title: Immunomodulatory drugs regulate HMGB1 release from activated human monocytes.
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.
authors.affiliation: Department of Women's and Children's Health, Pediatric Unit, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Schierbeck
authors.forename: Heidi
authors.initials: H
authors.lastname: Wähämaa
authors.forename: Ulf
authors.initials: U
authors.lastname: Andersson
authors.forename: Helena Erlandsson
authors.initials: HE
authors.lastname: Harris
mesh_terms: 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
chemical_list: 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
references.citation: Mod Rheumatol. 2005;15(6):405-9
references.pmid: 17029103
references.citation: Biochim Biophys Acta. 2010 Jan-Feb;1799(1-2):141-8
references.pmid: 20123076
references.citation: Arthritis Res Ther. 2008;10(1):R1
references.pmid: 18179697
references.citation: Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):296-301
references.pmid: 14695889
references.citation: EMBO Rep. 2006 Aug;7(8):774-8
references.pmid: 16858429
references.citation: J Thromb Haemost. 2006 Aug;4(8):1813-24
references.pmid: 16879225
references.citation: J Immunol. 2003 Apr 1;170(7):3890-7
references.pmid: 12646658
references.citation: J Immunol. 2009 May 1;182(9):5800-9
references.pmid: 19380828
references.citation: J Immunol. 2008 Feb 15;180(4):2531-7
references.pmid: 18250463
references.citation: Curr Mol Med. 2001 Dec;1(6):739-54
references.pmid: 11899260
references.citation: J Leukoc Biol. 2008 Jan;83(1):31-8
references.pmid: 17913975
references.citation: Clin Pharmacokinet. 2005;44(1):61-98
references.pmid: 15634032
references.citation: EMBO J. 2003 Oct 15;22(20):5551-60
references.pmid: 14532127
references.citation: Genes Immun. 2002 May;3(3):123-35
references.pmid: 12070776
references.citation: Ann Pharmacother. 2000 Feb;34(2):161-4
references.pmid: 10676822
references.citation: Crit Care. 2007;11(6):R122
references.pmid: 18042296
references.citation: Science. 1999 Jul 9;285(5425):248-51
references.pmid: 10398600
references.citation: Blood. 2005 Jul 15;106(2):609-16
references.pmid: 15802534
references.citation: Cardiovasc Pathol. 2008 May-Jun;17(3):129-38
references.pmid: 18402807
references.citation: J Immunol. 2001 Jul 1;167(1):30-5
references.pmid: 11418628
references.citation: FASEB J. 2007 Dec;21(14):3904-16
references.pmid: 17628015
references.citation: Nat Rev Immunol. 2005 Apr;5(4):331-42
references.pmid: 15803152
references.citation: J Immunol. 2006 Dec 1;177(11):7889-97
references.pmid: 17114460
references.citation: Am J Physiol Lung Cell Mol Physiol. 2005 May;288(5):L958-65
references.pmid: 15640285
references.citation: J Leukoc Biol. 2004 Feb;75(2):163-89
references.pmid: 14525967
references.citation: J Immunol. 2007 Jul 15;179(2):1236-44
references.pmid: 17617616
references.citation: Biochim Biophys Acta. 2010 Jan-Feb;1799(1-2):149-56
references.pmid: 19948257
references.citation: EMBO Rep. 2002 Oct;3(10):995-1001
references.pmid: 12231511
references.citation: Ann Rheum Dis. 2005 Apr;64(4):599-605
references.pmid: 15345503
references.citation: J Immunol. 2000 Sep 15;165(6):2950-4
references.pmid: 10975801
references.citation: Cytokine. 1992 Sep;4(5):353-60
references.pmid: 1420996
references.citation: Arthritis Rheum. 2003 Jul;48(7):2052-8
references.pmid: 12847700
references.citation: J Leukoc Biol. 2009 Sep;86(3):625-32
references.pmid: 19487305
references.citation: Arthritis Rheum. 2005 Dec;52(12):3880-9
references.pmid: 16320336
references.citation: Baillieres Clin Rheumatol. 1990 Dec;4(3):467-89
references.pmid: 2093438
references.citation: J Leukoc Biol. 2007 Jan;81(1):129-36
references.pmid: 16980509
references.citation: Am J Physiol Cell Physiol. 2006 Dec;291(6):C1318-25
references.pmid: 16855214
references.citation: Arthritis Res Ther. 2008;10(2):R33
references.pmid: 18346273
references.citation: Crit Care Med. 2007 Dec;35(12):2762-8
references.pmid: 17901837
references.citation: Nature. 2002 Jul 11;418(6894):191-5
references.pmid: 12110890
references.citation: Ann Rheum Dis. 1987 Jan;46(1):42-5
references.pmid: 3813674
references.citation: Surgery. 1999 Aug;126(2):389-92
references.pmid: 10455911