PPAR gamma-dependent anti-inflammatory action of rosiglitazone in human monocytes: suppression of TNF alpha secretion is not mediated by PTEN regulation

Biochem Biophys Res Commun. 2003 Apr 11;303(3):782-7. doi: 10.1016/s0006-291x(03)00418-2.


Thiazolidinediones (TZDs) are insulin-sensitising drugs that are ligands for the nuclear receptor PPAR gamma. They have been shown to inhibit PMA-stimulated secretion of TNFalpha from human monocytes, although only at concentrations well in excess of circulating levels observed during TZD therapy, suggesting a mechanism of action independent of PPAR gamma activation. Here we show that insulin-sensitising concentrations of the TZD rosiglitazone partially inhibit serum- or LPS- (but not PMA-) stimulated TNF alpha secretion from primary human monocytes, with an IC(50) of around 50nM. We also show that the observed effects are independent of PPAR gamma-mediated regulation of the lipid phosphatase PTEN. Reversed stimulus specificity, IC(50) in the insulin-sensitising range, and the fact that partial inhibition of TNF alpha secretion is also observed with a structurally unrelated PPAR gamma agonist, GW7845, demonstrate a mechanism of action distinct from that observed with higher TZD concentrations. These findings thus represent the first report of a PPAR gamma-dependent and therapeutically relevant anti-inflammatory action of TZDs in isolated human monocytes.

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Chromones / pharmacology
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Humans
  • In Vitro Techniques
  • Monocytes / drug effects*
  • Monocytes / physiology*
  • Morpholines / pharmacology
  • Oxazoles / pharmacology
  • PTEN Phosphohydrolase
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoric Monoester Hydrolases / genetics*
  • Phosphoric Monoester Hydrolases / metabolism*
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Rosiglitazone
  • Thiazoles / pharmacology*
  • Thiazolidinediones*
  • Transcription Factors / agonists
  • Transcription Factors / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism*
  • Tyrosine / analogs & derivatives*
  • Tyrosine / pharmacology


  • Anti-Inflammatory Agents, Non-Steroidal
  • Chromones
  • Enzyme Inhibitors
  • Morpholines
  • Oxazoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Thiazoles
  • Thiazolidinediones
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Proteins
  • Rosiglitazone
  • GW 7845
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Tyrosine
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human