PR-957, a selective inhibitor of immunoproteasome subunit low-MW polypeptide 7, attenuates experimental autoimmune neuritis by suppressing T h 17-cell differentiation and regulating cytokine production

FASEB J. 2017 Apr;31(4):1756-1766. doi: 10.1096/fj.201601147R. Epub 2017 Jan 17.

Abstract

Experimental autoimmune neuritis (EAN) is a CD4+ T-cell-mediated autoimmune inflammatory demyelinating disease of the peripheral nervous system. It has been replicated in an animal model of human inflammatory demyelinating polyradiculoneuropathy, Guillain-Barré syndrome. In this study, we evaluated the therapeutic efficacy of a selective inhibitor of the immunoproteasome subunit, low-MW polypeptide 7 (PR-957) in rats with EAN. Our results showed that PR-957 significantly delayed onset day, reduced severity and shortened duration of EAN, and alleviated demyelination and inflammatory infiltration in sciatic nerves. In addition to significantly regulating expression of the cytokine profile, PR-957 treatment down-regulated the proportion of proinflammatory T-helper (Th)17 cells in sciatic nerves and spleens of rats with EAN. Data presented show the role of PR-957 in the signal transducer and activator of transcription 3 (STAT3) pathway. PR-957 not only decreased expression of IL-6 and IL-23 but also led to down-regulation of STAT3 phosphorylation in CD4+ T cells. Regulation of the STAT3 pathway led to a reduction in retinoid-related orphan nuclear receptor γ t and IL-17 production. Furthermore, reduction of STAT3 phosphorylation may have directly suppressed Th17-cell differentiation. Therefore, our study demonstrates that PR-957 could potently alleviate inflammation in rats with EAN and that it may be a likely candidate for treating Guillain-Barré syndrome.-Liu, H., Wan, C., Ding, Y., Han, R., He, Y., Xiao, J., Hao, J. PR-957, a selective inhibitor of immunoproteasome subunit low-MW polypeptide 7, attenuates experimental autoimmune neuritis by suppressing Th17-cell differentiation and regulating cytokine production.

Keywords: Guillain-Barré syndrome; ONX-0914; inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • Interleukins / genetics
  • Interleukins / metabolism*
  • Male
  • Neuritis, Autoimmune, Experimental / drug therapy*
  • Oligopeptides / pharmacology
  • Oligopeptides / therapeutic use*
  • Orphan Nuclear Receptors / genetics
  • Orphan Nuclear Receptors / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors / pharmacology
  • Proteasome Inhibitors / therapeutic use*
  • Rats
  • Rats, Inbred Lew
  • STAT3 Transcription Factor / metabolism
  • Th17 Cells / cytology
  • Th17 Cells / drug effects*
  • Th17 Cells / metabolism

Substances

  • Interleukins
  • Oligopeptides
  • Orphan Nuclear Receptors
  • PR-957
  • Proteasome Inhibitors
  • STAT3 Transcription Factor
  • Stat3 protein, rat
  • LMP7 protein
  • Proteasome Endopeptidase Complex