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Sung Kyun Moon - One of the best experts on this subject based on the ideXlab platform.
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induction of beta defensin 2 by nthi requires tlr2 mediated myd88 and irak traf6 p38mapk signaling pathway in human middle ear epithelial cells
BMC Infectious Diseases, 2008Co-Authors: Haa Yung Lee, Sung Kyun Moon, Huiqi Pan, Tamotsu Takeshita, Jun Shimada, Arsen Akopyan, Jeong Im Woo, Ali AndalibiAbstract:All mucosal epithelia, including those of the tubotympanium, are secreting a variety of antimicrobial innate immune molecules (AIIMs). In our previous study, we showed the bactericidal/bacteriostatic functions of AIIMs against various otitis media pathogens. Among the AIIMs, human β-defensin 2 is the most potent molecule and is inducible by exposure to inflammatory stimuli such as bacterial components or proinflammatory cytokines. Even though the β-defensin 2 is an important AIIM, the induction mechanism of this molecule has not been clearly established. We believe that this report is the first attempt to elucidate NTHi induced β-defensin expression in airway mucosa, which includes the middle ear. Monoclonal antibody blocking method was employed in monitoring the TLR-dependent NTHi response. Two gene knock down methods – dominant negative (DN) plasmid and small interfering RNA (siRNA) – were employed to detect and confirm the involvement of several key genes in the signaling cascade resulting from the NTHi stimulated β-defensin 2 expression in human middle ear epithelial cell (HMEEC-1). The student's t-test was used for the statistical analysis of the data. The experimental results showed that the major NTHi-specific receptor in HMEEC-1 is the Toll-like receptor 2 (TLR2). Furthermore, recognition of NTHi component(s)/ligand(s) by TLR2, activated the Toll/IL-1 receptor (TIR)-MyD88-IRAK1-TRAF6-MKK3/6-p38 MAPK signal transduction pathway, ultimately leading to the induction of β-defensin 2. This study found that the induction of β-defensin 2 is highest in whole cell lysate (WCL) preparations of NTHi, suggesting that the ligand(s) responsible for this up-regulation may be soluble macromolecule(s). We also found that this induction takes place through the TLR2 dependent MyD88-IRAK1-TRAF6-p38 MAPK pathway, with the primary response occurring within the first hour of stimulation. In combination with our previous studies showing that IL-1α-induced β-defensin 2 expression takes place through a MyD88-independent Raf-MEK1/2-ERK MAPK pathway, we found that both signaling cascades act synergistically to up-regulate β-defensin 2 levels. We propose that this confers an essential evolutionary advantage to the cells in coping with infections and may serve to amplify the innate immune response through paracrine signaling.
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Synergistic effect of interleukin 1 alpha on nontypeable Haemophilus influenzae-induced up-regulation of human Beta-Defensin 2 in middle ear epithelial cells.
BMC Infectious Diseases, 2006Co-Authors: Sung Kyun Moon, Haa Yung Lee, Huiqi Pan, Tamotsu Takeshita, Raekil Park, Kiweon Cha, Ali Andalibi, David J. LimAbstract:Background We recently showed that Beta-Defensins have antimicrobial activity against nontypeable Haemophilus influenzae (NTHi) and that interleukin 1 alpha (IL-1 alpha) up-regulates the transcription of Beta-Defensin 2 (DEFB4 according to new nomenclature of the Human Genome Organization) in human middle ear epithelial cells via a Src-dependent Raf-MEK1/2-ERK signaling pathway. Based on these observations, we investigated if human middle ear epithelial cells could release IL-1 alpha upon exposure to a lysate of NTHi and if this cytokine could have a synergistic effect on Beta-Defensin 2 up-regulation by the bacterial components.
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synergistic effect of interleukin 1 alpha on nontypeable haemophilus influenzae induced up regulation of human beta defensin 2 in middle ear epithelial cells
BMC Infectious Diseases, 2006Co-Authors: Sung Kyun Moon, Haa Yung Lee, Huiqi Pan, Tamotsu Takeshita, Raekil Park, Kiweon Cha, Ali AndalibiAbstract:We recently showed that Beta-Defensins have antimicrobial activity against nontypeable Haemophilus influenzae (NTHi) and that interleukin 1 alpha (IL-1 alpha) up-regulates the transcription of Beta-Defensin 2 (DEFB4 according to new nomenclature of the Human Genome Organization) in human middle ear epithelial cells via a Src-dependent Raf-MEK1/2-ERK signaling pathway. Based on these observations, we investigated if human middle ear epithelial cells could release IL-1 alpha upon exposure to a lysate of NTHi and if this cytokine could have a synergistic effect on Beta-Defensin 2 up-regulation by the bacterial components. The studies described herein were carried out using epithelial cell lines as well as a murine model of acute otitis media (OM). Human cytokine macroarray analysis was performed to detect the released cytokines in response to NTHi exposure. Real time quantitative PCR was done to compare the induction of IL-1 alpha or Beta-Defensin 2 mRNAs and to identify the signaling pathways involved. Direct activation of the Beta-Defensin 2 promoter was monitored using a Beta-Defensin 2 promoter-Luciferase construct. An IL-1 alpha blocking antibody was used to demonstrate the direct involvement of this cytokine on DEFB4 induction. Middle ear epithelial cells released IL-1 alpha when stimulated by NTHi components and this cytokine acted in an autocrine/paracrine synergistic manner with NTHi to up-regulate Beta-Defensin 2. This synergistic effect of IL-1 alpha on NTHi-induced Beta-Defensin 2 up-regulation appeared to be mediated by the p38 MAP kinase pathway. We demonstrate that IL-1 alpha is secreted by middle ear epithelial cells upon exposure to NTHi components and that it can synergistically act with certain of these molecules to up-regulate Beta-Defensin 2 via the p38 MAP kinase pathway.
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gene regulatory regions required for beta defensin 2 up regulation by interleukin 1alpha in the human middle ear epithelial cell line
Korean Journal of Otolaryngology-head and Neck Surgery, 2005Co-Authors: Hyun Jun Kim, Jun Ho Bae, Yunhoon Choung, Keehyun Park, Sung Kyun MoonAbstract:BACKGROUND AND OBJECTIVES: Innate immunity is important in the middle ear because of the lack of immune cells in the region. Among innate immunities Beta-Defensin-2 is known to play an important role in the immune function of the middle ear. But we still do not understand well about the signal transduction pathway and gene regulatory region of Beta-Defensin-2 (hBD-2). MATERIALS AND METHOD: The expression of Beta-Defensin-2 (hBD-2) by IL-1alpha in HMEEC was detected by RT-PCR. The luciferase-expressing vector containing diverse lengths of the hBD-2 5' flanking region made by the progressive unidirectional deletion was transferred to HEEMC (Human Middle Ear Cell). We analyzed the function of 5' flanking region by luciferase activity measured using a luminometer after supplementing corresponding substrates to the cell lysate. RESULTS: hBD-2 was upregulated by IL-1alpha in HMEEC-1. The treatment of IL-1alpha up-regulated the activity of promoter by 7.60+/-1.45 (average+/-standard deviation) folds in 2.7 kpb sized 5' flanking region, 3.81+/-0.78 folds in 1.1 kbp, and 4.00+/-0.73 folds in 500 bp. CONCLUSION: These results indicate there are two effective gene regions that regulate the hBD-2 expression by IL-1alpha between 2.7 kbp and 1.1 kbp, and at 500 bp upstream of the translation starting point of hBD-2 in HMEEC-1
Ali Andalibi - One of the best experts on this subject based on the ideXlab platform.
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induction of beta defensin 2 by nthi requires tlr2 mediated myd88 and irak traf6 p38mapk signaling pathway in human middle ear epithelial cells
BMC Infectious Diseases, 2008Co-Authors: Haa Yung Lee, Sung Kyun Moon, Huiqi Pan, Tamotsu Takeshita, Jun Shimada, Arsen Akopyan, Jeong Im Woo, Ali AndalibiAbstract:All mucosal epithelia, including those of the tubotympanium, are secreting a variety of antimicrobial innate immune molecules (AIIMs). In our previous study, we showed the bactericidal/bacteriostatic functions of AIIMs against various otitis media pathogens. Among the AIIMs, human β-defensin 2 is the most potent molecule and is inducible by exposure to inflammatory stimuli such as bacterial components or proinflammatory cytokines. Even though the β-defensin 2 is an important AIIM, the induction mechanism of this molecule has not been clearly established. We believe that this report is the first attempt to elucidate NTHi induced β-defensin expression in airway mucosa, which includes the middle ear. Monoclonal antibody blocking method was employed in monitoring the TLR-dependent NTHi response. Two gene knock down methods – dominant negative (DN) plasmid and small interfering RNA (siRNA) – were employed to detect and confirm the involvement of several key genes in the signaling cascade resulting from the NTHi stimulated β-defensin 2 expression in human middle ear epithelial cell (HMEEC-1). The student's t-test was used for the statistical analysis of the data. The experimental results showed that the major NTHi-specific receptor in HMEEC-1 is the Toll-like receptor 2 (TLR2). Furthermore, recognition of NTHi component(s)/ligand(s) by TLR2, activated the Toll/IL-1 receptor (TIR)-MyD88-IRAK1-TRAF6-MKK3/6-p38 MAPK signal transduction pathway, ultimately leading to the induction of β-defensin 2. This study found that the induction of β-defensin 2 is highest in whole cell lysate (WCL) preparations of NTHi, suggesting that the ligand(s) responsible for this up-regulation may be soluble macromolecule(s). We also found that this induction takes place through the TLR2 dependent MyD88-IRAK1-TRAF6-p38 MAPK pathway, with the primary response occurring within the first hour of stimulation. In combination with our previous studies showing that IL-1α-induced β-defensin 2 expression takes place through a MyD88-independent Raf-MEK1/2-ERK MAPK pathway, we found that both signaling cascades act synergistically to up-regulate β-defensin 2 levels. We propose that this confers an essential evolutionary advantage to the cells in coping with infections and may serve to amplify the innate immune response through paracrine signaling.
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Synergistic effect of interleukin 1 alpha on nontypeable Haemophilus influenzae-induced up-regulation of human Beta-Defensin 2 in middle ear epithelial cells.
BMC Infectious Diseases, 2006Co-Authors: Sung Kyun Moon, Haa Yung Lee, Huiqi Pan, Tamotsu Takeshita, Raekil Park, Kiweon Cha, Ali Andalibi, David J. LimAbstract:Background We recently showed that Beta-Defensins have antimicrobial activity against nontypeable Haemophilus influenzae (NTHi) and that interleukin 1 alpha (IL-1 alpha) up-regulates the transcription of Beta-Defensin 2 (DEFB4 according to new nomenclature of the Human Genome Organization) in human middle ear epithelial cells via a Src-dependent Raf-MEK1/2-ERK signaling pathway. Based on these observations, we investigated if human middle ear epithelial cells could release IL-1 alpha upon exposure to a lysate of NTHi and if this cytokine could have a synergistic effect on Beta-Defensin 2 up-regulation by the bacterial components.
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synergistic effect of interleukin 1 alpha on nontypeable haemophilus influenzae induced up regulation of human beta defensin 2 in middle ear epithelial cells
BMC Infectious Diseases, 2006Co-Authors: Sung Kyun Moon, Haa Yung Lee, Huiqi Pan, Tamotsu Takeshita, Raekil Park, Kiweon Cha, Ali AndalibiAbstract:We recently showed that Beta-Defensins have antimicrobial activity against nontypeable Haemophilus influenzae (NTHi) and that interleukin 1 alpha (IL-1 alpha) up-regulates the transcription of Beta-Defensin 2 (DEFB4 according to new nomenclature of the Human Genome Organization) in human middle ear epithelial cells via a Src-dependent Raf-MEK1/2-ERK signaling pathway. Based on these observations, we investigated if human middle ear epithelial cells could release IL-1 alpha upon exposure to a lysate of NTHi and if this cytokine could have a synergistic effect on Beta-Defensin 2 up-regulation by the bacterial components. The studies described herein were carried out using epithelial cell lines as well as a murine model of acute otitis media (OM). Human cytokine macroarray analysis was performed to detect the released cytokines in response to NTHi exposure. Real time quantitative PCR was done to compare the induction of IL-1 alpha or Beta-Defensin 2 mRNAs and to identify the signaling pathways involved. Direct activation of the Beta-Defensin 2 promoter was monitored using a Beta-Defensin 2 promoter-Luciferase construct. An IL-1 alpha blocking antibody was used to demonstrate the direct involvement of this cytokine on DEFB4 induction. Middle ear epithelial cells released IL-1 alpha when stimulated by NTHi components and this cytokine acted in an autocrine/paracrine synergistic manner with NTHi to up-regulate Beta-Defensin 2. This synergistic effect of IL-1 alpha on NTHi-induced Beta-Defensin 2 up-regulation appeared to be mediated by the p38 MAP kinase pathway. We demonstrate that IL-1 alpha is secreted by middle ear epithelial cells upon exposure to NTHi components and that it can synergistically act with certain of these molecules to up-regulate Beta-Defensin 2 via the p38 MAP kinase pathway.
Jürgen Harder - One of the best experts on this subject based on the ideXlab platform.
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staphylococcus epidermidis induced interleukin 1 beta and human beta defensin 2 expression in human keratinocytes is regulated by the host molecule a20 tnfaip3
Acta Dermato-venereologica, 2019Co-Authors: Maren Simanski, Franziska Rademacher, Annasophie Erkens, Jürgen HarderAbstract:Staphylococcus epidermidis is an abundant skin commensal capable of activating cutaneous defense responses, such as induction of cytokines and antimicrobial peptides. To permanently colonize human skin and prevent inflammation S. epidermidis needs to control the induction of host defense mediators. We report here that S. epidermidis induces expression of the host regulator protein A20 in human keratinocytes, thereby controlling expression and release of interleukin-1 beta. siRNA-mediated knockdown of A20 expression strongly enhanced the induction of interleukin-1 beta gene expression and protein release in keratinocytes stimulated with S. epidermidis. Furthermore, siRNA-mediated knockdown of A20 resulted in enhanced gene expression and secretion of the antimicrobial peptide human Beta-Defensin-2 in keratinocytes facing S. epidermidis. Mechanistically, A20 negatively controlled S. epidermidis-induced activation of the transcription factor NF-kappaB. Together, these data indicate that S. epidermidis exploits A20 to attenuate cutaneous defense responses, which may help S. epidermidis to persist on human skin.
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nod2 card15 mediates induction of the antimicrobial peptide human beta defensin 2
Journal of Biological Chemistry, 2006Co-Authors: Eske Voss, Jens M. Schröder, Jan Wehkamp, Kai Wehkamp, Eduard F Stange, Jürgen HarderAbstract:Abstract Production of inducible antimicrobial peptides offers a first and rapid defense response of epithelial cells against invading microbes. Human Beta-Defensin-2 (hBD-2) is an antimicrobial peptide induced in various epithelia upon extracellular as well as intracellular bacterial challenge. Nucleotide-binding oligomerization domain protein 2 (NOD2/CARD15) is a cytosolic protein involved in intracellular recognition of microbes by sensing peptidoglycan fragments (e.g. muramyl dipeptide). We used luciferase as a reporter gene for a 2.3-kb hBD-2 promoter to test the hypothesis that NOD2 mediates the induction of hBD-2. Activation of NOD2 in NOD2-overexpressing human embryonic kidney 293 cells through its ligand muramyl dipeptide (MDP) induced hBD-2 expression. In contrast, overexpression of NOD2 containing the 3020insC frame-shift mutation, the most frequent NOD2 variant associated with Crohn disease, resulted in defective induction of hBD-2 through MDP. Luciferase gene reporter analyses and site-directed mutagenesis experiments demonstrated that functional binding sites for NF-κB and AP-1 in the hBD-2 promoter are required for NOD2-mediated induction of hBD-2 through MDP. Moreover, the NF-κB inhibitor Helenalin as well as a super-repressor form of the NF-κB inhibitor IκB strongly inhibited NOD2-mediated hBD-2 promoter activation. Expression of NOD2 was detected in primary keratinocytes, and stimulation of these cells with MDP induced hBD-2 peptide release. In contrast, small interference RNA-mediated down-regulation of NOD2 expression in primary keratinocytes resulted in a defective induction of hBD-2 upon MDP treatment. Together, these data suggest that NOD2 serves as an intracellular pattern recognition receptor to enhance host defense by inducing the production of antimicrobial peptides such as hBD-2.
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nf κb and ap 1 mediated induction of human beta defensin 2 in intestinal epithelial cells by escherichia coli nissle 1917 a novel effect of a probiotic bacterium
Infection and Immunity, 2004Co-Authors: Jan Wehkamp, Jürgen Harder, Kai Wehkamp, Birte Wehkampvon Meissner, Miriam Schlee, Corinne Enders, Ulrich Sonnenborn, Sabine Nuding, Stig Bengmark, Klaus FellermannAbstract:Little is known about the defensive mechanisms induced in epithelial cells by pathogenic versus probiotic bacteria. The aim of our study was to compare probiotic bacterial strains such as Escherichia coli Nissle 1917 with nonprobiotic, pathogenic and nonpathogenic bacteria with respect to innate defense mechanisms in the intestinal mucosal cell. Here we report that E. coli strain Nissle 1917 and a variety of other probiotic bacteria, including lactobacilli--in contrast to more than 40 different E. coli strains tested--strongly induce the expression of the antimicrobial peptide human Beta-Defensin-2 (hBD-2) in Caco-2 intestinal epithelial cells in a time- and dose-dependent manner. Induction of hBD-2 through E. coli Nissle 1917 was further confirmed by activation of the hBD-2 promoter and detection of the hBD-2 peptide in the culture supernatants of E. coli Nissle 1917-treated Caco-2 cells. Luciferase gene reporter analyses and site-directed mutagenesis experiments demonstrated that functional binding sites for NF-kappaB and AP-1 in the hBD-2 promoter are required for induction of hBD-2 through E. coli Nissle 1917. Treatment with the NF-kappaB inhibitor Helenalin, as well as with SP600125, a selective inhibitor of c-Jun N-terminal kinase, blocked hBD-2 induction by E. coli Nissle 1917 in Caco-2 cells. SB 202190, a specific p38 mitogen-activated protein kinase inhibitor, and PD 98059, a selective inhibitor of extracellular signal-regulated kinase 1/2, were ineffective. This report demonstrates that probiotic bacteria may stimulate the intestinal innate defense through the upregulation of inducible antimicrobial peptides such as hBD-2. The induction of hBD-2 may contribute to an enhanced mucosal barrier to the luminal bacteria.
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mucoid pseudomonas aeruginosa tnf alpha and il 1beta but not il 6 induce human beta defensin 2 in respiratory epithelia
American Journal of Respiratory Cell and Molecular Biology, 2000Co-Authors: Jürgen Harder, Ulf Meyerhoffert, Luis M Teran, Lars Schwichtenberg, Joachim Bartels, Steffen Maune, Jensmichael SchroderAbstract:Cultured lung epithelial cells release antibacterial activity upon contact with Pseudomonas aeruginosa (PA), which is impaired in cystic fibrosis (CF). In order to identify the factors responsible for killing PA by a biochemical approach, we purified antimicrobial activity from supernatants of the A549 lung epithelial cell line, previously stimulated with PA bacteria, by subsequent high performance liquid chromatography. NH(2)-terminal sequencing of a major bactericidal compound revealed it to be identical with human Beta-Defensin-2 (hBD-2). A mucoid phenotype of PA, but not two nonmucoid PA strains, high concentrations (> 10 microg/ml) of PA lipopolysaccharide, tumor necrosis factor alpha, and interleukin (IL)-1beta, but not IL-6, dose-dependently induced hBD-2 messenger RNA in cultured normal bronchial, tracheal, as well as normal and CF-derived nasal epithelial cells. Genomic analysis of hBD-2 revealed a promoter region containing several putative transcription factor binding sites, including nuclear factor (NF) kappaB, activator protein (AP)-1, AP-2, and NF-IL-6, known to be involved in the regulation of inflammatory responses. Thus, hBD-2 represents a major inducible antimicrobial factor released by airway epithelial cells either on contact with mucoid PA or by endogenously produced primary cytokines. Therefore, it might be important in lung infections caused by mucoid PA, including those seen in patients with CF.
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Human Beta-Defensin-2.
The International Journal of Biochemistry & Cell Biology, 1999Co-Authors: Jens M. Schröder, Jürgen HarderAbstract:Human Beta-Defensin-2 (HBD-2) is a cysteine-rich cationic low molecular weight antimicrobial peptide recently discovered in psoriatic lesional skin. It is produced by a number of epithelial cells and exhibits potent antimicrobial activity against Gram-negative bacteria and Candida, but not Gram-positive Staphylococcus aureus. HBD-2 represents the first human defensin that is produced following stimulation of epithelial cells by contact with microorganisms such as Pseudomonas aeruginosa or cytokines such as TNF-alpha and IL-1 beta. The HBD-2 gene and protein are locally expressed in keratinocytes associated with inflammatory skin lesions such as psoriasis as well as in the infected lung epithelia of patients with cystic fibrosis. It is intriguing to speculate that HBD-2 is a dynamic component of the local epithelial defense system of the skin and respiratory tract having a role to protect surfaces from infection, and providing a possible reason why skin and lung infections with Gram-negative bacteria are rather rare.
Tamotsu Takeshita - One of the best experts on this subject based on the ideXlab platform.
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induction of beta defensin 2 by nthi requires tlr2 mediated myd88 and irak traf6 p38mapk signaling pathway in human middle ear epithelial cells
BMC Infectious Diseases, 2008Co-Authors: Haa Yung Lee, Sung Kyun Moon, Huiqi Pan, Tamotsu Takeshita, Jun Shimada, Arsen Akopyan, Jeong Im Woo, Ali AndalibiAbstract:All mucosal epithelia, including those of the tubotympanium, are secreting a variety of antimicrobial innate immune molecules (AIIMs). In our previous study, we showed the bactericidal/bacteriostatic functions of AIIMs against various otitis media pathogens. Among the AIIMs, human β-defensin 2 is the most potent molecule and is inducible by exposure to inflammatory stimuli such as bacterial components or proinflammatory cytokines. Even though the β-defensin 2 is an important AIIM, the induction mechanism of this molecule has not been clearly established. We believe that this report is the first attempt to elucidate NTHi induced β-defensin expression in airway mucosa, which includes the middle ear. Monoclonal antibody blocking method was employed in monitoring the TLR-dependent NTHi response. Two gene knock down methods – dominant negative (DN) plasmid and small interfering RNA (siRNA) – were employed to detect and confirm the involvement of several key genes in the signaling cascade resulting from the NTHi stimulated β-defensin 2 expression in human middle ear epithelial cell (HMEEC-1). The student's t-test was used for the statistical analysis of the data. The experimental results showed that the major NTHi-specific receptor in HMEEC-1 is the Toll-like receptor 2 (TLR2). Furthermore, recognition of NTHi component(s)/ligand(s) by TLR2, activated the Toll/IL-1 receptor (TIR)-MyD88-IRAK1-TRAF6-MKK3/6-p38 MAPK signal transduction pathway, ultimately leading to the induction of β-defensin 2. This study found that the induction of β-defensin 2 is highest in whole cell lysate (WCL) preparations of NTHi, suggesting that the ligand(s) responsible for this up-regulation may be soluble macromolecule(s). We also found that this induction takes place through the TLR2 dependent MyD88-IRAK1-TRAF6-p38 MAPK pathway, with the primary response occurring within the first hour of stimulation. In combination with our previous studies showing that IL-1α-induced β-defensin 2 expression takes place through a MyD88-independent Raf-MEK1/2-ERK MAPK pathway, we found that both signaling cascades act synergistically to up-regulate β-defensin 2 levels. We propose that this confers an essential evolutionary advantage to the cells in coping with infections and may serve to amplify the innate immune response through paracrine signaling.
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Synergistic effect of interleukin 1 alpha on nontypeable Haemophilus influenzae-induced up-regulation of human Beta-Defensin 2 in middle ear epithelial cells.
BMC Infectious Diseases, 2006Co-Authors: Sung Kyun Moon, Haa Yung Lee, Huiqi Pan, Tamotsu Takeshita, Raekil Park, Kiweon Cha, Ali Andalibi, David J. LimAbstract:Background We recently showed that Beta-Defensins have antimicrobial activity against nontypeable Haemophilus influenzae (NTHi) and that interleukin 1 alpha (IL-1 alpha) up-regulates the transcription of Beta-Defensin 2 (DEFB4 according to new nomenclature of the Human Genome Organization) in human middle ear epithelial cells via a Src-dependent Raf-MEK1/2-ERK signaling pathway. Based on these observations, we investigated if human middle ear epithelial cells could release IL-1 alpha upon exposure to a lysate of NTHi and if this cytokine could have a synergistic effect on Beta-Defensin 2 up-regulation by the bacterial components.
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synergistic effect of interleukin 1 alpha on nontypeable haemophilus influenzae induced up regulation of human beta defensin 2 in middle ear epithelial cells
BMC Infectious Diseases, 2006Co-Authors: Sung Kyun Moon, Haa Yung Lee, Huiqi Pan, Tamotsu Takeshita, Raekil Park, Kiweon Cha, Ali AndalibiAbstract:We recently showed that Beta-Defensins have antimicrobial activity against nontypeable Haemophilus influenzae (NTHi) and that interleukin 1 alpha (IL-1 alpha) up-regulates the transcription of Beta-Defensin 2 (DEFB4 according to new nomenclature of the Human Genome Organization) in human middle ear epithelial cells via a Src-dependent Raf-MEK1/2-ERK signaling pathway. Based on these observations, we investigated if human middle ear epithelial cells could release IL-1 alpha upon exposure to a lysate of NTHi and if this cytokine could have a synergistic effect on Beta-Defensin 2 up-regulation by the bacterial components. The studies described herein were carried out using epithelial cell lines as well as a murine model of acute otitis media (OM). Human cytokine macroarray analysis was performed to detect the released cytokines in response to NTHi exposure. Real time quantitative PCR was done to compare the induction of IL-1 alpha or Beta-Defensin 2 mRNAs and to identify the signaling pathways involved. Direct activation of the Beta-Defensin 2 promoter was monitored using a Beta-Defensin 2 promoter-Luciferase construct. An IL-1 alpha blocking antibody was used to demonstrate the direct involvement of this cytokine on DEFB4 induction. Middle ear epithelial cells released IL-1 alpha when stimulated by NTHi components and this cytokine acted in an autocrine/paracrine synergistic manner with NTHi to up-regulate Beta-Defensin 2. This synergistic effect of IL-1 alpha on NTHi-induced Beta-Defensin 2 up-regulation appeared to be mediated by the p38 MAP kinase pathway. We demonstrate that IL-1 alpha is secreted by middle ear epithelial cells upon exposure to NTHi components and that it can synergistically act with certain of these molecules to up-regulate Beta-Defensin 2 via the p38 MAP kinase pathway.
Maria Vincenza Carriero - One of the best experts on this subject based on the ideXlab platform.
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antimicrobial human beta defensin 2 stimulates migration proliferation and tube formation of human umbilical vein endothelial cells
Peptides, 2009Co-Authors: Adone Baroni, Giovanna Donnarumma, Iole Paoletti, Immacolata Longanesicattani, Katia Bifulco, Maria Antonietta Tufano, Maria Vincenza CarrieroAbstract:Human Beta-Defensin-2 (hBD-2) is an antimicrobial peptide which is released upon microbial invasion and contributes to mucosal and epithelial defense modulating both innate and adaptive immunity. We found that hBD-2 stimulates chemotaxis of human endothelial cells with an extent similar to that exerted by the vascular endothelial growth factor (VEGF). The hBD-2-dependent chemotaxis is dose-dependent, maximal effect being reached at 500 ng/ml concentration. In the absence of any growth factor, hBD-2 favors wound healing of endothelial cells, causing an about 2-fold increase in the speed of wound closure with respect to the control. Furthermore, hBD-2 promotes endothelial cell proliferation, although at a minor extent as compared to VEGF. When plated on matrigel enriched with angiogenic factors, endothelial cells form a three-dimensional network of tubes that gives rise to capillary-like structures. Similarly to VEGF, hBD-2 promotes capillary-like tube formation of human endothelial cells. Pro-angiogenic effect promoted by hBD-2 is dose-dependent, peaks at a 500 ng/ml hBD-2 concentration and is prevented by blocking anti-αvβ3 monoclonal antibody. However, hBD-2-induced pro-angiogenic activity is not due to endogenously produced VEGF because it is not prevented by neutralizing anti-VEGF antibodies. Overall, our findings suggest that hBD-2 could link inflammation and the host defense through its pro-angiogenic activity.
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antimicrobial human beta defensin 2 stimulates migration proliferation and tube formation of human umbilical vein endothelial cells
Peptides, 2009Co-Authors: Adone Baroni, Giovanna Donnarumma, Iole Paoletti, Immacolata Longanesicattani, Katia Bifulco, Maria Antonietta Tufano, Maria Vincenza CarrieroAbstract:Human Beta-Defensin-2 (hBD-2) is an antimicrobial peptide which is released upon microbial invasion and contributes to mucosal and epithelial defense modulating both innate and adaptive immunity. We found that hBD-2 stimulates chemotaxis of human endothelial cells with an extent similar to that exerted by the vascular endothelial growth factor (VEGF). The hBD-2-dependent chemotaxis is dose-dependent, maximal effect being reached at 500 ng/ml concentration. In the absence of any growth factor, hBD-2 favors wound healing of endothelial cells, causing an about 2-fold increase in the speed of wound closure with respect to the control. Furthermore, hBD-2 promotes endothelial cell proliferation, although at a minor extent as compared to VEGF. When plated on matrigel enriched with angiogenic factors, endothelial cells form a three-dimensional network of tubes that gives rise to capillary-like structures. Similarly to VEGF, hBD-2 promotes capillary-like tube formation of human endothelial cells. Pro-angiogenic effect promoted by hBD-2 is dose-dependent, peaks at a 500 ng/ml hBD-2 concentration and is prevented by blocking anti-alphavbeta3 monoclonal antibody. However, hBD-2-induced pro-angiogenic activity is not due to endogenously produced VEGF because it is not prevented by neutralizing anti-VEGF antibodies. Overall, our findings suggest that hBD-2 could link inflammation and the host defense through its pro-angiogenic activity.