PDK1 promotes the inflammatory progress of fibroblast-like synoviocytes by phosphorylating RSK2

Cell Immunol. 2017 May:315:27-33. doi: 10.1016/j.cellimm.2016.10.007. Epub 2016 Nov 1.

Abstract

This study investigated the role of PDK1 in inflammatory response which is initiated by TNF-α and analyzed the association between PDK1 and RSK2. TNF-α were added into MH7A cells to induce inflammation condition. Through overexpressing or suppressing PDK1 in MH7A cells, the role of PDK1 in cell invasiveness and inflammatory factors was determined. Levels of MMPs protein and inflammatory cytokines were assessed with PDK1 siRNA and TNF-α treatment. Inhibition of RSK2 was used to investigate the function of RSK2 on PDK1-induced inflammation. The phosphorylation of RSK2 was detected when PDK1 was inhibited. Luciferase reporter assay was performed to detect the transcriptional activity of NF-κB. We found highly expressed PDK1 could promote cell invasion and secretion of IL-1β and IL-6 in MH7A cells. Inhibition of RSK2 reduced the PDK1-induced cell invasion and cytokines secretion in MH7A cells. In response to TNF-α, PDK1 could phosphorylate RSK2 and activated RSK2, then promoting the activation of NF-κB. This may be a possible therapeutic option of rheumatoid arthritis.

Keywords: Fibroblast-like synoviocytes; PDK1; RSK2; Rheumatoid arthritis.

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases / antagonists & inhibitors
  • 3-Phosphoinositide-Dependent Protein Kinases / biosynthesis
  • 3-Phosphoinositide-Dependent Protein Kinases / genetics
  • 3-Phosphoinositide-Dependent Protein Kinases / physiology*
  • Animals
  • Arthritis, Experimental / enzymology*
  • Arthritis, Experimental / pathology
  • Arthritis, Rheumatoid / enzymology*
  • Arthritis, Rheumatoid / pathology
  • Cell Line
  • Cell Movement
  • Cytokines / metabolism
  • Disease Progression
  • Enzyme Induction / drug effects
  • Humans
  • Male
  • Mice
  • Mice, Inbred DBA
  • NF-KappaB Inhibitor alpha / metabolism
  • NF-kappa B / metabolism
  • Phosphorylation
  • Protein Processing, Post-Translational*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Ribosomal Protein S6 Kinases, 90-kDa / genetics
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • Synovial Membrane / pathology
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Cytokines
  • NF-kappa B
  • RNA, Small Interfering
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • 3-Phosphoinositide-Dependent Protein Kinases
  • PDPK1 protein, human
  • Pdpk1 protein, mouse
  • Ribosomal Protein S6 Kinases, 90-kDa
  • ribosomal protein S6 kinase, 90kDa, polypeptide 3