Rho and Akt, but did not involve its role as a Ras inhibitor. Indeed, inhibition of Rho by C3 toxin and Akt by LY294002 blocked Sema4D-mediated endothelial cell migration and tubulogenesis. We also observed that Sema4D treatment of endothelial cells induced production of the NF-κB downstream target IL-8, a response necessary for angiogenesis. Finally, we could show through co-immunofluorescence for p65 and CD31 that Sema4D produced by tumor xenografts in nude mice activated NF-κB in vessels of the tumor stroma. Conclusion/Significance These findings provide evidence that Sema4D/Plexin-B1-mediated NF-κB activation and IL-8 production is critical in the generation a pro-angiogenic phenotype in endothelial cells and suggests a new therapeutic target for the anti-angiogenic treatment of some cancers.
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Affiliation(s)
- Ying-Hua Yang
- Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland, United States of America
| | - Hua Zhou
- Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland, United States of America
| | - Nada O. Binmadi
- Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland, United States of America
| | - Patrizia Proia
- Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland, United States of America
- Department of Sports Science (DISMOT), University of Palermo, Palermo, Italy
| | - John R. Basile
- Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland, United States of America
- Marlene and Stuart Greenebaum Cancer Center, Baltimore, Maryland, United States of America
- * E-mail:
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Cathelicidins in inflammation and tissue repair: Potential therapeutic applications for gastrointestinal disorders. Acta Pharmacol Sin 2010; 31:1118-22. [PMID: 20676121 DOI: 10.1038/aps.2010.117] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cathelicidins, a family of host defense peptides, are highly expressed during infection, inflammation and wound healing. These peptides not only have broad-spectrum antimicrobial activities, but also modulate inflammation by altering cytokine response and chemoattraction of inflammatory cells in diseased tissues. In this connection, a mouse cathelicidin has been demonstrated to prevent inflammation in the colon through enhancing mucus production and reducing production of pro-inflammatory cytokines. In addition, cathelicidins promote wound healing through stimulation of re-epithelialization and angiogenesis at injured tissues. In an animal model of gastric ulceration, the rat cathelicidin promotes ulcer healing by inducing proliferation of gastric epithelial cells both in vitro and in vivo. In conclusion, cathelicidins represent an important group of effector molecules in the innate immune system that operates a complex integration of inflammation and tissue repair in the gastrointestinal mucosa and other organs.
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Wu WKK, Sung JJY, To KF, Yu L, Li HT, Li ZJ, Chu KM, Yu J, Cho CH. The host defense peptide LL-37 activates the tumor-suppressing bone morphogenetic protein signaling via inhibition of proteasome in gastric cancer cells. J Cell Physiol 2010; 223:178-86. [PMID: 20054823 DOI: 10.1002/jcp.22026] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The human cathelicidin LL-37, a pleiotropic host defense peptide, is down-regulated in gastric adenocarcinomas. We therefore investigated whether this peptide suppresses gastric cancer growth. LL-37 lowered gastric cancer cell proliferation and delayed G(1)-S transition in vitro and inhibits the growth of gastric cancer xenograft in vivo. In this connection, LL-37 increased the tumor-suppressing bone morphogenetic protein (BMP) signaling, manifested as an increase in BMP4 expression and the subsequent Smad1/5 phosphorylation and the induction of p21(Waf1/Cip1). The anti-mitogenic effect, Smad1/5 phosphorylation, and p21(Waf1/Cip1) up-regulation induced by LL-37 were reversed by the knockdown of BMP receptor II. The activation of BMP signaling was paralleled by the inhibition of chymotrypsin-like and caspase-like activity of proteasome. In this regard, proteasome inhibitor MG-132 mimicked the effect of LL-37 by up-regulating BMP4 expression and Smad1/5 phosphorylation. Further analysis of clinical samples revealed that LL-37 and p21(Waf1/Cip1) mRNA expressions were both down-regulated in gastric cancer tissues and their expressions were positively correlated. Collectively, we describe for the first time that LL-37 inhibits gastric cancer cell proliferation through activation of BMP signaling via a proteasome-dependent mechanism. This unique biological activity may open up novel therapeutic avenue for the treatment of gastric cancer.
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Affiliation(s)
- William Ka Kei Wu
- Department of Medicine & Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
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31
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Leszczyńska K, Namiot A, Fein DE, Wen Q, Namiot Z, Savage PB, Diamond S, Janmey PA, Bucki R. Bactericidal activities of the cationic steroid CSA-13 and the cathelicidin peptide LL-37 against Helicobacter pylori in simulated gastric juice. BMC Microbiol 2009; 9:187. [PMID: 19728885 PMCID: PMC2748089 DOI: 10.1186/1471-2180-9-187] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2009] [Accepted: 09/03/2009] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The worldwide appearance of drug-resistant strains of H. pylori motivates a search for new agents with therapeutic potential against this family of bacteria that colonizes the stomach, and is associated with adenocarcinoma development. This study was designed to assess in vitro the anti-H. pylori potential of cathelicidin LL-37 peptide, which is naturally present in gastric juice, its optimized synthetic analog WLBU2, and the non-peptide antibacterial agent ceragenin CSA-13. RESULTS In agreement with previous studies, increased expression of hCAP-18/LL-37 was observed in gastric mucosa obtained from H. pylori infected subjects. MBC (minimum bactericidal concentration) values determined in nutrient-containing media range from 100-800 microg/ml for LL-37, 17.8-142 microg/ml for WLBU2 and 0.275-8.9 microg/ml for ceragenin CSA-13. These data indicate substantial, but widely differing antibacterial activities against clinical isolates of H. pylori. After incubation in simulated gastric juice (low pH with presence of pepsin) CSA-13, but not LL-37 or WLBU2, retained antibacterial activity. Compared to LL-37 and WLBU2 peptides, CSA-13 activity was also more resistant to inhibition by isolated host gastric mucins. CONCLUSION These data indicate that cholic acid-based antimicrobial agents such as CSA-13 resist proteolytic degradation and inhibition by mucin and have potential for treatment of H. pylori infections, including those caused by the clarithromycin and/or metronidazole-resistant strains.
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Affiliation(s)
- Katarzyna Leszczyńska
- Department of Diagnostic Microbiology, Medical University of Bialystok, 15-230 Bialystok, Poland.
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Nishi J, Fumoto S, Ishii H, Kodama Y, Nakashima M, Sasaki H, Nakamura J, Nishida K. Highly stomach-selective gene transfer following gastric serosal surface instillation of naked plasmid DNA in rats. J Gastroenterol 2009; 43:912-9. [PMID: 19107334 DOI: 10.1007/s00535-008-2301-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2008] [Accepted: 05/13/2008] [Indexed: 02/04/2023]
Abstract
BACKGROUND The purpose of this study was to achieve stomach-selective gene transfer in rats by our simple and novel administration method, which is gastric serosal surface instillation of naked plasmid DNA (pDNA). METHODS Naked pDNA encoding firefly luciferase as a reporter gene was instilled onto the gastric serosal surface in male Wistar rats. As controls, we performed intraperitoneal, intragastric and intravenous administration of naked pDNA. At appropriate time intervals, we measured luciferase activities in the stomach and other tissues. RESULTS Gene expression in the stomach 6 h after gastric serosal surface instillation of naked pDNA (5 microg) was significantly higher than that after using other administration methods. The present study is the first report on stomach-selective gene transfer following instillation of naked pDNA onto the gastric serosal surface in rats. Also, the gene expression level in the stomach 6 h after gastric serosal surface instillation of naked pDNA was markedly higher than that in other tissues. In a dose-dependent study, the gene expression level was saturated over 5 microg. Gene expression in the stomach was detected 3 h after gastric serosal surface instillation of naked pDNA. The gene expression level peaked 12-24 h after instillation of naked pDNA, then decreased to a level similar to 3 h at 48 h. CONCLUSIONS Gastric serosal surface in stillation of naked pDNA can be a highly stomach-selective gene transfer method in rats.
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Affiliation(s)
- Junya Nishi
- Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
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Pálffy R, Gardlík R, Behuliak M, Kadasi L, Turna J, Celec P. On the physiology and pathophysiology of antimicrobial peptides. Mol Med 2009; 15:51-9. [PMID: 19015736 PMCID: PMC2583110 DOI: 10.2119/molmed.2008.00087] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2008] [Accepted: 11/06/2008] [Indexed: 12/23/2022] Open
Abstract
Antimicrobial peptides (AMP) are a heterogeneous group of molecules involved in the nonspecific immune responses of a variety of organisms ranging from prokaryotes to mammals, including humans. AMP have various physical and biological properties, yet the most common feature is their antimicrobial effect. The majority of AMP disrupt the integrity of microbial cells by 1 of 3 known mechanisms--the barrel-stave pore model, the thoroidal pore model, or the carpet model. Results of growing numbers of descriptive and experimental studies show that altered expression of AMP in various tissues is important in the pathogenesis of several gastrointestinal, respiratory, and other diseases. We discuss novel approaches and strategies to further improve the promising future of therapeutic applications of AMP. The spread of antibiotic resistance increases the importance of developing a clinical role for AMP.
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Affiliation(s)
- Roland Pálffy
- BiomeD Research and Publishing Group, Bratislava, Slovak Republic
- Institute of Pathophysiology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovak Republic
| | - Roman Gardlík
- BiomeD Research and Publishing Group, Bratislava, Slovak Republic
- Institute of Pathophysiology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovak Republic
| | - Michal Behuliak
- BiomeD Research and Publishing Group, Bratislava, Slovak Republic
- Institute of Pathophysiology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovak Republic
| | - Ludevit Kadasi
- Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovak Republic
| | - Jan Turna
- Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovak Republic
| | - Peter Celec
- BiomeD Research and Publishing Group, Bratislava, Slovak Republic
- Institute of Pathophysiology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovak Republic
- Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovak Republic
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Pistolic J, Cosseau C, Li Y, Yu J(J, Filewod NC, Gellatly S, Rehaume LM, Bowdish DM, Hancock RE. Host defence peptide LL-37 induces IL-6 expression in human bronchial epithelial cells by activation of the NF-kappaB signaling pathway. J Innate Immun 2008; 1:254-67. [PMID: 20375583 PMCID: PMC7312842 DOI: 10.1159/000171533] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2008] [Accepted: 08/21/2008] [Indexed: 12/30/2022] Open
Abstract
LL-37, the only member of the cathelicidin family of cationic host defence peptides in humans, has been shown to mediate multiple immunomodulatory effects and as such is thought to be an important component of innate immune responses. A growing body of evidence indicates that LL-37 affects lung mucosal responses to pathogens through altered regulation of cell migration, proliferation, wound healing and cell apoptosis. These functions are consistent with LL-37 playing a role in regulating lung epithelial inflammatory responses; however, that role has not been clearly defined. In this report we have demonstrated that host defence peptide LL-37 induced cytokine (IL-6) and chemokine (CXCL-1/GRO-alpha and CXCL-8/IL-8) release from human bronchial epithelial cells. It was demonstrated that LL-37-mediated IL-6 release was time and dose dependent and that LL-37 up-regulated this pleiotropic cytokine at the transcriptional level. Using specific inhibitors it was shown that NF-kappaB signaling led to the LL-37-stimulated production of IL-6. LL-37 stimulation of airway epithelial cells activated NF-kappaB signaling, as demonstrated by the phosphorylation and degradation of Ikappa-Balpha, and consequent nuclear translocation of p65 and p50 NF-kappaB subunits. Furthermore this host defence peptide augmented flagellin-mediated cytokine production, indicating that LL-37 likely modulates Toll-like receptor 5-mediated responses.
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Affiliation(s)
- Jelena Pistolic
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, B.C., Canada
| | - Celine Cosseau
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, B.C., Canada
| | - Yuexin Li
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, B.C., Canada
| | - Jie (Jessie) Yu
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, B.C., Canada
| | - Niall C.J. Filewod
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, B.C., Canada
| | - Shaan Gellatly
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, B.C., Canada
| | - Linda M. Rehaume
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, B.C., Canada
| | - Dawn M.E. Bowdish
- Sir William Dunn School of Pathology, Universityof Oxford, Oxford, UK
| | - Robert E.W. Hancock
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, B.C., Canada
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Tai EKK, Wong HPS, Lam EKY, Wu WKK, Yu L, Koo MWL, Cho CH. Cathelicidin stimulates colonic mucus synthesis by up-regulating MUC1 and MUC2 expression through a mitogen-activated protein kinase pathway. J Cell Biochem 2008; 104:251-8. [PMID: 18059019 DOI: 10.1002/jcb.21615] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Mucus forms the physical barrier along the gastrointestinal tract. It plays an important role to prevent mucosal damage and inflammation. Our animal study showed that antibacterial peptide 'cathelicidin' increased mucus thickness and prevented inflammation in the colon. In the current study, we examined the direct effect and mechanisms by which the peptide increased mucus synthesis in a human colonic cell line (HT-29). Human cathelicidin (LL-37) dose-dependently (10-40 microg/ml) and significantly stimulated mucus synthesis by increasing the D-[6-(3)H] glucosamine incorporation in the cells. Real-time PCR data showed that addition of LL-37 induced more than 50% increase in MUC1 and MUC2 mRNA levels. Treatment with MUC1 and MUC2 siRNAs normalized the stimulatory action of LL-37 on mucus synthesis. LL-37 also activated the phosphorylation of mitogen-activated protein (MAP) kinase in the cells. A specific inhibitor of the MAP kinase pathway, U0126, completely blocked the increase of MUC1 and MUC2 expression as well as mucus synthesis by LL-37. Taken together, LL-37 can directly stimulate mucus synthesis through activation of MUC1 and MUC2 expression and MAP kinase pathway in human colonic cells.
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Affiliation(s)
- Emily K K Tai
- Department of Pharmacology, The University of Hong Kong, Hong Kong, China
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36
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Laine L, Takeuchi K, Tarnawski A. Gastric mucosal defense and cytoprotection: bench to bedside. Gastroenterology 2008; 135:41-60. [PMID: 18549814 DOI: 10.1053/j.gastro.2008.05.030] [Citation(s) in RCA: 490] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2008] [Revised: 04/07/2008] [Accepted: 05/05/2008] [Indexed: 02/06/2023]
Abstract
The gastric mucosa maintains structural integrity and function despite continuous exposure to noxious factors, including 0.1 mol/L HCl and pepsin, that are capable of digesting tissue. Under normal conditions, mucosal integrity is maintained by defense mechanisms, which include preepithelial factors (mucus-bicarbonate-phospholipid "barrier"), an epithelial "barrier" (surface epithelial cells connected by tight junctions and generating bicarbonate, mucus, phospholipids, trefoil peptides, prostaglandins (PGs), and heat shock proteins), continuous cell renewal accomplished by proliferation of progenitor cells (regulated by growth factors, PGE(2) and survivin), continuous blood flow through mucosal microvessels, an endothelial "barrier," sensory innervation, and generation of PGs and nitric oxide. Mucosal injury may occur when noxious factors "overwhelm" an intact mucosal defense or when the mucosal defense is impaired. We review basic components of gastric mucosal defense and discuss conditions in which mucosal injury is directly related to impairment in mucosal defense, focusing on disorders with important clinical sequelae: nonsteroidal anti-inflammatory drug (NSAID)-associated injury, which is primarily related to inhibition of cyclooxygenase (COX)-mediated PG synthesis, and stress-related mucosal disease (SRMD), which occurs with local ischemia. The annual incidence of NSAID-associated upper gastrointestinal (GI) complications such as bleeding is approximately 1%-1.5%; and reductions in these complications have been demonstrated with misoprostol, proton pump inhibitors (PPIs) (only documented in high-risk patients), and COX-2 selective inhibitors. Clinically significant bleeding from SRMD is relatively uncommon with modern intensive care. Pharmacologic therapy with antisecretory drugs may be used in high-risk patients (eg, mechanical ventilation >or=48 hours), although the absolute risk reduction is small, and a decrease in mortality is not documented.
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Affiliation(s)
- Loren Laine
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
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37
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Nishi J, Fumoto S, Ishii H, Kodama Y, Nakashima M, Sasaki H, Nakamura J, Nishida K. Improved stomach selectivity of gene expression following microinstillation of plasmid DNA onto the gastric serosal surface in mice. Eur J Pharm Biopharm 2008; 69:633-9. [DOI: 10.1016/j.ejpb.2007.12.018] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2007] [Revised: 09/01/2007] [Accepted: 12/19/2007] [Indexed: 12/11/2022]
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Aberg KM, Radek KA, Choi EH, Kim DK, Demerjian M, Hupe M, Kerbleski J, Gallo RL, Ganz T, Mauro T, Feingold KR, Elias PM. Psychological stress downregulates epidermal antimicrobial peptide expression and increases severity of cutaneous infections in mice. J Clin Invest 2008; 117:3339-49. [PMID: 17975669 DOI: 10.1172/jci31726] [Citation(s) in RCA: 165] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2007] [Accepted: 07/16/2007] [Indexed: 01/10/2023] Open
Abstract
The skin is the first line of defense against microbial infection, and psychological stress (PS) has been shown to have adverse effects on cutaneous barrier function. Here we show that PS increased the severity of group A Streptococcus pyogenes (GAS) cutaneous skin infection in mice; this was accompanied by increased production of endogenous glucocorticoids (GCs), which inhibited epidermal lipid synthesis and decreased lamellar body (LB) secretion. LBs encapsulate antimicrobial peptides (AMPs), and PS or systemic or topical GC administration downregulated epidermal expression of murine AMPs cathelin-related AMP and beta-defensin 3. Pharmacological blockade of the stress hormone corticotrophin-releasing factor or of peripheral GC action, as well as topical administration of physiologic lipids, normalized epidermal AMP levels and delivery to LBs and decreased the severity of GAS infection during PS. Our results show that PS decreases the levels of 2 key AMPs in the epidermis and their delivery into LBs and that this is attributable to increased endogenous GC production. These data suggest that GC blockade and/or topical lipid administration could normalize cutaneous antimicrobial defense during PS or GC increase. We believe this to be the first mechanistic link between PS and increased susceptibility to infection by microbial pathogens.
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Affiliation(s)
- Karin M Aberg
- Dermatology and Medical (Metabolism) Services, Veterans Affairs Medical Center, and Department of Dermatology, UCSF, San Francisco, California 94121, USA
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