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IFN regulatory factor-2 regulates macrophage apoptosis through a STAT1/3- and caspase-1-dependent mechanism
- Source :
- ResearcherID
- Publication Year :
- 2007
-
Abstract
- IFN regulatory factor (IRF)-2−/− mice are significantly more resistant to LPS challenge than wild-type littermates, and this was correlated with increased numbers of apoptotic Kupffer cells. To assess the generality of this observation, and to understand the role of IRF-2 in apoptosis, responses of peritoneal macrophages from IRF-2+/+ and IRF-2−/− mice to apoptotic stimuli, including the fungal metabolite, gliotoxin, were compared. IRF-2−/− macrophages exhibited a consistently higher incidence of apoptosis that failed to correlate with caspase-3/7 activity. Using microarray gene expression profiling of liver RNA samples derived from IRF-2+/+ and IRF-2−/− mice treated with saline or LPS, we identified >40 genes that were significantly down-regulated in IRF-2−/− mice, including Stat3, which has been reported to regulate apoptosis. Compared with IRF-2+/+ macrophages, STAT3α mRNA was up-regulated constitutively or after gliotoxin treatment of IRF-2−/− macrophages, whereas STAT3β mRNA was down-regulated. Phospho-Y705-STAT3, phospho-S727-STAT1, and phospho-p38 protein levels were also significantly higher in IRF-2−/− than control macrophages. Activation of the STAT signaling pathway has been shown to elicit expression of CASP1 and apoptosis. IRF-2−/− macrophages exhibited increased basal and gliotoxin-induced caspase-1 mRNA expression and enhanced caspase-1 activity. Pharmacologic inhibition of STAT3 and caspase-1 abolished gliotoxin-induced apoptosis in IRF-2−/− macrophages. A novel IFN-stimulated response element, identified within the murine promoter of Casp1, was determined to be functional by EMSA and supershift analysis. Collectively, these data support the hypothesis that IRF-2 acts as a transcriptional repressor of Casp1, and that the absence of IRF-2 renders macrophages more sensitive to apoptotic stimuli in a caspase-1-dependent process.
- Subjects :
- Lipopolysaccharides
STAT3 Transcription Factor
Kupffer Cells
Immunology
Response element
Caspase 1
Down-Regulation
Apoptosis
chemistry.chemical_compound
Mice
Gliotoxin
Immunology and Allergy
Animals
STAT1
STAT3
Promoter Regions, Genetic
Cells, Cultured
Caspase 7
Mice, Knockout
Messenger RNA
biology
Caspase 3
RNA
Molecular biology
Cell biology
Repressor Proteins
STAT1 Transcription Factor
chemistry
biology.protein
Macrophages, Peritoneal
Immunosuppressive Agents
Interferon Regulatory Factor-2
Subjects
Details
- ISSN :
- 00221767
- Volume :
- 178
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Accession number :
- edsair.doi.dedup.....4370b2ec43e22e5326f36be9fc562664