umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Inhibition of pSTAT1 by tofacitinib accounts for the early improvement of experimental chronic synovitis
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Bone and Joint Research Unit, Rheumatology Department, IIS-Fundación Jiménez Díaz UAM, Avenida Reyes Católicos, 2. 28040, Madrid, Spain.
Show others and affiliations
2019 (English)In: Journal of Inflammation, ISSN 1476-9255, E-ISSN 1476-9255, Vol. 16, article id 2Article in journal (Refereed) Published
Abstract [en]

Background: In order to gain insight into the early effects drawn by JAK inhibitors on intra-joint JAK/STAT-dependent signaling, we sought synovial activation of STATs and their end-products, along with their modification with tofacitinib (TOFA), at flare-up in antigen induced arthritis (AIA). New Zealand rabbits were randomly assigned to four groups –healthy controls, AIA, TOFA-treated AIA, or TOFA-treated controls–. AIA was induced with 4 weekly intra-articular ovalbumin injections in sensitized animals. TOFA (10 mg·kg− 1·day− 1) was administered for the last 2 weeks. Animals were euthanized 24 h after the last injection.

Results: AIA animals showed high-grade synovitis, which was partially improved by TOFA. No effects of the treatment were found on serum C-reactive protein or on the synovial macrophage infiltration at this stage. Synovial MMP-1,-3 and -13 expression levels in treated AIA rabbits were found to drop to those of controls, while a downregulation of IL6, IFNγ and TNF was evident in treated versus untreated AIA rabbits. Concurrently, a reduction in pSTAT1 and SOCS1, but not in pSTAT3, SOCS3 or active NFκB-p65, was noted with TOFA.

Conclusions: Studying the mechanism of action of immunomodulatory drugs represents a major challenge in vivo, since drug-dependent decreases in inflammation very likely mask direct effects on disease mechanisms. This study design allowed us to prevent any confounding effect resulting from reductions in the overall inflammatory status, hence assessing the true pharmacological actions of TOFA in a very severe synovitis. Our findings point to pSTAT1 and MMPs as early molecular readouts of response to this JAK inhibitor.

Place, publisher, year, edition, pages
BioMed Central, 2019. Vol. 16, article id 2
Keywords [en]
Rheumatoid arthritis, Synovitis, Janus kinase inhibitors, Tofacitinib
National Category
Rheumatology and Autoimmunity
Identifiers
URN: urn:nbn:se:umu:diva-156597DOI: 10.1186/s12950-019-0206-2ISI: 000457197600001PubMedID: 30728752OAI: oai:DiVA.org:umu-156597DiVA, id: diva2:1290445
Available from: 2019-02-20 Created: 2019-02-20 Last updated: 2019-02-20Bibliographically approved

Open Access in DiVA

fulltext(9711 kB)44 downloads
File information
File name FULLTEXT01.pdfFile size 9711 kBChecksum SHA-512
a1671ee878a122dbc3789fa3888e9ca6b3208dd99404ebecc516a8dd04d5b2422fadbf01aa98457bf8cc3c393b59ce1f0ccf47902574268c427d820fe515901d
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed
By organisation
Department of Molecular Biology (Faculty of Medicine)
In the same journal
Journal of Inflammation
Rheumatology and Autoimmunity

Search outside of DiVA

GoogleGoogle Scholar
Total: 44 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 67 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf