Helminths-based bi-functional molecule, tuftsin-phosphorylcholine (TPC), ameliorates an established murine arthritis

PLoS One. 2018 Aug 8;13(8):e0200615. doi: 10.1371/journal.pone.0200615. eCollection 2018.

Abstract

A novel small molecule named tuftsin-phosphorylcholine (TPC), which is linked to the biological activity of helminths, was constructed. The current study address the effect of TPC treatment in established collagen-induced arthritis (CIA) mice and propose TPC bi-functional activity. TPC treatment was initiated when clinical score was 2 to 4. Arthritis scores in TPC treated mice were lower compared to mice treated with vehicle (P < 0.001). Joint staining showed normal joint structure in TPC-treated mice compared to control groups treated with phosphate buffered saline (PBS), phosphorylcholine, or tuftsin, which exhibited severely inflamed joints. TPC enhanced anti-inflammatory response due to increased IL-10 secretion, and reduced pro-inflammatory cytokine secretion (IL-1-β, IL-6, TNF-αP < 0.001). Furthermore, TPC therapy increased expansion of CD4+CD25+FOXP3+T regulatory cells and IL-10+CD5+CD1d+B regulatory cells. We propose that the immunomodulatory activity of TPC can be a result of a bi-specific activity of TPC: (a) The tuftsin part of the TPC shifts RAW macrophage cells from pro-inflammatory macrophages M1 to anti-inflammatory M2-secreting IL-10 (P < 0.001) through neuropilin-1 and (b) TPC significantly reduce mouse TLR4 expression via NFkB pathway by HEKTM cells (P < 0.02) via the phosphorylcholine site of the molecule. Our results indicate that TPC, significantly ameliorated established CIA by its immunomodulatory activity. These data could lead to a novel self bi-functional small molecule for treating patients with progressive RA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / drug therapy*
  • Arthritis, Experimental / pathology
  • B-Lymphocytes / cytology
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / metabolism
  • Disease Models, Animal
  • HEK293 Cells
  • Helminths / metabolism*
  • Humans
  • Interleukin-10 / metabolism
  • Interleukin-1beta / metabolism
  • Joints / pathology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred DBA
  • NF-kappa B / metabolism
  • Neuropilin-1 / metabolism
  • Phosphorylcholine / pharmacology
  • Phosphorylcholine / therapeutic use*
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / metabolism
  • Toll-Like Receptor 4 / drug effects
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism
  • Tuftsin / pharmacology
  • Tuftsin / therapeutic use*

Substances

  • Interleukin-1beta
  • NF-kappa B
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Phosphorylcholine
  • Interleukin-10
  • Neuropilin-1
  • Tuftsin

Grant support

This study was supported by the Morris Family Foundation 96754 to YS (Los Angeles, CA, USA). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.