TY - JOUR T1 - Impaired protein tyrosine phosphatase PTPRR reduces response to corticosteroid in mononuclear cells JF - European Respiratory Journal JO - Eur Respir J VL - 42 IS - Suppl 57 SP - P575 AU - Yoshiki Kobayashi AU - Anna Miller-Larsson AU - Kazuhiro Ito AU - Peter J. Barnes AU - Nicolas Mercado Y1 - 2013/09/01 UR - http://erj.ersjournals.com/content/42/Suppl_57/P575.abstract N2 - Introduction: We have recently found that impaired nuclear translocation of glucocorticoid receptor (GR) due to its hyperphosphorylation at Ser226 via c-Jun N-terminal kinase 1 (JNK1) is one of the causes of corticosteroid (CS) insensitivity. Protein tyrosine phosphatases (PTPs) are known as critical regulators of physiological signalling molecules such as mitogen-activated protein kinases (MAPKs).Aims: To elucidate the involvement of MAPK-PTPs (PTPRR, PTPN5 and PTPN7), which have the potential to dephosphorylate MAPKs, in regulation of CS sensitivity.Methods: Effects of MAPK-PTPs RNAi were evaluated in U937 cells. CS sensitivity was determined by the dexamethasone ability to inhibit TNFα-induced IL-8 and to translocate GR from cytoplasm into nucleus (NT). Phosphorylation levels of GR-Ser226 and JNK1, and protein expression of PTPRR were evaluated by western-blot in U937 cells and/or peripheral blood mononuclear cells (PBMCs). Phosphatase activity of immunopurified PTPRR was analyzed by fluorescence-based assay.Results: PTPRR reduction (but not PTPN5, nor PTPN7) attenuated CS sensitivity in line with enhancement of GR-Ser226 phosphorylation. In addition, PTPRR reduction caused less NT of GR. Under IL-2/IL-4-induced CS insensitive condition, PTPRR expression/activity were reduced and PTPRR was dissociated from JNK1/GR. In PBMCs from severe asthmatics, PTPRR expression correlated negatively with JNK1/GR-Ser226 phosphorylation levels.Conclusion: Reduction of PTPRR leads to lower dephosphorylation of GR-Ser226 via JNK1 and to lower NT of GR, resulting in CS insensitivity. This novel mechanism may be one of the causes of CS insensitivity in patients with severe asthma. ER -