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Pivotal role of protein tyrosine phosphatase 1B (PTP1B) in the macrophage response to pro-inflammatory and anti-inflammatory challenge.
- Source :
-
Cell death & disease [Cell Death Dis] 2014 Mar 13; Vol. 5, pp. e1125. Date of Electronic Publication: 2014 Mar 13. - Publication Year :
- 2014
-
Abstract
- Inhibition of protein tyrosine phosphatase 1B (PTP1B) has been suggested as an attractive target to improve insulin sensitivity in different cell types. In the present work, we have investigated the effect of PTP1B deficiency on the response of human and murine macrophages. Using in vitro and in vivo approaches in mice and silencing PTP1B in human macrophages with specific siRNAs, we have demonstrated that PTP1B deficiency increases the effects of pro-inflammatory stimuli in both human and rodent macrophages at the time that decreases the response to alternative stimulation. Moreover, the absence of PTP1B induces a loss of viability in resting macrophages and mainly after activation through the classic pathway. Analysis of early gene expression in macrophages treated with pro-inflammatory stimuli confirmed this exacerbated inflammatory response in PTP1B-deficient macrophages. Microarray analysis in samples from wild-type and PTP1B-deficient macrophages obtained after 24 h of pro-inflammatory stimulation showed an activation of the p53 pathway, including the excision base repair pathway and the insulin signaling pathway in the absence of PTP1B. In animal models of lipopolysaccharide (LPS) and D-galactosamine challenge as a way to reveal in vivo inflammatory responses, animals lacking PTP1B exhibited a higher rate of death. Moreover, these animals showed an enhanced response to irradiation, in agreement with the data obtained in the microarray analysis. In summary, these results indicate that, although inhibition of PTP1B has potential benefits for the treatment of diabetes, it accentuates pro-inflammatory responses compromising at least macrophage viability.
- Subjects :
- Animals
Cell Survival
Cells, Cultured
Disease Models, Animal
Galactosamine
Gene Expression Profiling methods
Humans
Immunity, Innate
Inflammation chemically induced
Inflammation genetics
Inflammation immunology
Inflammation pathology
Lipopolysaccharides
Macrophages, Peritoneal immunology
Macrophages, Peritoneal pathology
Male
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Oligonucleotide Array Sequence Analysis
Protein Tyrosine Phosphatase, Non-Receptor Type 1 deficiency
Protein Tyrosine Phosphatase, Non-Receptor Type 1 genetics
RNA Interference
Signal Transduction
Time Factors
Transfection
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
Inflammation enzymology
Inflammation Mediators metabolism
Macrophage Activation
Macrophages, Peritoneal enzymology
Protein Tyrosine Phosphatase, Non-Receptor Type 1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 5
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 24625984
- Full Text :
- https://doi.org/10.1038/cddis.2014.90