title: Regulation of colonic epithelial repair in mice by Toll-like receptors and hyaluronic acid.
abstract: OBJECTIVE
  The protective component of the host response to dextran sodium sulfate (DSS)-induced colitis in the mouse is mediated through the activation of Toll-like receptor (TLR) 4, the induction of cyclooxygenase (COX)-2, and prostaglandin E(2) production. TLR4 ligands include bacterial lipopolysaccharide and hyaluronic acid, a component of the extracellular matrix. Our hypothesis is that hyaluronic acid, through TLRs, plays a protective role in the host response to DSS-induced colitis.
  
  
  METHODS
  DSS (2.5%) was administered for 7 days in wild-type and MyD88(-/-) mice. The mice also received intraperitoneal hyaluronic acid. The expression of hyaluronic acid, COX-2, and macrophage inflammatory protein (MIP)-2 was evaluated by immunohistochemistry.
  
  
  RESULTS
  DSS induced a marked increase in hyaluronic acid in the lamina propria of wild-type but not MyD88(-/-) mice. Treatment with DSS also induced the MyD88-dependent expression of hyaluronic acid synthases 2 and 3, enzymes involved in hyaluronic acid synthesis, in lamina propria macrophages. Exogenous hyaluronic acid induced the expression of tumor necrosis factor alpha, MIP-2, and COX-2 in the colon in a MyD88-dependent manner. In wild-type but not MyD88(-/-), TLR4(-/-), COX-2(-/-) mice, hyaluronic acid was protective against DSS-induced colitis. In wild-type mice, hyaluronic acid was therapeutic in established DSS-induced colitis.
  
  
  CONCLUSIONS
  Endogenous hyaluronic acid expression is markedly increased in DSS-induced colitis and preserves the epithelium through TLR activation and COX-2 expression. Furthermore, exogenous hyaluronic acid, through the activation of TLRs and the production of prostaglandin E(2) through COX-2, has protective effects in DSS-induced colitis.
authors.affiliation: Division of Gastroenterology, Washington University, St Louis, Missouri, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Zheng
authors.forename: Terrence E
authors.initials: TE
authors.lastname: Riehl
authors.forename: William F
authors.initials: WF
authors.lastname: Stenson
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000378:metabolism*; D049109:Cell Proliferation; D054426:Chemokine CXCL2 / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008024:Ligands; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000893:Anti-Inflammatory Agents; C476399:Cd44 protein, mouse; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D018960:Hyaluronan Receptors; D008024:Ligands; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D006820:Hyaluronic Acid; D016264:Dextran Sulfate; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D014453:Glucuronosyltransferase; C491099:Has2 protein, mouse; C491356:Has3 protein, mouse; D000076002:Hyaluronan Synthases