Abstract
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
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Chromones / pharmacology
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Humans
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In Vitro Techniques
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Monocytes / drug effects*
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Monocytes / physiology*
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Morpholines / pharmacology
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Oxazoles / pharmacology
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PTEN Phosphohydrolase
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoric Monoester Hydrolases / genetics*
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Phosphoric Monoester Hydrolases / metabolism*
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Cytoplasmic and Nuclear / agonists
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Rosiglitazone
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Thiazoles / pharmacology*
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Thiazolidinediones*
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Transcription Factors / agonists
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Transcription Factors / metabolism*
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Tumor Necrosis Factor-alpha / metabolism*
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Tumor Suppressor Proteins / genetics*
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Tumor Suppressor Proteins / metabolism*
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Tyrosine / analogs & derivatives*
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Tyrosine / pharmacology
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Chromones
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Enzyme Inhibitors
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Morpholines
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Oxazoles
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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RNA, Messenger
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Receptors, Cytoplasmic and Nuclear
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Thiazoles
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Thiazolidinediones
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Transcription Factors
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Tumor Necrosis Factor-alpha
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Tumor Suppressor Proteins
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Rosiglitazone
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GW 7845
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Tyrosine
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Phosphoric Monoester Hydrolases
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PTEN Phosphohydrolase
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PTEN protein, human