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Tofacitinib regulates synovial inflammation in psoriatic arthritis, inhibiting STAT activation and induction of negative feedback inhibitors
  1. W Gao,
  2. T McGarry,
  3. C Orr,
  4. J McCormick,
  5. D J Veale,
  6. U Fearon
  1. Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre, St Vincent's University Hospital, Dublin, Ireland
  1. Correspondence to Dr U Fearon, Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre, St. Vincent's University Hospital, Dublin 4, Ireland; ursula.fearon{at}ucd.ie

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.

  • Psoriatic Arthritis
  • Synovitis
  • Inflammation

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