title: Homocysteine triggers mucosal microvascular activation in inflammatory bowel disease.
abstract: OBJECTIVE
  Increased homocysteine contributes to the pathophysiology of several chronic inflammatory diseases. Whether homocysteine could participate in mucosal inflammation in inflammatory bowel disease (IBD) has not been explored yet. Our aims were to study the levels of plasma and mucosal homocysteine in IBD patients and to assess whether homocysteine can trigger an inflammatory reaction on human intestinal microvascular endothelial cells (HIMECs).
  
  
  METHODS
  Homocysteine was measured in the plasma, mucosal biopsy, and lamina propria mononuclear cell (LPMC) supernatants from normal and IBD subjects. HIMEC were cultured in presence of homocysteine, TNF-alpha, or folic acid, alone or in combination. Expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular cell adhesion molecule 1 was measured by flow cytometry and monocyte chemoattractant protein-1 (MCP-1) production by ELISA. Phosphorylation of p38 and p42/44 was assessed by immunoblot in HIMEC extracts. T-cell- and monocyte-HIMEC adhesion assays were used to evaluate the impact of homocysteine on leukocyte adhesion to intestinal endothelial cells.
  
  
  RESULTS
  Patients with IBD displayed significantly higher homocysteine plasma and mucosal levels than control subjects. IBD-derived LPMC released higher homocysteine than control-derived LPMC. Treatment of HIMEC with homocysteine, and synergistically with the combination of TNF-alpha and homocysteine, triggered HIMEC inflammation, resulting in VCAM-1 up-regulation, MCP-1 production, and p38 phosphorylation. These events lead to an increased capacity of HIMEC to adhere T- and monocyte cells and were blocked by folic acid treatment.
  
  
  CONCLUSIONS
  Homocysteine is increased in both the mucosa and plasma of patients with Crohn's disease and ulcerative colitis and contributes to the inflammatory state of the mucosal IBD endothelium. Therefore, homocysteine could play a proinflammatory role in IBD, which can be efficiently targeted by folic acid supplementation.
authors.affiliation: Department of Internal Medicine, Institute of General Pathology, Catholic University, Rome, Italy. sdanese@hotmail.com
authors.forename: Silvio
authors.initials: S
authors.lastname: Danese
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sgambato
authors.forename: Alfredo
authors.initials: A
authors.lastname: Papa
authors.forename: Franco
authors.initials: F
authors.lastname: Scaldaferri
authors.forename: Roberto
authors.initials: R
authors.lastname: Pola
authors.forename: Miquel
authors.initials: M
authors.lastname: Sans
authors.forename: Maria
authors.initials: M
authors.lastname: Lovecchio
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gasbarrini
authors.forename: Achille
authors.initials: A
authors.lastname: Cittadini
authors.forename: Antonio
authors.initials: A
authors.lastname: Gasbarrini
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018932:Chemokine CCL2 / Q000097:blood; D003093:Colitis, Ulcerative / Q000503:physiopathology*; D003424:Crohn Disease / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000503:physiopathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005492:Folic Acid / Q000097:blood; D006710:Homocysteine / Q000502:physiology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D007413:Intestinal Mucosa / Q000098:blood supply*; D007957:Leukocyte Adherence Inhibition Test; D008297:Male; D008833:Microcirculation / Q000503:physiopathology; D008875:Middle Aged; D012016:Reference Values; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood
chemical_list: D018932:Chemokine CCL2; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D006710:Homocysteine; D018799:Intercellular Adhesion Molecule-1; D005492:Folic Acid