title: Pivotal role of protein tyrosine phosphatase 1B (PTP1B) in the macrophage response to pro-inflammatory and anti-inflammatory challenge.
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.
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain.
authors.forename: P G
authors.initials: PG
authors.lastname: Través
authors.affiliation: 1] Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain [2] Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (Ciberdem), ISCIII, Madrid, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Pardo
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Pimentel-Santillana
authors.affiliation: 1] Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain [2] Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (Ciberdem), ISCIII, Madrid, Spain.
authors.forename: Á
authors.initials: Á
authors.lastname: González-Rodríguez
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Mojena
authors.affiliation: Structural Biology and Biocomputing Programme, Spanish National Cancer Research Center (CNIO), ISCIII, Madrid, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Rico
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain.
authors.forename: Y
authors.initials: Y
authors.lastname: Montenegro
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Calés
authors.affiliation: 1] Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain [2] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), ISCIII, Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Martín-Sanz
authors.affiliation: 1] Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain [2] Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (Ciberdem), ISCIII, Madrid, Spain.
authors.forename: A M
authors.initials: AM
authors.lastname: Valverde
authors.affiliation: 1] Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain [2] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), ISCIII, Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Boscá
mesh_terms: D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005688:Galactosamine; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016159:Tumor Suppressor Protein p53; D005688:Galactosamine; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse