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.
Highlights
Several reports suggested that Protein tyrosine phosphatase 1B (PTP1B) is an important modulator of the activation process of macrophages restricting the time of pro-inflammatory signaling in response to TLR and to both type I and type II IFN signaling.[14,18,30,31,32]
Keeping in mind these ideas, we have investigated whether the deficiency of PTP1B in murine and human macrophages affects the regulation of the response of these cells to pro-inflammatory and anti-inflammatory stimuli
This enhanced activation in PTP1B KO macrophages was not restricted to Toll-like receptor 4 (TLR4) signaling and occurred in response to TLR2 and TLR3 challenge, confirming preliminary data in the Raw 264.7 macrophage cell line.[18]
Summary
PTP1B is a critical node of insulin signaling due to its ability to dephosphorylate and inactivate the insulin receptor, thereby switching off insulin signaling.[2,3] PTP1B-deficient mice are a unique model of insulin hypersensitivity due to enhanced insulin action.[4,5,6] These mice are protected against diet[4,6] and age-induced obesity and insulin resistance linked to a low grade of chronic inflammation in white adipose tissue.[7,8] PTP1B is involved in the control of immune cell signaling,[9,10] controlling cytokine signaling pathways by dephosphorylation of janus kinase 2 (JAK2), non-receptor tyrosine-protein kinase 2 (TYK2) and signal transducer and activator of transcription 5 (STAT5).[11,12] it has been reported that interleukin-4 (IL-4) induced PTP1B mRNA in a phosphatidylinositol 3-kinase (PI3K)-dependent manner and enhanced PTP1B protein stability to suppress IL-4induced STAT6 signaling.[13]. PTP1B-deficient mice exhibited an increase in monocyte/ macrophages in the spleen and the bone marrow.[14] This was due to a decreased threshold of response to macrophage colony-stimulating factor (M-CSF) by enhancing tyrosine phosphorylation of the activation loop of its receptor (M-CSF1R). In the absence of PTP1B tissue macrophages display an activated phenotype assessed by the increased expression of CD80 that has a role in the maintenance of inflammation. This effect might require developmental adaptations in macrophages since short-term treatment of mice with the PTP1B inhibitor suramin protects against apoptotic liver damage induced by CD95 and against endotoxic shock mediated by tumor necrosis factor-a (TNF-a).[15]
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