Nucleotide binding oligomerization domain 2 deficiency leads to dysregulated TLR2 signaling and induction of antigen-specific colitis.

Abstract

In this study, we determined conditions leading to the development of colitis in mice with nucleotide binding oligomerization domain 2 (NOD2) deficiency, a susceptibility factor in Crohn's disease. We found that NOD2-deficient antigen-presenting cells (APCs) produced increased amounts of interleukin (IL)-12 in the presence of ovalbumin (OVA) peptide and peptidoglycan or recombinant E. coli that express OVA peptide (ECOVA). Furthermore, these APCs elicited heightened interferon-gamma (IFN-gamma) responses from cocultured OVA-specific CD4+ T cells. We then demonstrated that NOD2-deficient mice adoptively transferred OVA-specific CD4+ T cells and that administered intrarectal ECOVA developed colitis associated with the expansion of OVA-specific CD4+ T cells producing IFN-gamma. Importantly, this colitis was highly dependent on Toll-like receptor 2 (TLR2) function since it was suppressed in NOD2 and TLR2 double-deficient mice. Thus, NOD2-deficient mice become susceptible to colitis as a result of increased TLR2 responses when they have the capacity to respond to an antigen expressed by mucosal bacteria.

• Authors: Tomohiro Watanabe, Atsushi Kitani, Peter J Murray, Yoshio Wakatsuki, Ivan J Fuss, Warren Strober
• Journal: Immunity (Immunity) Vol. 25 Issue 3 Pg. 473-85 (Sep 2006) ISSN: 1074-7613 [Print] United States
• PMID: 16949315 (Publication Type: Journal Article)

Chemical References

• Antigens, Bacterial
• Epitopes
• Intracellular Signaling Peptides and Proteins
• NOD2 protein, human
• Nod2 Signaling Adaptor Protein
• TLR2 protein, human
• Toll-Like Receptor 2

Topics

• Animals
• Antigen-Presenting Cells (immunology, metabolism)
• Antigens, Bacterial (immunology)
• Cells, Cultured
• Colitis (genetics, immunology, metabolism)
• Epitopes (immunology)
• Humans
• Inflammatory Bowel Diseases (genetics, immunology, metabolism)
• Intestinal Mucosa (immunology, microbiology)
• Intracellular Signaling Peptides and Proteins (deficiency, genetics, physiology)
• Male
• Mice
• Mice, Knockout
• Mice, Transgenic
• Nod2 Signaling Adaptor Protein
• Protein Structure, Tertiary (genetics)
• Signal Transduction (genetics)
• Toll-Like Receptor 2 (deficiency, genetics, physiology)