The Glutathione Peroxidase 1–Protein Tyrosine Phosphatase 1B–Protein Phosphatase 2A Axis. A Key Determinant of Airway Inflammation and Alveolar Destruction

Abstract

Protein phosphatase-2A (PP2A) is a primary serine-threonine phosphatase that modulates inflammatory responses in asthma and chronic obstructive pulmonary disease (COPD). Despite its importance, the mechanisms that regulate lung PP2A activity remain to be determined. The redox-sensitive enzyme protein tyrosine phosphatase-1B (PTP1B) activates PP2A by dephosphorylating the catalytic subunit of the protein at tyrosine 307. This study aimed to identify how the interaction between the intracellular antioxidant glutathione peroxidase-1 (GPx-1) and PTP1B affected lung PP2A activity and airway inflammation. Experiments using gene silencing techniques in mouse lung or human small airway epithelial cells determined that knocking down PTP1B expression blocked GPx-1's activation of PP2A and negated the anti-inflammatory effects of GPx-1 protein in the lung. Similarly, the expression of human GPx-1 in transgenic mice significantly increased PP2A and PTP1B activities and prevented chronic cigarette smoke-induced airway inflammation and alveolar destruction. GPx-1 knockout mice, however, exhibited an exaggerated emphysema phenotype, correlating with a nonresponsive PP2A pathway. Importantly, GPx-1-PTP1B-PP2A signaling becomes inactivated in advanced lung disease. Indeed, PTP1B protein was oxidized in the lungs of subjects with advanced emphysema, and cigarette smoke did not increase GPx-1 or PTP1B activity within epithelial cells isolated from subjects with COPD, unlike samples of healthy lung epithelial cells. In conclusion, these findings establish that the GPx-1-PTP1B-PP2A axis plays a critical role in countering the inflammatory and proteolytic responses that result in lung-tissue destruction in response to cigarette smoke exposure.Keywords: phosphorylation; inflammation; oxidation; kinase Protein phosphatase-2A (PP2A) is the major serine-threonine eukaryotic phosphatase (1), and accounts for up to 1% of total cellular protein (2). Altered PP2A activity plays a key role in cancer (3), neurodegenerative diseases (4), and innate immune responses (5). In the lung, PP2A is a key modulator of inflammatory responses in asthma (6) and chronic obstructive pulmonary disease (COPD) (5). Despite its importance in these and other biological processes, the mechanisms by which PP2A is regulated within the lung remains to be determined. Increasing evidence indicates that PP2A activity is sensitive to the redox status of the cell (7). Indeed, deficiencies in PP2A activity during Alzheimer disease (8) and chronic lymphocytic leukemia (9) are associated with enhanced oxidative stress and impaired antioxidant defenses (10,11). Despite the established links between oxidative stress and altered PP2A activity, the biological pathways by which redox factors modulate PP2A activity to influence disease development are not yet known.Increased oxidative injury has been detected in the lungs of patients with COPD, and animal studies demonstrate that inflammation in this disease can be regulated by the redox status of the lung (12, 13). COPD is the th...

Inducible liver-specific knockdown of protein tyrosine phosphatase 1B improves glucose and lipid homeostasis in adult mice

“…It is interesting to note that in our experiment insulin treatment of the control mice led to increased GS phosphorylation, whilst in the SA-Ptp1b −/− mice it led to the expected dephosphorylation. At the moment, it is unclear how hepatic PTP1B inhibition affects GS phosphorylation independently of its effects on the IR; however, PTP1B has been shown to regulate protein phosphatase 2 (PP2A) activation [36] as well as regulate hepatic Srebp1 gene expression through the PP2A axis [37], which may then affect the GS hepatic phosphorylation state [38]. This is currently under investigation in our laboratory, but is consistent with data from Ptp1b −/− immortalised cells treated with insulin, which were also shown to exhibit enhanced dephosphorylation of the S641 site on GS [39].…”

Protein tyrosine phosphatase 1B (PTP1B) is dispensable for IgE-mediated cutaneous reaction in vivo

“…However, a role of PTP1B in mast cells has not been studied previously. Given that PTP1B has been implicated in the pathogenesis of allergic inflammation [22][23][24], we reason that PTP1B may regulate mast cell activation.…”

Recent developments in the role of reactive oxygen species in allergic asthma

“…The expression of human glutathione peroxidase-1 (GPx-1) in transgenic mice significantly increased protein phosphatase-2A (PP2A) and protein tyrosine phosphatase-1B (PTP1B) activities and prevented chronic CS-induced airway inflammation. However, the reverse was observed in GPx-1 knockout mice, including an exaggerated emphysema phenotype and airway inflammation (76).…”

“…The role of LTC 4 in allergic asthma has been extensively evaluated (85). LTC 4 is produced in mast cells by assembly of a biosynthetic complex at the nuclear envelope, consisting of cytosolic phospholipase A2 (cPLA2), (64) Oxi-CaMKII inhibitor KN-93 KN-93 significantly decreased goblet cell hyperplasia, bronchial epithelial thickness, airway eosinophilia, the eosinophil chemoattractant molecule, Ccl-11, and NF-κB activity in allergic asthma (61) Leukotriene C4 (LTC 4 ) inhibitor A LTC 4 inhibitor reduced NOX4 levels and attenuated cell death (32) Galangin Galangin demonstrated decreased airway remodeling, angiogenic activity, and ASMC proliferation through the TGF-β1-ROS-MAPK pathway (65)(66)(67) Astragalin Astragalin suppressed LPS-induced ROS production and eotaxin-1 expression in epithelial cells through the TLR4-PKCγ1-PKCβ2-NADPH signaling pathway (68,69) Glutathione GSH balances Th1/Th2 responses, alters nitric oxide metabolism and inhibits ROS (55,59,70) SOD SODs protects against the harmful effects of ROS and airway inflammation (71)(72)(73) Glutathione peroxidases Glutathione peroxidases prevent airway inflammation and alveolar destruction (74)(75)(76) Vitamins C and E Vitamins C and E reduce AHR, inflammation, and oxidative stress (77)(78)(79) TLR7, toll-like receptor 7; Oxi-CaMKII, oxidative-CaMKII; SOD, superoxide dismutase; AHR, airway hyper-reactivity; Nrf2, nuclear factor E2-related factor 2; Cu/Zn SOD, copper/zinc superoxide dismutase; ROS, reactive oxygen species; NOX4, NADPH oxidase 4; LPS, lipopolysaccharide; Th2, type 2 helper T.…”