J Biol Chem 2006,
PMID: 16319062
Voss, Eske; Wehkamp, Jan; Wehkamp, Kai; Stange, Eduard F; Schröder, Jens M; Harder, Jürgen
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-kappaB and AP-1 in the hBD-2 promoter are required for NOD2-mediated induction of hBD-2 through MDP. Moreover, the NF-kappaB inhibitor Helenalin as well as a super-repressor form of the NF-kappaB inhibitor IkappaB 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.
Diseases/Pathways annotated by Medline MESH: Crohn Disease
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Text Mining Data
beta-defensin-2 → NOD2/CARD15: "
NOD2/CARD15 mediates induction of the antimicrobial peptide human
beta-defensin-2
"
hBD-2 → NOD2: "
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
"
hBD-2 → NOD2: "
Activation of NOD2 in NOD2 overexpressing human embryonic kidney 293 cells through its ligand muramyl dipeptide ( MDP ) induced hBD-2 expression
"
hBD-2 ⊣ NOD2: "
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
"
hBD-2 → AP-1: "
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 NOD2 mediated induction of hBD-2 through MDP
"
hBD-2 → NOD2: "
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 NOD2 mediated induction of hBD-2 through MDP
"
hBD-2 → NF-kappaB: "
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 NOD2 mediated induction of hBD-2 through MDP
"
hBD-2 → NOD2: "
Moreover, the NF-kappaB inhibitor Helenalin as well as a super-repressor form of the NF-kappaB inhibitor IkappaB strongly inhibited NOD2 mediated hBD-2 promoter activation
"
hBD-2 → NOD2: "
Expression of NOD2 was detected in primary keratinocytes, and stimulation of these cells with MDP induced hBD-2 peptide release
"
hBD-2 ⊣ NOD2: "
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
"
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