Expression of γ-IFN responsive genes in scavenger receptor over-expressing monocytes is associated with xanthomatosis

• Published in: Atherosclerosis Vol. 138; no. 2; pp. 335 - 345
• Main Authors: Grewal, Thomas, Boudreau, Mathieu, Roy, Madeleine, Chamberland, Ann, Lefebvre, Chantal, Lavigne, Jaques, Davignon, Jean, Minnich, Anne
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ireland Ltd 01.06.1998; Elsevier
• Subjects: Adult; Aged; Biological and medical sciences; Cells, Cultured; Chemokine CXCL10; Chemokines, CXC - biosynthesis; Chemokines, CXC - genetics; Disorders of blood lipids. Hyperlipoproteinemia; Female; Foam cell; Gene Expression Regulation; Humans; Interferon-gamma - metabolism; Interferon-Stimulated Gene Factor 3; IP-10; Macrophage activation; Male; Medical sciences; Membrane Proteins; Metabolic diseases; Middle Aged; Monocytes - metabolism; Receptors, Immunologic - biosynthesis; Receptors, Lipoprotein; Receptors, Scavenger; RNA, Messenger - analysis; Scavenger receptor; Scavenger Receptors, Class B; STAT1 α; Transcription Factors - biosynthesis; Transcription Factors - genetics; Xanthoma; Xanthomatosis - blood; Xanthomatosis - genetics; γ-Interferon; EDTA, ethylenediaminetetraacetic acid; EGF, epidermal growth factor; Xanthoma; hGBP, human GTP-binding protein; Foam cell; AcLDL, acetylated LDL; IP-10, γ-interferon-inducible protein 10; MCP-1, monocyte chemoattractant protein-1; STAT1 α; Macrophage activation; GAS, γ-interferon activation site; M-CSF, monocyte-colony stimulating factor; PDGF, platelet derived growth factor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; LDL, low density lipoprotein; Scavenger receptor; SR, scavenger receptor; STAT, signal transducer and activator of transcription; NF- κB, nuclear factor- κB; PBS, phosphate buffered saline; IP-10; FH, familial hypercholesterolemia; LPDS, lipoprotein deficient serum; γ-Interferon; γ-IFN, γ-interferon; IL, interleukin; TNF α, tumor necrosis factor α; LPS, lipopolysaccharide; OxLDL, oxidized LDL; FCS, fetal calf serum; PMA, phorbol 12-myristate 13-acetate; Human; Cell culture; Xanthomatosis; Skin disease; Metabolic diseases; Lipids; Hyperlipoproteinemia; Gene expression; Hereditary; Enzymopathy; Genetic determinism; Spumous cell; Hypercholesterolemia; Gene; Complication; Hyperlipemia; Dyslipemia; Gamma interferon; Macrophage
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/S0021-9150(98)00048-3

We have recently described an inherited over-expression of the macrophage scavenger receptor (SR) in blood monocytes from members of a kindred, only two of whom displayed extensive xanthomatosis. Using mRNA differential display we demonstrated abnormally high expression of the signal transducer and activator of transcription (STAT1 α) in monocytes from the proband II-2. Expression of γ-interferon inducible protein 10 (IP-10), a STAT1 α-responsive gene and mediator of inflammatory response, was also abnormally expressed in the monocytes from II-2. Over-expression of both genes was restricted to monocytes from II-2 and was not observed in monocytes from the clinically unaffected family members, unlike that of SR. Gel retardation assays with THP-1 cell extracts identified γ-IFN inducible DNA binding activity to three potential STAT1 DNA binding elements in the human IP-10 promoter region from nucleotides −245 to −188. Taken together these results suggest that γ-interferon mediated cell activation is responsible for STAT1 α-induced transcription of the IP-10 gene in THP-1 macrophages as well as in monocytes from II-2. Analysis of monocytes from familial hypercholesterolemic (FH) subjects, who frequently develop xanthomatosis, revealed a significant number of subjects with elevated STAT1 α and IP-10 expression. Our data suggest that the inflammatory effects of γ-IFN signaling could play a role in foam cell formation and xanthomatosis.