Investigation of toll-like receptor (TLR) 4 inhibitor TAK-242 as a new potential anti-rheumatoid arthritis drug.
Adjuvant-induced arthritis (AIA) rat model
Damage-associated molecular patterns (DAMPs)
Fibroblast-like synoviocytes (FLS)
Lipopolysaccharide (LPS)
Poly(I:C)
Rheumatoid arthritis (RA)
TAK-242 (resatorvid)
TLR4 inhibitor
Journal
Arthritis research & therapy
ISSN: 1478-6362
Titre abrégé: Arthritis Res Ther
Pays: England
ID NLM: 101154438
Informations de publication
Date de publication:
23 01 2020
23 01 2020
Historique:
received:
14
06
2019
accepted:
07
01
2020
entrez:
25
1
2020
pubmed:
25
1
2020
medline:
25
11
2020
Statut:
epublish
Résumé
Proper blocking of toll-like receptor (TLR) activation during disease progression has been reported to have inhibitory effect on the pathogenesis of rheumatoid arthritis (RA). We tested whether the TLR4 inhibitor TAK-242 had potential as a remedy for rheumatoid arthritis. The therapeutic effect of TAK-242 was tested in vitro using the human rheumatoid fibroblast-like synoviocyte (FLS) line MH7A or primary human FLS and in an adjuvant-induced arthritis (AIA) rat model. TAK-242 dose dependently inhibited the increased expression of IL-6, IL-8, MMP-1, and VEGF in LPS-stimulated MH7A cells. It also inhibited the expression of IL-6 and IL-8 in poly(I:C), TLR3 activator-stimulated primary FLS, but not in IL-1β-stimulated primary FLS. These findings suggest that TAK-242 blocks a specific signaling pathway to some degree. Further, TAK-242 slightly inhibited mobilization of NF-κB into nuclei. In the AIA rat model, TAK-242 significantly reversed the body weight and paw thickness of AIA rats to the normal state at a dose of 5 mg/kg, but not at 3 mg/kg, and reduced the increased serum level of IL-6 and VEGF in AIA rats. It also significantly ameliorated inflammatory symptoms of joint tissues at day 21 of treatment, according to histology and RT-PCR. Based on the drug repositioning concept, TAK-242, which is used for the treatment of TLR4-mediated inflammatory diseases, shows potential for cost-effective development as a remedy for rheumatoid arthritis or to control the progression of RA.
Sections du résumé
BACKGROUND
Proper blocking of toll-like receptor (TLR) activation during disease progression has been reported to have inhibitory effect on the pathogenesis of rheumatoid arthritis (RA). We tested whether the TLR4 inhibitor TAK-242 had potential as a remedy for rheumatoid arthritis.
METHODS
The therapeutic effect of TAK-242 was tested in vitro using the human rheumatoid fibroblast-like synoviocyte (FLS) line MH7A or primary human FLS and in an adjuvant-induced arthritis (AIA) rat model.
RESULTS
TAK-242 dose dependently inhibited the increased expression of IL-6, IL-8, MMP-1, and VEGF in LPS-stimulated MH7A cells. It also inhibited the expression of IL-6 and IL-8 in poly(I:C), TLR3 activator-stimulated primary FLS, but not in IL-1β-stimulated primary FLS. These findings suggest that TAK-242 blocks a specific signaling pathway to some degree. Further, TAK-242 slightly inhibited mobilization of NF-κB into nuclei. In the AIA rat model, TAK-242 significantly reversed the body weight and paw thickness of AIA rats to the normal state at a dose of 5 mg/kg, but not at 3 mg/kg, and reduced the increased serum level of IL-6 and VEGF in AIA rats. It also significantly ameliorated inflammatory symptoms of joint tissues at day 21 of treatment, according to histology and RT-PCR.
CONCLUSIONS
Based on the drug repositioning concept, TAK-242, which is used for the treatment of TLR4-mediated inflammatory diseases, shows potential for cost-effective development as a remedy for rheumatoid arthritis or to control the progression of RA.
Identifiants
pubmed: 31973752
doi: 10.1186/s13075-020-2097-2
pii: 10.1186/s13075-020-2097-2
pmc: PMC6979396
doi:
Substances chimiques
Antirheumatic Agents
0
Sulfonamides
0
Toll-Like Receptor 4
0
ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
16Références
PLoS One. 2011;6(8):e23539
pubmed: 21858160
Mol Pain. 2014 Feb 06;10:10
pubmed: 24499354
Eur J Pharmacol. 2018 May 5;826:85-95
pubmed: 29501867
Front Immunol. 2014 Sep 25;5:461
pubmed: 25309543
Arthritis Res Ther. 2009;11(2):R49
pubmed: 19327174
Autoimmun Rev. 2017 Feb;16(2):103-113
pubmed: 27988432
Rheumatology (Oxford). 2006 Dec;45(12):1558-65
pubmed: 16705046
Crit Care Med. 2010 Aug;38(8):1685-94
pubmed: 20562702
Cell Rep. 2015 Jun 30;11(12):1941-52
pubmed: 26095366
J Med Chem. 2005 Nov 17;48(23):7457-67
pubmed: 16279805
Chem Biol Interact. 2016 Oct 25;258:175-86
pubmed: 27613480
Mol Pharmacol. 2011 Jan;79(1):34-41
pubmed: 20881006
Vaccines (Basel). 2017 Oct 04;5(4):null
pubmed: 28976923
Autoimmunity. 1998;28(4):197-208
pubmed: 9892501
Br J Pharmacol. 2009 Aug;157(7):1250-62
pubmed: 19563534
J Neuroinflammation. 2018 Nov 5;15(1):306
pubmed: 30396359
J Biochem. 1998 Dec 1;124(6):1153-62
pubmed: 9832620
Nat Rev Rheumatol. 2016 Jun;12(6):344-57
pubmed: 27170508
Arch Pharm Res. 2016 Aug;39(8):1032-49
pubmed: 27515048
Eur J Pharmacol. 2008 Apr 14;584(1):40-8
pubmed: 18299127
Eur J Pharm Biopharm. 2018 Dec;133:162-175
pubmed: 30339889
Arthritis Res Ther. 2007;9(4):R80
pubmed: 17697361
Nat Rev Immunol. 2006 Nov;6(11):823-35
pubmed: 17063184
JAMA. 2013 Mar 20;309(11):1154-62
pubmed: 23512062
Cytokine. 2016 Jan;77:115-26
pubmed: 26556105
Nat Rev Immunol. 2013 Jun;13(6):453-60
pubmed: 23681101
J Mol Med (Berl). 2015 Dec;93(12):1341-54
pubmed: 26184970
Front Physiol. 2018 May 08;9:504
pubmed: 29867550
Front Biosci. 2005 Sep 01;10:2478-88
pubmed: 15970510
Expert Opin Ther Pat. 2016 Jun;26(6):719-30
pubmed: 27136061
Life Sci. 2019 Feb 1;218:284-291
pubmed: 30611783
Life Sci. 2007 Sep 29;81(16):1309-16
pubmed: 17920637
Eur J Pharm Biopharm. 2017 Jun;115:229-242
pubmed: 28315446