PPAR gamma-dependent anti-inflammatory action of rosiglitazone in human monocytes: suppression of TNF alpha secretion is not mediated by PTEN regulation.
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.
Hong
Guizhu
G
GlaxoSmithKline Translational Medicine and Technology Group, GSK Clinical Research Unit, ACCI, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2GG, UK.
Davis
Bill
B
Khatoon
Nachima
N
Baker
Sharon F
SF
Brown
John
J
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D051059:PTEN Phosphohydrolase; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D010080:Oxazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D000077154:Rosiglitazone; C401311:GW 7845; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D014443:Tyrosine; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human