title: Homocysteine up-regulates vascular transmembrane chemokine CXCL16 and induces CXCR6+ lymphocyte recruitment in vitro and in vivo.
abstract: OBJECTIVE
  Hyperhomocysteinemia induces endothelial dysfunction and promotes atherosclerotic vascular disease. Infiltrates of activated macrophages and lymphocytes are observed in human and experimental atherosclerotic lesions, their emigration being guided by endothelial-leukocyte adhesion molecules and chemoattractants. The CXC-chemokine CXCL16 functions as an adhesion molecule by interacting with its receptor (CXCR6) and also as a scavenger for oxidized low density lipoprotein (oxLDL). We investigated the modulation of CXCL16 on cultured endothelial cells (EC) and the recruitment of CXCR6(+) lymphocytes in response to homocysteine (Hcy), in vitro and in vivo.
  
  
  RESULTS
  Hcy-stimulated EC show a significant increase in CXCL16 mRNA and protein expression. Incubation of EC with d,l-Hcy and l-Hcy significantly increased CXCR6(+) lymphocyte adhesion to EC while l-Cysteine (l-Cys) had no effect. Furthermore, EC stimulation with Hcy increased uptake of DiI-oxLDL. An anti-CXCL16 monoclonal antibody, antioxidants (Tiron) and PPAR-gamma agonists (Pioglitazone) considerably reduced CXCR6(+) lymphocyte adhesion and uptake of DiI-oxLDL. Upon injection in the peritoneal cavities of mice, l-Hcy and not l-Cys, increased the number of CXCR6(+) lymphocytes, which was reduced by coinjection with Pioglitazone or anti-human CXCL16 antibody.
  
  
  CONCLUSIONS
  Hyperhomocysteinemia up-regulates CXCL16 leading to increased recruitment of CXCR6(+) lymphocytes and scavenging of modified lipids via a potential involvement of a PPAR-gamma-dependent mechanism. CXCL16 may therefore contribute to the formation and progression of atherosclerotic lesions under conditions of hyperhomocysteinemia.
authors.affiliation: Institute for Molecular Cardiovascular Research, University Hospital, Aachen, Germany. potilia@gmx.de
authors.forename: O
authors.initials: O
authors.lastname: Postea
authors.forename: R R
authors.initials: RR
authors.lastname: Koenen
authors.forename: M
authors.initials: M
authors.lastname: Hristov
authors.forename: C
authors.initials: C
authors.lastname: Weber
authors.forename: A
authors.initials: A
authors.lastname: Ludwig
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D054427:Chemokine CXCL6 / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism; D054387:Receptors, CXCR / Q000378:metabolism*; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000975:Antioxidants; C106330:CXCR6 protein, human; D054427:Chemokine CXCL6; C482906:Cxcr6 protein, mouse; D008077:Lipoproteins, LDL; D047495:PPAR gamma; D054387:Receptors, CXCR; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D011991:Receptors, Virus; C099252:oxidized low density lipoprotein; D006710:Homocysteine