Cardiovascular inflammation and lesion cell apoptosis: a novel connection via the interferon-inducible immunoproteasome.
OBJECTIVE
Increasing evidence suggests that chronic inflammation contributes to atherogenesis, and that acute inflammatory events cause plaque rupture, thrombosis, and myocardial infarction. The present studies examined how inflammatory factors, such as interferon-gamma (IFNgamma), cause increased sensitivity to apoptosis in vascular lesion cells.


RESULTS
Cells from the fibrous cap of human atherosclerotic lesions were sensitized by interferon-gamma (IFNgamma) to Fas-induced apoptosis, in a Bcl-X(L) reversible manner. Microarray profiling identified 72 INFgamma-induced transcripts with potential relevance to apoptosis. Half could be excluded because they were induced by IRF-1 overexpression, which did not sensitize to apoptosis. IFNgamma treatment strongly reduced Mcl-1, phospho-Bcl-2 (ser70), and phospho-Bcl-X(L) (ser62) protein levels. Candidate transcripts were modulated by siRNA, overexpression, or inhibitors to assess the effect on IFNgamma-induced Fas sensitivity. Surprisingly, siRNA knockdown of PSMB8 (LMP7), an "immunoproteasome" component, reversed IFNgamma-induced sensitivity to Fas ligation and prevented Fas/IFNgamma-induced degradation of Mcl-1, but did not protect p-Bcl-2 or p-Bcl-X(L). Proteasome inhibition markedly increased Mcl-1, p-Bcl-2, and p-Bcl-X(L) levels after IFNgamma treatment.


CONCLUSIONS
Although critical for antigen presentation, the immunoproteasome appears to be a key link between inflammatory factors and the control of vascular cell apoptosis and may thus be an important factor in plaque rupture and myocardial infarction.
Yang
Zhaoqing
Z
The George Washington Medical Center, Department of Biochemistry and Molecular Biology, 2300 I Street NW, Ross Hall 541, Washington, DC 20037, USA.
Gagarin
Dmitry
D
St Laurent
Georges
G
Hammell
Neil
N
Toma
Ian
I
Hu
Chien-An
CA
Iwasa
Ayaka
A
McCaffrey
Timothy A
TA
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D046988:Proteasome Endopeptidase Complex; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics
D009097:Multienzyme Complexes; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D051020:bcl-X Protein; D007371:Interferon-gamma; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex