Identification of Pharmacological Modulators of HMGB1-Induced Inflammatory Response by Cell-Based Screening

Domokos Gerö, Petra Szoleczky, Katalin Modis, John P. Pribis, Yousef Al-Abed, Huan Yang, Sangeeta Chevan, Timothy R. Billiar, Kevin J. Tracey, Csaba Szabo

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

High mobility group box 1 (HMGB1), a highly conserved, ubiquitous protein, is released into the circulation during sterile inflammation (e.g. arthritis, trauma) and circulatory shock. It participates in the pathogenesis of delayed inflammatory responses and organ dysfunction. While several molecules have been identified that modulate the release of HMGB1, less attention has been paid to identify pharmacological inhibitors of the downstream inflammatory processes elicited by HMGB1 (C23-C45 disulfide C106 thiol form). In the current study, a cell-based medium-throughput screening of a 5000+ compound focused library of clinical drugs and drug-like compounds was performed in murine RAW264.7 macrophages, in order to identify modulators of HMGB1-induced tumor-necrosis factor alpha (TNFα) production. Clinically used drugs that suppressed HMGB1-induced TNFα production included glucocorticoids, beta agonists, and the anti-HIV compound indinavir. A re-screen of the NIH clinical compound library identified beta-agonists and various intracellular cAMP enhancers as compounds that potentiate the inhibitory effect of glucocorticoids on HMGB1-induced TNFα production. The molecular pathways involved in this synergistic anti-inflammatory effect are related, at least in part, to inhibition of TNFα mRNA synthesis via a synergistic suppression of ERK/IκB activation. Inhibition of TNFα production by prednisolone+salbutamol pretreatment was also confirmed in vivo in mice subjected to HMGB1 injection; this effect was more pronounced than the effect of either of the agents administered separately. The current study unveils several drug-like modulators of HMGB1-mediated inflammatory responses and offers pharmacological directions for the therapeutic suppression of inflammatory responses in HMGB1-dependent diseases.

Original languageEnglish (US)
Article numbere65994
JournalPLoS One
Volume8
Issue number6
DOIs
StatePublished - Jun 14 2013

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Modulators
tumor necrosis factor-alpha
Screening
Tumor Necrosis Factor-alpha
inflammation
Pharmacology
screening
drugs
beta-adrenergic agonists
glucocorticoids
Pharmaceutical Preparations
Glucocorticoids
cells
Indinavir
prednisolone
Albuterol
Macrophages
mice
arthritis
Prednisolone

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Identification of Pharmacological Modulators of HMGB1-Induced Inflammatory Response by Cell-Based Screening. / Gerö, Domokos; Szoleczky, Petra; Modis, Katalin; Pribis, John P.; Al-Abed, Yousef; Yang, Huan; Chevan, Sangeeta; Billiar, Timothy R.; Tracey, Kevin J.; Szabo, Csaba.

In: PLoS One, Vol. 8, No. 6, e65994, 14.06.2013.

Research output: Contribution to journalArticle

Gerö, D, Szoleczky, P, Modis, K, Pribis, JP, Al-Abed, Y, Yang, H, Chevan, S, Billiar, TR, Tracey, KJ & Szabo, C 2013, 'Identification of Pharmacological Modulators of HMGB1-Induced Inflammatory Response by Cell-Based Screening', PLoS One, vol. 8, no. 6, e65994. https://doi.org/10.1371/journal.pone.0065994
Gerö, Domokos ; Szoleczky, Petra ; Modis, Katalin ; Pribis, John P. ; Al-Abed, Yousef ; Yang, Huan ; Chevan, Sangeeta ; Billiar, Timothy R. ; Tracey, Kevin J. ; Szabo, Csaba. / Identification of Pharmacological Modulators of HMGB1-Induced Inflammatory Response by Cell-Based Screening. In: PLoS One. 2013 ; Vol. 8, No. 6.
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