title: 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.affiliation: Gastroenterology Division, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Lohr
authors.forename: Hardik
authors.initials: H
authors.lastname: Sardana
authors.forename: Seakwoo
authors.initials: S
authors.lastname: Lee
authors.forename: Feng
authors.initials: F
authors.lastname: Wu
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.forename: Abdel Rahim
authors.initials: AR
authors.lastname: Hamad
authors.forename: Shukti
authors.initials: S
authors.lastname: Chakravarti
mesh_terms: D000818:Animals; D015153:Blotting, Western; D011508:Chondroitin Sulfate Proteoglycans / Q000502:physiology*; D003092:Colitis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005434:Flow Cytometry; D006241:Haptens / Q000633:toxicity; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007632:Keratan Sulfate / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D000071234:Lumican; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D016207:Cytokines; D006241:Haptens; D008070:Lipopolysaccharides; C000604307:Lum protein, mouse; D000071234:Lumican; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D014302:Trinitrobenzenesulfonic Acid; D007632:Keratan Sulfate