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Regulation of macrophage‐specific gene expression by degenerated lipoproteins
Author(s) -
Furukawa Yusuke,
Kubo Nobuhiko,
Kikuchi Jiro,
Tokura Akihiko,
Fujita Nobuya,
Sakurabayashi Ikunosuke
Publication year - 2000
Publication title -
electrophoresis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.666
H-Index - 158
eISSN - 1522-2683
pISSN - 0173-0835
DOI - 10.1002/(sici)1522-2683(20000101)21:2<338::aid-elps338>3.0.co;2-9
Subject(s) - downregulation and upregulation , microbiology and biotechnology , foam cell , apoptosis , biology , macrophage , programmed cell death , gene expression , chemistry , gene , biochemistry , in vitro
The effect of aggregated low‐density lipoprotein (agLDL) on cell viability and macrophage‐specific gene expression using human peripheral blood monocytes in culture was investigated. AgLDL suppressed activation‐induced cell death of phorbol ester‐treated macrophages. The inhibition of apoptosis was accompanied by downregulation of apoptosis‐promoting proteases, including interleukin‐1β‐converting enzyme (ICE) and CPP32 and upregulation of anti‐apoptotic cytokine (interleukin‐1β (IL‐1β)). In contrast, macrophage‐colony stimulating factor (M‐CSF) enhanced cell death of lipid‐bearing macrophages, suggesting that the anti‐atherogenic action of M‐CSF is at least in part mediated through apoptotic elimination of macrophages. Then, we attempted to isolate the genes specifically induced by agLDL in macrophages using a subtraction‐based cloning strategy. One of the genes isolated, termed LIG (LDL‐inducible gene), encodes a human homolog of E2 ubiquitin‐conjugating enzyme. Ubiquitination of multiple intracellular proteins was observed in agLDL‐treated macrophages, which coincided with upregulation of LIG. These results suggest that LIG acts as a direct mediator of foam cell formation through polyubiquitination and subsequent degradation of cellular proteins with apoptosis‐inducing properties. The regulation of apoptosis by macrophage‐specific gene expression may contribute to foam cell formation and atherosclerosis.