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Homocysteine Triggers Mucosal Microvascular Activation in Inflammatory Bowel Disease

Danese, Silvio, M.D.; Sgambato, Alessandro, M.D.; Papa, Alfredo, M.D.; Scaldaferri, Franco, M.D.; Pola, Roberto, M.D.; Sans, Miquel, M.D.; Lovecchio, Maria, M.D.; Gasbarrini, Giovanni, M.D.; Cittadini, Achille, M.D.; Gasbarrini, Antonio, M.D.

American Journal of Gastroenterology: April 2005 - Volume 100 - Issue 4 - p 886–895

OBJECTIVES 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-α, 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-α 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.

Department of Internal Medicine; Institute of General Pathology, Catholic University, Rome, Italy; and Hospital Clinic, Division of Gastroenterology, Barcelona, Spain

Reprint requests and correspondence: Silvio Danese, M.D., Department of Internal Medicine, Catholic University School of Medicine, L.go Vito 1, 00168 Rome, Italy, email:

Received September 8, 2004; accepted October 20, 2004.

© The American College of Gastroenterology 2005. All Rights Reserved.
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