BJ-3105, a 6-Alkoxypyridin-3-ol Analog, Impairs T Cell Differentiation and Prevents Experimental Autoimmune Encephalomyelitis Disease Progression

PLoS One. 2017 Jan 17;12(1):e0168942. doi: 10.1371/journal.pone.0168942. eCollection 2017.

Abstract

CD4+ T cells are essential in inflammation and autoimmune diseases. Interferon-γ (IFN-γ) secreting T helper (Th1) and IL-17 secreting T helper (Th17) cells are critical for several autoimmune diseases. To assess the inhibitory effect of a given compound on autoimmune disease, we screened many compounds with an in vitro Th differentiation assay. BJ-3105, a 6-alkoxypyridin-3-ol analog, inhibited IFN-γ and IL-17 production from polyclonal CD4+ T cells and ovalbumin (OVA)-specific CD4+ T cells which were activated by T cell receptor (TCR) engagement. BJ-3105 ameliorated the experimental autoimmune encephalomyelitis (EAE) model by reducing Th1 and Th17 generation. Notably, Th cell differentiation was significantly suppressed by BJ-3105 treatment without inhibiting in vitro proliferation of T cells or inducing programmed cell death. Mechanistically, BJ-3105 inhibited the phosphorylation of JAK and its downstream signal transducer and activator of transcription (STAT) that is critical for Th differentiation. These results demonstrated that BJ-3105 inhibits the phosphorylation of STAT in response to cytokine signals and subsequently suppressed the differentiation of Th cell responses.

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Differentiation / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Encephalomyelitis, Autoimmune, Experimental / prevention & control*
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Pyridines / chemistry*
  • Pyridines / pharmacology*
  • Th1 Cells / immunology*
  • Th17 Cells / immunology*

Substances

  • BJ-3105
  • Pyridines
  • pyridine

Grant support

This work was supported by a Yeungnam University Research Grant, 213A367004, (http://www.yu.ac.kr/index.php). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.