Homocysteine up-regulates vascular transmembrane chemokine CXCL16 and induces CXCR6+ lymphocyte recruitment in vitro and in vivo.
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.
Postea
O
O
Institute for Molecular Cardiovascular Research, University Hospital, Aachen, Germany. potilia@gmx.de
Koenen
R R
RR
Hristov
M
M
Weber
C
C
Ludwig
A
A
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*
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