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Alpha-1-anti-trypsin-Fc fusion protein ameliorates gouty arthritis by reducing release and extracellular processing of IL-1β and by the induction of endogenous IL-1Ra
  1. Leo A B Joosten1,2,3,
  2. Tania O Crişan2,3,
  3. Tania Azam1,
  4. Maartje C P Cleophas2,3,
  5. Marije I Koenders4,
  6. Frank L van de Veerdonk2,3,
  7. Mihai G Netea2,3,
  8. Soohyun Kim5,
  9. Charles A Dinarello1,2,3
  1. 1Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA
  2. 2Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
  3. 3Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands
  4. 4Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands
  5. 5Laboratory of Cytokine Immunology, Konkuk University, Seoul, Korea
  1. Correspondence to Professor Leo A B Joosten, Department of Internal Medicine (463), Radboud University Medical Center, Geert Grooteplein zuid 8, Nijmegen 6525 GA, The Netherlands; leo.joosten{at}radboudumc.nl

Abstract

Objectives In the present study, we generated a new protein, recombinant human alpha-1-anti-trypsin (AAT)-IgG1 Fc fusion protein (AAT-Fc), and evaluated its properties to suppress inflammation and interleukin (IL)-1β in a mouse model of gouty arthritis.

Methods A combination of monosodium urate (MSU) crystals and the fatty acid C16.0 (MSU/C16.0) was injected intra-articularly into the knee to induce gouty arthritis. Joint swelling, synovial cytokine production and histopathology were determined after 4 h. AAT-Fc was evaluated for inhibition of MSU/C16.0-induced IL-1β release from human blood monocytes and for inhibition of extracellular IL-1β precursor processing.

Results AAT-Fc markedly suppressed MSU/C16.0-induced joint inflammation by 85–91% (p<0.001). Ex vivo production of IL-1β and IL-6 from cultured synovia were similarly reduced (63% and 65%, respectively). The efficacy of 2.0 mg/kg AAT-Fc in reducing inflammation was comparable to 80 mg/kg of plasma-derived AAT. Injection of AAT-Fc into mice increased circulating levels of endogenous IL-1 receptor antagonist by fourfold. We also observed that joint swelling was reduced by 80%, cellular infiltration by 95% and synovial production of IL-1β by 60% in transgenic mice expressing low levels of human AAT. In vitro, AAT-Fc reduced MSU/C16.0-induced release of IL-1β from human blood monocytes and inhibited proteinase-3-mediated extracellular processing of the IL-1β precursor into active IL-1β.

Conclusions A single low dose of AAT-Fc is highly effective in reducing joint inflammation in this model of acute gouty arthritis. Considering the long-term safety of plasma-derived AAT use in humans, subcutaneous AAT-Fc emerges as a promising therapy for gout attacks.

  • Gout
  • Inflammation
  • Cytokines
  • Treatment

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