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Cardiovascular inflammation and lesion cell apoptosis: a novel connection via the interferon-inducible immunoproteasome.

ABSTRACT: 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.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.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.

SUBMITTER: Yang Z

PROVIDER: S-EPMC2762196 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Cardiovascular inflammation and lesion cell apoptosis: a novel connection via the interferon-inducible immunoproteasome.

Yang Zhaoqing Z Gagarin Dmitry D St Laurent Georges G Hammell Neil N Toma Ian I Hu Chien-An CA Iwasa Ayaka A McCaffrey Timothy A TA

Arteriosclerosis, thrombosis, and vascular biology 20090514 8

<h4>Objective</h4>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.<h4>Methods and results</h4>Cells from the fibrous cap of human atherosclerotic lesions were sensitized by interferon-gamma (IFNgamma) to Fas-i ...[more]

PMID: 19443843

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Project description:BACKGROUND:In early autoimmune neuroinflammation, interferon (IFN)? and its upregulation of the immunoproteasome (iP) is pathologic. However, during chronic multiple sclerosis (MS), IFN? has protective properties. Although dysregulation of the iP has been implicated in neurodegeneration, its function remains to be fully elucidated. Here, we demonstrate that IFN? signaling in regional astrocytes induces the iP and promotes protection of the CNS during chronic autoimmunity. METHODS:In a multiple sclerosis (MS) brain, we evaluated mRNA expression and labeled postmortem MS brainstem and spinal cord for iP subunits and indicators of oxidative stress. Primary regional human astrocytes were analyzed for iP regulation and function by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot, OxyBlot, and reactive oxygen species and caspase activity detection assays. Following immunization with myelin oligodendrocyte glycoprotein (MOG)35-55, the role of IFN? signaling and the iP during chronic experimental autoimmune encephalomyelitis (EAE) were assessed using pharmacologic inhibition of the iP and genetic interruption of IFN? signaling specifically in astrocytes. Central nervous system (CNS) tissues were analyzed by immunohistochemistry (IHC) and immunofluorescence, and cell-specific colocalization was quantified. RESULTS:In MS tissue, iP expression was enhanced in the spinal cord compared to brainstem lesions, which correlated with a decrease in oxidative stress. In vitro, IFN? stimulation enhanced iP expression, reduced reactive oxygen species burden, and decreased oxidatively damaged and poly-ubiquitinated protein accumulation preferentially in human spinal cord astrocytes, which was abrogated with the use of the iP inhibitor, ONX 0914. During the chronic phase of an MS animal model, EAE, ONX 0914 treatment exacerbated the disease and led to increased oxidative stress and poly-ubiquitinated protein buildup. Finally, mice with astrocyte-specific loss of the IFN? receptor exhibited worsened chronic EAE associated with reduced iP expression, enhanced lesion size and oxidative stress, and poly-ubiquitinated protein accumulation in astrocytes. CONCLUSIONS:Taken together, our data reveal a protective role for IFN? in chronic neuroinflammation and identify a novel function of the iP in astrocytes during CNS autoimmunity.

Dataset Information

Cardiovascular inflammation and lesion cell apoptosis: a novel connection via the interferon-inducible immunoproteasome.

Publications

Cardiovascular inflammation and lesion cell apoptosis: a novel connection via the interferon-inducible immunoproteasome.

Similar Datasets

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