title: Down-regulation of Na+/H+exchanger 1 by Toll-like receptor stimulation in macrophages.
abstract: The role of Na+/H+exchanger 1 (NHE1) in various cell types, including inflammatory cells, has been extensively studied. However, regulation of NHE1 protein level in activated inflammatory cells is yet to be characterized. In this study, we investigated whether Toll-like receptor (TLR) ligands can regulate NHE1 protein level in the mouse macrophage-like RAW 264 cell line. We found that lipopolysaccharide (LPS), a TLR4 ligand, lowered NHE1 level and activity in RAW 264 cells and in primary murine macrophages. Other TLR ligands, such as zymosan A and poly(I:C), also displayed reduced NHE1 level. LPS promoted NHE1 ubiquitination and reduced the expression of calcineurin homologous protein 1 (CHP1), a regulator of NHE1 activity and stability. These responses were inhibited by c-Jun N-terminal kinase (JNK) inhibitor SP600125 and dexamethasone. A proteasome inhibitor, but not caspase-3 or lysosomal inhibitors, blocked the LPS-induced NHE1 down-regulation. These results suggested that LPS promotes the degranulation of NHE1 mediated by the ubiquitin-proteasome system and CHP1 downregulation resulting from activation of JNK.
authors: Laboratory of Pharmacotherapy of Lifestyle Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan.
authors: Shiho
authors: S
authors: Takakuwa
authors: Laboratory of Pharmacotherapy of Lifestyle Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan.
authors: Natsumi
authors: N
authors: Mizuno
authors: Laboratory of Pharmacotherapy of Lifestyle Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan.
authors: Takayuki
authors: T
authors: Takano
authors: Laboratory of Pharmacotherapy of Lifestyle Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan.
authors: Sanki
authors: S
authors: Asakawa
authors: Laboratory of Pharmacotherapy of Lifestyle Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan.
authors: Taiki
authors: T
authors: Sato
authors: Laboratory of Pharmacotherapy of Lifestyle Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan.
authors: Masahiro
authors: M
authors: Hiratsuka
authors: Laboratory of Pharmacotherapy of Lifestyle Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan. Electronic address: hirasawa@m.tohoku.ac.jp.
authors: Noriyasu
authors: N
authors: Hirasawa
mesh_terms: D000818:Animals; D015415:Biomarkers; D002460:Cell Line; D015536:Down-Regulation; D005786:Gene Expression Regulation; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D000074082:Sodium-Hydrogen Exchanger 1 / Q000235:genetics / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000819:agonists* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D008070:Lipopolysaccharides; D000074082:Sodium-Hydrogen Exchanger 1; D051193:Toll-Like Receptors; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Lipopolysaccharide; Macrophage; Na(+)/H(+) exchanger 1; c-Jun N-terminal kinase