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Expression of gamma-IFN responsive genes in scavenger receptor over-expressing monocytes is associated with
1Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal, Quebec, Canada. grewal@uke.uni-hamburg.de
Abstract:
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 (STAT1alpha) in monocytes from the proband II-2. Expression of gamma-interferon inducible protein 10 (IP-10), a STAT1alpha-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 gamma-IFN inducible DNA binding activity to three potential STATI DNA binding elements in the human IP-10 promoter region from nucleotides - 245 to - 188. Taken together these results suggest that gamma-interferon mediated cell activation is responsible for STAT1alpha-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 STAT1alpha and IP-10 expression. Our data suggest that the inflammatory effects of gamma-IFN signaling could play a role in foam cell formation and xanthomatosis.
Insights
Inherited macrophage scavenger receptor (SR) over-expression linked to xanthomatosis. Elevated signal transducer and activator of transcription 1-alpha (STAT1alpha) and gamma-interferon inducible protein 10 (IP-10) in monocytes suggest inflammation
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- Inherited macrophage scavenger receptor (SR) over-expression is linked to xanthomatosis.
- Signal transducer and activator of transcription 1-alpha (STAT1alpha) and its responsive gene, gamma-interferon inducible protein 10 (IP-10), were investigated.
Purpose of the Study:
- To investigate the role of STAT1alpha and IP-10 in familial hypercholesterolemia and xanthomatosis.
- To explore the mechanism of gamma-interferon signaling in monocyte activation.
Main Methods:
- mRNA differential display to identify over-expressed genes.
- Gel retardation assays to analyze DNA binding activity.
- Monocyte analysis from familial hypercholesterolemia subjects.
Main Results:
- Abnormally high expression of STAT1alpha and IP-10 found in monocytes of a proband with xanthomatosis.
- STAT1alpha-induced transcription of IP-10 mediated by gamma-interferon signaling confirmed.
- Elevated STAT1alpha and IP-10 expression observed in familial hypercholesterolemia subjects.
Conclusions:
- Gamma-interferon signaling may contribute to foam cell formation and xanthomatosis.
- STAT1alpha and IP-10 over-expression in monocytes could be a key factor in xanthomatosis development.
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