CXCL16/SR-PSOX Is an Interferon-γ–Regulated Chemokine and Scavenger Receptor Expressed in Atherosclerotic Lesions

Abstract

Objective-Atherosclerosis is an inflammatory disease. Several chemokines are important for monocyte/macrophage and T-cell recruitment to the lesion. CXCL16 is a recently discovered chemokine that is expressed in soluble and transmembrane forms, ligates CXCR6 chemokine receptor, and guides migration of activated Th1 and Tc1 cells. It is identical to scavenger receptor SR-PSOX, which mediates uptake of oxidized low-density lipoprotein. We investigated whether CXCL16 expression is controlled by interferon-␥ (IFN-␥)-cytokine abundant in atherosclerotic lesions. Methods and Results-CXCL16 and CXCR6 expression was identified by polymerase chain reaction and histochemistry in atherosclerotic lesions from humans and apolipoprotein-E-deficient mice. In vitro IFN-␥ induced CXCL16 in human monocytic THP-1 cells and primary human monocytes, which led to increased uptake of oxidized low-density lipoprotein in THP-1 cells, which could be blocked by peptide antibodies against CXCL16. In vivo IFN-␥ induced CXCL16 expression in murine atherosclerotic lesions. Conclusions-We

Site‐directed mutagenesis of the chemokine receptor CXCR6 suggests a novel paradigm for interactions with the ligand CXCL16

“…Both CXCR6 and its ligand CXCL16 have been implicated in the pathogenesis of atherosclerosis by virtue of their expression within the atherosclerotic lesions of humans and apolipoprotein Edeficient mice [8,24]. Recent data from studies using mice deficient in either CXCR6 or CXCL16 support a role for both ligand and receptor in atherogenesis [25,26].…”

Pathogenic role of the CXCL16–CXCR6 pathway in rheumatoid arthritis

“…Firststrand complementary DNA (cDNA) was synthesized using oligo(dT) [12][13][14][15][16][17][18] primers (Amersham Pharmacia Biotech, Piscat-away, NJ) and SuperScript II reverse transcriptase (Invitrogen). The amount of cDNA for amplification was adjusted to the amount of RNA measured by optical density meter as well as ␤-actin polymerase chain reaction (PCR) products, using serially diluted cDNA.…”

ERK Is Integral to the IFN-γ–Mediated Activation of STAT1, the Expression of Key Genes Implicated in Atherosclerosis, and the Uptake of Modified Lipoproteins by Human Macrophages

“…We therefore determined the effect of the ERK1/2 inhibitor PD98059 on the IFN-g-induced uptake of AcLDL by THP-1 macrophages. THP-1 macrophages are used extensively to study macrophage foam cell formation, including the action of IFN-g, and express all the major proteins involved in this process, including scavenger receptors (8,(19)(20)(21). Initial experiments showed that maximal AcLDL uptake occurred at 24 h, which was therefore used for all subsequent experiments.…”