title: Gold sodium thiomalate and chloroquine inhibit cytokine production in monocytic THP-1 cells through distinct transcriptional and posttranslational mechanisms.
abstract: Gold sodium thiomalate (GST), chloroquine (CQ), and methotrexate have been widely used in the therapy of rheumatoid arthritis and other inflammatory conditions. Using the human monocytic cell line THP-1 we have analyzed effects of these drugs on cytokine production and intracellular signaling. GST and CQ were equally effective in reducing lipopolysaccharide (LPS)-induced IL-1 beta release while CQ was a more effective inhibitor of TNF-alpha production than GST. Methotrexate did not affect production of these cytokines. CQ reduced IL-1 beta mRNA expression and strongly inhibited phosphorylation of mitogen-activated protein kinase (MAPK) p38, and to a lesser extent c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2. In contrast, GST did not affect cytokine mRNA expression or MAPK activation. However, GST selectively inhibited the activity of the interleukin-1 converting enzyme (ICE)/caspase-1. These data demonstrate that CQ inhibits IL-1 beta release from monocytes by interfering with pretranscriptional signaling and TNF-alpha release by posttranslational events whereas GST downregulates IL-1 beta secretion by interfering with posttranslational IL-1 beta processing.
authors.affiliation: Department of Rheumatology and Clinical Immunology/Allergology, University Hospital, Inselspital, Berne, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Seitz
authors.forename: Jean
authors.initials: J
authors.lastname: Valbracht
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Quach
authors.forename: Martin
authors.initials: M
authors.lastname: Lotz
mesh_terms: D018501:Antirheumatic Agents / Q000494:pharmacology; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis*; D006052:Gold Sodium Thiomalate / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008727:Methotrexate / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018501:Antirheumatic Agents; D016207:Cytokines; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D006052:Gold Sodium Thiomalate; D002738:Chloroquine; D020928:Mitogen-Activated Protein Kinases; D020170:Caspase 1; D008727:Methotrexate