Nitric oxide is involved in activation of Toll-like receptor 4 signaling through tyrosine nitration of Src homology protein tyrosine phosphatase 2 in murine dextran sulfate-induced colitis

Xin Tun, Keiji Yasukawa, Ken ichi Yamada

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Ulcerative colitis is characterized by colonic mucosal bleeding and ulceration, often with repeated active and remission stages. One factor in ulcerative colitis development is increased susceptibility to commensal bacteria and lipopolysaccharide (LPS). LPS activates macrophages to release nitric oxide (NO) through Toll-like receptor 4 (TLR4) signaling. However, whether NO is beneficial or detrimental to colitis remains controversial. In this study, we investigated whether NO enhances the development of colitis in mice treated with dextran sulfate sodium (DSS) and inflammation in cells treated with low-dose LPS. An NO donor, NOC18, induced colitis and increased CD14 protein and nitrotyrosine levels in colonic macrophages from mice treated with DSS for 7d (molecular weight: 5000). In the mouse peritoneal macrophage cell line RAW264.7 stimulated with 3ng/mL LPS, NO activated the CD14-TLR4-nuclear factor kappa B (NF-κB) axis. Low-dose LPS stimulation did not change the levels of signal transducer and activator of transcription (STAT) 3 phosphorylation, CD14, inducible NO synthase, interleukin (IL)-6, or NF-κB. In addition, low-dose LPS increased phosphorylation of src homology protein tyrosine phosphatase 2 (SHP2), a negative regulator of STAT3 phosphorylation. However, NO decreased SHP2 phosphorylation and significantly activated the downstream signaling molecules. NO increased SHP2 nitration in LPS-stimulated RAW264.7 cells and DSS-treated mice. These results indicate that SHP2 nitration in macrophages might be involved in activation of the CD14-TLR4-NF-κB axis through STAT3 signaling in mice with DSS-induced colitis.

Original languageEnglish
Pages (from-to)1843-1852
Number of pages10
JournalBiological and Pharmaceutical Bulletin
Volume41
Issue number12
DOIs
Publication statusPublished - 2018

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

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