Extracellular matrix protein lumican regulates inflammation in a mouse model of colitis.

Abstract

BACKGROUND:

Abnormal innate immune response contributes to inflammatory bowel disease (IBD) and experimental mouse colitis. Colitis studies have focused primarily on key regulators of innate immunity, like pathogen recognition receptors and cytoplasmic mediators. Extracellular matrix (ECM) proteins are emerging as modulators of inflammatory responses by virtue of their interactions with pathogen-associated molecular patterns (PAMPs), cytokines, growth factors, receptors, and ECM fragments that mimic pathogens or cytokines. The ECM proteins have not been investigated in IBD at great depth from this standpoint. We have shown previously that the ECM protein lumican modulates host sensing of bacterial lipopolysaccharides (LPS) by Toll-like receptor (TLR) 4, and neutrophil chemotaxis via integrins.

METHODS:

Here we investigated the role of lumican in the development of colitis mediated by intrarectal administration of the hapten 2-4-5, trinitrobenzene sulfonic acid (TNBS) in Lum(+/+) and Lum(-/-) mice.

RESULTS:

The TNBS treated Lum(+/+) mouse colons showed marked increases in CXCL1, tumor necrosis factor alpha (TNF-α), and neutrophil infiltration, whereas these responses were significantly dampened in the Lum(-/-) mice. The nuclear factor kappa B (NF-κB) transcription factor, known to regulate inflammatory genes, showed a robust increase after TNBS treatment in Lum(+/+) but not in Lum(-/-) colons. Also, nuclear translocation of NF-κB was delayed in LPS stimulated Lum(-/-) primary peritoneal macrophages.

CONCLUSIONS:

The Lum(-/-) mice have low innate immune and inflammatory responses, but more severe body weight loss and tissue damage, a phenomenon seen in the innate immune impaired Tlr4(-/-) and MyD88(-/-) mice. Therefore, lumican promotes intestinal homeostasis by aiding innate immune and inflammatory responses that are beneficial in the early stages of colitis.

• Authors: Kristin Lohr, Hardik Sardana, Seakwoo Lee, Feng Wu, David L Huso, Abdel Rahim Hamad, Shukti Chakravarti
• Journal: Inflammatory bowel diseases (Inflamm Bowel Dis) Vol. 18 Issue 1 Pg. 143-51 (Jan 2012) ISSN: 1536-4844 [Electronic] England
• PMID: 21484968 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.

Chemical References

• Chondroitin Sulfate Proteoglycans
• Cytokines
• Haptens
• Lipopolysaccharides
• Lum protein, mouse
• Lumican
• NF-kappa B
• Toll-Like Receptor 4
• Tumor Necrosis Factor-alpha
• Trinitrobenzenesulfonic Acid
• Keratan Sulfate

Topics

• Animals
• Blotting, Western
• Chondroitin Sulfate Proteoglycans (physiology)
• Colitis (etiology, metabolism, pathology)
• Cytokines (metabolism)
• Disease Models, Animal
• Electrophoretic Mobility Shift Assay
• Female
• Flow Cytometry
• Haptens (toxicity)
• Inflammation (etiology, metabolism, pathology)
• Keratan Sulfate (physiology)
• Lipopolysaccharides (pharmacology)
• Lumican
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (metabolism)
• Toll-Like Receptor 4 (metabolism)
• Trinitrobenzenesulfonic Acid (toxicity)
• Tumor Necrosis Factor-alpha