Immunomodulatory drugs regulate HMGB1 release from activated human monocytes.
Several HMGB1-specific antagonists have provided beneficial results in multiple models of inflammatory disease-preclinical trials including arthritis. Since no HMGB1-specific targeted therapy has yet reached the clinic, we have performed in vitro studies to investigate whether any of a selection of well-established antirheumatic drugs inhibit HMGB1 release as part of its mode of action. Freshly purified peripheral blood monocytes from healthy donors were stimulated in cultures with LPS and IFNγ to cause HMGB1 and TNF release detected in ELISPOT assays. Effects on the secretion were assessed in cultures supplemented with dexamethasone, cortisone, chloroquine, gold sodium thiomalate, methotrexate, colchicine, etanercept or anakinra. Pharmacologically relevant doses of dexamethasone, gold sodium thiomalate and chloroquine inhibited the extracellular release of HMGB1 in a dose-dependent mode. Immunostaining demonstrated that dexamethasone caused intracellular HMGB1 retention. No effects on HMGB1 secretion were observed in cultures with activated monocytes by any of the other studied agents. TNF production in LPS/IFNγ-activated monocytes was readily downregulated by dexamethasone and, to some extent, by chloroquine and etanercept. We conclude that dexamethasone, gold sodium thiomalate and chloroquine share a capacity to inhibit HMGB1 release from activated monocytes.
Schierbeck
Hanna
H
Department of Women's and Children's Health, Pediatric Unit, Karolinska Institutet, Stockholm, Sweden.
Wähämaa
Heidi
H
Andersson
Ulf
U
Harris
Helena Erlandsson
HE
D000818:Animals; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D003078:Colchicine / Q000494:pharmacology; D003348:Cortisone / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D006052:Gold Sodium Thiomalate / Q000494:pharmacology; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D024243:HMGB1 Protein; D007155:Immunologic Factors; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D006052:Gold Sodium Thiomalate; D003907:Dexamethasone; D002738:Chloroquine; D003078:Colchicine; D003348:Cortisone; D008727:Methotrexate
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