Format

Send to

Choose Destination
Ann Rheum Dis. 2016 Jan;75(1):311-5. doi: 10.1136/annrheumdis-2014-207201. Epub 2015 Sep 9.

Tofacitinib regulates synovial inflammation in psoriatic arthritis, inhibiting STAT activation and induction of negative feedback inhibitors.

Author information

1
Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre, St Vincent's University Hospital, Dublin, Ireland.

Abstract

BACKGROUND:

Psoriatic arthritis (PsA) is a chronic inflammatory disease, characterised by synovitis and destruction of articular cartilage/bone. Janus-kinase and signal transducer and activator of transcription (JAK-STAT) signalling pathway is implicated in the pathogenesis of PsA.

OBJECTIVES:

To examine the effect of tofacitinib (JAK inhibitor) on proinflammatory mechanisms in PsA.

METHODS:

Primary PsA synovial fibroblasts (PsAFLS) and ex vivo PsA synovial explants were cultured with tofacitinib (1 µM). PhosphoSTAT3 (pSTAT3), phosphoSTAT1 (pSTAT1), suppressor of cytokine signaling-3 (SOCS3), protein inhibitor of activated Stat3 (PIAS3) and nuclear factor kappa B cells (NFκBp65) were quantified by western blot. The effect of tofacitinib on PsAFLS migration, invasion, Matrigel network formation and matrix metallopeptidase (MMP)2/9 was quantified by invasion/migration assays and zymography. Interleukin (IL)-6, IL-8, IFN-gamma-inducible protein 10 (IP-10) monocyte chemoattractant protein (MCP)-1, IL-17, IL-10, MMP3 and tissue inhibitor of metalloproteinases 3 (TIMP3) were assessed by ELISA.

RESULTS:

Tofacitinib significantly decreased pSTAT3, pSTAT1, NFκBp65 and induced SOCS3 and PIAS3 expression in PsAFLS and synovial explant cultures (p<0.05). Functionally, PsAFLS invasion, network formation and migration were inhibited by tofacitinib (all p<0.05). In PsA explant, tofacitinib significantly decreased spontaneous secretion of IL-6, IL-8, MCP-1, MMP9/MMP2, MMP3 (all p<0.05) and decreased the MMP3/TIMP3 ratio (p<0.05), with no effect observed for IP-10 or IL-10.

CONCLUSIONS:

This study further supports JAK-STAT inhibition as a therapeutic target for the treatment of PsA.

KEYWORDS:

Inflammation; Psoriatic Arthritis; Synovitis

PMID:
26353790
PMCID:
PMC4717390
DOI:
10.1136/annrheumdis-2014-207201
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center