Combinations of TLR and NOD2 ligands stimulate rat microglial P2X4R expression

Biochem Biophys Res Commun. 2006 Oct 27;349(3):1156-62. doi: 10.1016/j.bbrc.2006.08.146. Epub 2006 Sep 1.


As ATP-gated ion channels, P2X4 receptors (P2X4R) of microglial cells play a crucial role in central nervous system (CNS) inflammation. In this study, we used rat microglial cell cultures to examine P2X4R expression in response to stimulation by combination of toll-like receptors (TLRs) and nucleotide-binding oligomerization domain 2 (NOD2) receptors. Various TLR1-9 ligands and NOD2 agonist muramyldipeptide (MDP) were investigated. Our results showed that certain combination of ligands had additive effects on upregulating microglial P2X4R at both mRNA and protein levels, and induced nitric oxide increase and tumor necrosis factor-alpha production. Thus TLRs and NOD2 combinations are contributors to the signaling cascades resulting in purinergic microglial activation.

MeSH terms

  • Animals
  • Cells, Cultured
  • Dipeptides / pharmacology
  • Flow Cytometry
  • Intracellular Signaling Peptides and Proteins / agonists
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Ligands
  • Microglia / drug effects
  • Microglia / metabolism*
  • Nitric Oxide / metabolism
  • Nod2 Signaling Adaptor Protein
  • RNA, Messenger / genetics
  • Rats
  • Receptors, Purinergic P2 / genetics
  • Receptors, Purinergic P2 / metabolism*
  • Receptors, Purinergic P2X4
  • Toll-Like Receptors / metabolism*
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Up-Regulation / drug effects


  • Dipeptides
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • NOD2 protein, rat
  • Nod2 Signaling Adaptor Protein
  • P2rx4 protein, rat
  • RNA, Messenger
  • Receptors, Purinergic P2
  • Receptors, Purinergic P2X4
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide