Gold sodium thiomalate and chloroquine inhibit cytokine production in monocytic THP-1 cells through distinct transcriptional and posttranslational mechanisms.
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.
Seitz
Michael
M
Department of Rheumatology and Clinical Immunology/Allergology, University Hospital, Inselspital, Berne, Switzerland.
Valbracht
Jean
J
Quach
Jacqueline
J
Lotz
Martin
M
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
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