Down-regulation of Na+/H+ exchanger 1 by Toll-like receptor stimulation in macrophages

Shiho Takakuwa, Natsumi Mizuno, Takayuki Takano, Sanki Asakawa, Taiki Sato, Masahiro Hiratsuka, Noriyasu Hirasawa

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)176-182
Number of pages7
JournalImmunobiology
Volume222
Issue number2
DOIs
Publication statusPublished - 2017 Feb 1

Keywords

  • Lipopolysaccharide
  • Macrophage
  • Na/H exchanger 1
  • c-Jun N-terminal kinase

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Hematology

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