Constitutive TLR4 signalling in intestinal epithelium reduces tumor load by increasing apoptosis in APC(Min/+) mice.

Abstract

The microbial pattern-recognizing Toll-like receptors (TLRs) are major signal transducers known to shape and influence the postnatal maturation of host intestinal epithelium. Perturbations in this intricate host-microbe cross-talk have been reported to be associated with uncontrolled epithelial cell growth and thus potential cancer development by mechanisms which are largely unknown. We therefore generated transgenic mice carrying a constitutively active TLR4 (CD4-TLR4) linked to an intestinal epithelial cell-specific promoter. Ex vivo analysis of transgenic crypt-villus organoid cultures revealed an increased proliferative capacity and a lowered cyclooxygenase 2 (Cox-2) expression in these organoids compared with wild-type control cultures. Introducing the CD4-TLR4 transgene into APC(Min/+) mice (CD4-TLR4-APC(Min/+)), a model of colorectal carcinoma, resulted in a dramatic drop in tumor load as compared with control APC(Min/+) mice. Intestinal tumors from CD4-TLR4-APC(Min/+) mice displayed reduced Cox-2 protein, elevated interferon β expression and increased caspase-3 activity, which correlated with increased apoptosis in vivo. Thus, our data reveal that host microbiota-mediated signal transduction via TLR4 in intestinal epithelial cells is far more complex than what is previously reported.

• Authors: Y Li, W L Teo, M J Low, L Meijer, I Sanderson, S Pettersson, G Greicius
• Journal: Oncogene (Oncogene) Vol. 33 Issue 3 Pg. 369-77 (Jan 16 2014) ISSN: 1476-5594 [Electronic] England
• PMID: 23318418 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adenomatous Polyposis Coli Protein
• Toll-Like Receptor 4
• Interferon-beta
• Cyclooxygenase 2
• Caspase 3

Topics

• Adenomatous Polyposis Coli Protein (genetics, metabolism)
• Animals
• Apoptosis
• Caspase 3 (metabolism)
• Cell Transformation, Neoplastic (genetics, metabolism)
• Cells, Cultured
• Colorectal Neoplasms (genetics, metabolism, pathology)
• Cyclooxygenase 2 (metabolism)
• Female
• Humans
• Immunoblotting
• Immunohistochemistry
• Interferon-beta (metabolism)
• Intestinal Mucosa (metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Mice, Transgenic
• Organoids (cytology, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Toll-Like Receptor 4 (genetics, metabolism)
• Tumor Burden (genetics)