Modulating Toll-like receptor 4 signaling pathway protects mice from experimental colitis.

Abstract

BACKGROUND/AIM:

Several reports have indicated that environmental factors and defects in innate immunity are central to the pathogenesis of inflammatory bowel disease (IBD). Although bacteria producing lipopolysaccharide (LPS), which is a Toll-like receptor (TLR) 4 agonist, play a crucial role in the development of experimental colitis, LPS tolerance following initial exposure to LPS can result in a state of hyporesponsiveness to subsequent LPS challenge. Therefore, we initiated this study to explore the role of LPS tolerance in the development of colitis.

METHODS:

Dextran sulfate sodium (DSS) colitis was induced in Balb/c mice with or without daily intraperitoneal administration of LPS. Disease activity and cytokine mRNA expression in the colon were evaluated. To confirm LPS tolerance, mouse conventional bone marrow-derived dendritic cells (BMDC) were preincubated with or without LPS, and were restimulated with LPS 24 h after first exposure. Cytokine production was measured by ELISA, and mRNA expression was evaluated by RT-PCR. Furthermore, we investigated the expression of negative regulators of LPS tolerance in BMDC.

RESULTS:

Administration of LPS significantly suppressed colonic inflammation of DSS-induced colitis. After subsequent stimulation with LPS, TNF-α production was reduced in BMDC. IRAK-M, a negative regulator of TLR4 signaling, mRNA expression was up-regulated in LPS-treated BMDC.

CONCLUSION:

LPS tolerance was able to protect mice from DSS-induced colitis, and IRAK-M participated in this tolerance. Taken together, these observations suggest that loss of exposure to LPS is involved in the pathogenesis of IBD.

• Authors: Keietsu Saito, Kyoko Katakura, Ryoma Suzuki, Toshimitsu Suzuki, Hiromasa Ohira
• Journal: Fukushima journal of medical science (Fukushima J Med Sci) Vol. 59 Issue 2 Pg. 81-8 ( 2013) ISSN: 2185-4610 [Electronic] Japan
• PMID: 24500383 (Publication Type: Journal Article)

Chemical References

• Cytokines
• Lipopolysaccharides
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Dextran Sulfate

Topics

• Animals
• Cells, Cultured
• Colitis (chemically induced, immunology, prevention & control)
• Cytokines (biosynthesis)
• Dextran Sulfate
• Female
• Lipopolysaccharides (pharmacology)
• Mice
• Mice, Inbred BALB C
• Signal Transduction (physiology)
• Toll-Like Receptor 4 (physiology)