Abstract
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.
Highlights
HMGB1 is a ubiquitous nonhistone nuclear protein as well as an extracellular molecule regulating innate and adaptive immunity
Our results demonstrate that treatments with dexamethasone, chloroquine or gold sodium thiomalate have the ability to inhibit HMGB1 release
CD14 purified monocytes from peripheral blood of healthy donors were activated by LPS/IFNγ and HMGB1, and TNF secretion was assessed with ELISPOT assays
Summary
HMGB1 is a ubiquitous nonhistone nuclear protein as well as an extracellular molecule regulating innate and adaptive immunity. HMGB1 reaches the extracellular milieu via active or passive cellular release. Active secretion of HMGB1 occurs when cells including macrophages, monocytes, NK cells, dendritic cells, endothelial cells, platelets, neurons and astrocytes are exposed to exogenous pathogen-derived molecules like lipopolysaccharide (LPS) or endogenously derived inflammatory mediators like IL-1β, nitric oxide, IFNβ and IFNγ [3,4,5,6]. Active release is initiated through plasma membrane receptor interactions with subsequent intracellular signal transduction leading to a slow release of HMGB1. Active secretion of HMGB1 from macrophages/monocytes begins 8–12 hours after ligation of appropriate cell surface receptors. This represents a significantly delayed onset of release as compared with most other proinflammatory mediators produced by these cells. Signaling via NF-κB [7], phosphatidyli-
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