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

Gerö, D and Szoleczky, P and Módis, K and Pribis, JP and Al-Abed, Y and Yang, H and Chevan, S and Billiar, TR and Tracey, KJ and Szabo, C (2013) Identification of Pharmacological Modulators of HMGB1-Induced Inflammatory Response by Cell-Based Screening. PLoS ONE, 8 (6).

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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. © 2013 Gerö et al.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Gerö, D
Szoleczky, P
Módis, K
Pribis, JP
Al-Abed, Y
Yang, H
Chevan, S
Billiar, TRbilliar@pitt.eduBILLIAR
Tracey, KJ
Szabo, C
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorSobol, Robert W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 14 June 2013
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 8
Number: 6
DOI or Unique Handle: 10.1371/journal.pone.0065994
Schools and Programs: School of Medicine > Surgery
Refereed: Yes
Date Deposited: 15 Jul 2013 20:17
Last Modified: 04 Feb 2019 15:57
URI: http://d-scholarship.pitt.edu/id/eprint/19205

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