β-Defensin-2 Expression Is Regulated by TLR Signaling in Intestinal Epithelial Cells

Vora, Puja; Youdim, Adrienne; Thomas, Lisa S.; Fukata, Masayuki; Tesfay, Samuel; Lukasek, Katie; Michelsen, Kathrin S.; Wada, Akihiro; Hirayama, Toshiya; Arditi, Moshe; Abreu, María T.

doi:10.4049/jimmunol.173.9.5398

Cited by 322 publications

(250 citation statements)

References 61 publications

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“…These results indicate that NF-B and, to a lesser degree, AP-1 play a critical role in the regulation of the NOD2-mediated hBD-2 induction. These results are consistent with previous reports demonstrating an important role of NF-B for induction of hBD-2 in epithelial cells upon stimulation with bacteria or bacterial products (23,25,26,(45)(46)(47).…”

Section: Discussionsupporting

confidence: 83%

NOD2/CARD15 Mediates Induction of the Antimicrobial Peptide Human Beta-defensin-2

Voss

Wehkamp²,

Wehkamp

et al. 2006

Journal of Biological Chemistry

308

219

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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 frameshift 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-B and AP-1 in the hBD-2 promoter are required for NOD2-mediated induction of hBD-2 through MDP. Moreover, the NF-B inhibitor Helenalin as well as a super-repressor form of the NF-B inhibitor IB 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 downregulation 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.Human epithelia are in permanent contact with various potential pathogenic microorganisms. To overcome these microbial threats, epithelia have developed a chemical defense system based on the production of various antimicrobial proteins (1-4). Human beta-defensin-2 (hBD-2) 2 was the first inducible human antimicrobial protein discovered and was originally isolated from lesional psoriatic skin (5). hBD-2 belongs to the beta-defensin family, a group of small (4 -5 kDa), cationic antibiotic peptides first discovered in cattle (6). hBD-2 exhibits a broad spectrum of antimicrobial activity, and its capacity to kill bacteria in vivo has been demonstrated in a mouse gene therapy study with hBD-2-transfected tumor cells. Following a bacterial infection, mice with hBD-2-bearing tumors bore fewer viable bacteria than controls (7). In addition to its capacity to serve as an antibiotic peptide, hBD-2 may promote adaptive immune responses by recruiting dendritic and T cells to the site of microbial invasion through interaction with CCR6 (8). Furthermore hBD-2 was found to be a specific chemoattractant for tumor necrosis factor-␣ (TNF-␣)-treated human neutrophils (9). hBD-2 is expressed in many epithelia (e.g. skin, respiratory tract, dig...

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Section: Discussionsupporting

confidence: 83%

NOD2/CARD15 Mediates Induction of the Antimicrobial Peptide Human Beta-defensin-2

Voss

Wehkamp²,

Wehkamp

et al. 2006

Journal of Biological Chemistry

308

219

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“…We have recently demonstrated that TLR4-and TLR2-dependent pathways can stimulate ␤-defensin-2 expression by intestinal epithelial cells (36). These data suggest that, like Paneth cells, intestinal epithelial cells respond to PAMPs by secreting antimicrobial peptides.…”

Section: Secretion Of Anti-microbial Peptidesmentioning

confidence: 90%

TLR Signaling in the Gut in Health and Disease

Abreu

Fukata

Arditi

2005

The Journal of Immunology

Self Cite

536

382

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The human intestine has evolved in the presence of diverse enteric microflora. TLRs convert the recognition of pathogen-associated molecules in the gut into signals for anti-microbial peptide expression, barrier fortification, and proliferation of epithelial cells. Healing of injured intestinal epithelium and clearance of intramucosal bacteria require the presence of intact TLR signaling. Nucleotide oligomerization domain (Nod)1 and Nod2 are additional pattern recognition receptors that are required for defense against invasive enteric pathogens. Through spatial and functional localization of TLR and Nod molecules, the normal gut maintains a state of controlled inflammation. By contrast, patients with inflammatory bowel disease demonstrate inflammation in response to the normal flora. A subset of these patients carry polymorphisms in TLR and CARD15/NOD2 genes. A better understanding of the delicate regulation of TLR and Nod molecules in the gut may lead to improved treatment for enteric infections and idiopathic inflammatory bowel diseases.

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“…Epithelial cells on intestinal villi act as sensors of the luminal environment, and intestinal epithelial cell monolayers in vitro can release inflammatory cytokines in response to pathogen attachment and invasion (1,2). Intestinal epithelial cells express a variety of potential sensing receptors, including TLRs (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), that may play a role in mucosal responses to microbial components.…”

mentioning

confidence: 99%

TLRs Regulate the Gatekeeping Functions of the Intestinal Follicle-Associated Epithelium

Chabot

Wagner

Farrant

et al. 2006

The Journal of Immunology

139

116

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Initiation of adaptive mucosal immunity occurs in organized mucosal lymphoid tissues such as Peyer’s patches of the small intestine. Mucosal lymphoid follicles are covered by a specialized follicle-associated epithelium (FAE) that contains M cells, which mediate uptake and transepithelial transport of luminal Ags. FAE cells also produce chemokines that attract Ag-presenting dendritic cells (DCs). TLRs link innate and adaptive immunity, but their possible role in regulating FAE functions is unknown. We show that TLR2 is expressed in both FAE and villus epithelium, but TLR2 activation by peptidoglycan or Pam3Cys injected into the intestinal lumen of mice resulted in receptor redistribution in the FAE only. TLR2 activation enhanced transepithelial transport of microparticles by M cells in a dose-dependent manner. Furthermore, TLR2 activation induced the matrix metalloproteinase-dependent migration of subepithelial DCs into the FAE, but not into villus epithelium of wild-type and TLR4-deficient mice. These responses were not observed in TLR2-deficient mice. Thus, the FAE of Peyer’s patches responds to TLR2 ligands in a manner that is distinct from the villus epithelium. Intraluminal LPS, a TLR4 ligand, also enhanced microparticle uptake by the FAE and induced DC migration into the FAE, suggesting that other TLRs may modulate FAE functions. We conclude that TLR-mediated signals regulate the gatekeeping functions of the FAE to promote Ag capture by DCs in organized mucosal lymphoid tissues.

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β-Defensin-2 Expression Is Regulated by TLR Signaling in Intestinal Epithelial Cells

Cited by 322 publications

References 61 publications

NOD2/CARD15 Mediates Induction of the Antimicrobial Peptide Human Beta-defensin-2

NOD2/CARD15 Mediates Induction of the Antimicrobial Peptide Human Beta-defensin-2

TLR Signaling in the Gut in Health and Disease

TLRs Regulate the Gatekeeping Functions of the Intestinal Follicle-Associated Epithelium

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