Crohn’s disease and the NOD2 gene: a role for paneth cells

Lala, Sanjay G.; Ogura, Yasunori; Osborne, Caroline; Hor, Sok Ying; Bromfield, A; Davies, Susan; Ogunbiyi, Olagunju; Núñez, Gabriel; Keshav, Satish

doi:10.1016/s0016-5085(03)00661-9

Cited by 473 publications

(315 citation statements)

References 27 publications

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“…The Crohn's disease-associated mutations in CARD15/NOD2 result in decreased responsiveness to bacterial muramyl dipeptide (56,57). Recent data demonstrate that CARD15/NOD2 is highly expressed by Paneth cells (58) and have antibacterial properties (59). Some have suggested that deficiency in antimicrobial peptide expression may contribute to the pathogenesis of Crohn's disease (60).…”

Section: Discussionmentioning

confidence: 99%

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

Vora¹,

Youdim²,

Thomas³

et al. 2004

The Journal of Immunology

319

225

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The intestinal epithelium serves as a barrier to the intestinal flora. In response to pathogens, intestinal epithelial cells (IEC) secrete proinflammatory cytokines. To aid in defense against bacteria, IEC also secrete antimicrobial peptides, termed defensins. The aim of our studies was to understand the role of TLR signaling in regulation of β-defensin expression by IEC. The effect of LPS and peptidoglycan on β-defensin-2 expression was examined in IEC lines constitutively or transgenically expressing TLRs. Regulation of β-defensin-2 was assessed using promoter-reporter constructs of the human β-defensin-2 gene. LPS and peptidoglycan stimulated β-defensin-2 promoter activation in a TLR4- and TLR2-dependent manner, respectively. A mutation in the NF-κB or AP-1 site within the β-defensin-2 promoter abrogated this response. In addition, inhibition of Jun kinase prevents up-regulation of β-defensin-2 protein expression in response to LPS. IEC respond to pathogen-associated molecular patterns with expression of the antimicrobial peptide β-defensin-2. This mechanism may protect the intestinal epithelium from pathogen invasion and from potential invaders among the commensal flora.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Vora¹,

Youdim²,

Thomas³

et al. 2004

The Journal of Immunology

319

225

View full text Add to dashboard Cite

show abstract

“…3). Nod2 is highly expressed by monocytes and Paneth cells (80). Expression of Nod2 can be induced by IFN-␥ and TNF-␣ in intestinal epithelial cells (81,82) and is seen in the inflamed colon in Crohn's disease (83).…”

Section: Nod Proteins and Their Role In Intestinal Defensementioning

confidence: 99%

TLR Signaling in the Gut in Health and Disease

Abreu

Fukata

Arditi

2005

The Journal of Immunology

528

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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“…Regarding initial defenses, a defect in bacterial recognition and responses at the intestinal epithelial surface might result in alterations in the population of commensal organisms, and/or increased invasion, which in turn, could contribute to an increased propensity toward intestinal inflammation. Nod2 is highly expressed in Paneth cells of the small intestine [54,55] and Nod2 mutations are associated with ileal location of disease [56] . Studies in humans and mice have shown that normal Nod2 function is required for optimal defensin expression and therefore, impaired defensin expression and regulation may contribute to the increased CD susceptibility observed in Nod2 risk allele carriers [57][58][59] .…”

Section: Nod2 (Card15) Associations To Ileal CDmentioning

confidence: 99%

Inflammatory bowel disease: Genetic and epidemiologic considerations

Cho

2008

WJG

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Genome-wide association studies have firmly established that many genomic loci contribute to inflammatory bowel disease, especially in Crohn's disease. These studies have newly-established the importance of the interleukin 23 and autophagy pathways in disease pathogenesis. Future challenges include: (1) the establishment of precisely causal alleles, (2) definition of altered functional outcomes of associated and causal alleles and (3) integration of genetic findings with environmental factors.

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Crohn’s disease and the NOD2 gene: a role for paneth cells

Cited by 473 publications

References 27 publications

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

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

TLR Signaling in the Gut in Health and Disease

Inflammatory bowel disease: Genetic and epidemiologic considerations

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