Regulation of macrophage-specific gene expression by degenerated lipoproteins.
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-1beta-converting enzyme (ICE) and CPP32 and upregulation of anti-apoptotic cytokine (interleukin-1beta (IL-1beta)). 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.
Furukawa
Y
Y
Division of Molecular Hemopoiesis, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan. furuyu@jichi.ac.jp
Kubo
N
N
Kikuchi
J
J
Tokura
A
A
Fujita
N
N
Sakurabayashi
I
I
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects* / Q000235:genetics; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology*; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics
D008077:Lipoproteins, LDL; D011506:Proteins