title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Tania O
authors.initials: TO
authors.lastname: Crişan
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Tania
authors.initials: T
authors.lastname: Azam
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Maartje C P
authors.initials: MC
authors.lastname: Cleophas
authors.affiliation: Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Marije I
authors.initials: MI
authors.lastname: Koenders
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Laboratory of Cytokine Immunology, Konkuk University, Seoul, Korea.
authors.forename: Soohyun
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D015210:Arthritis, Gouty / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006074:Gout Suppressants / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007270:Injections, Intra-Articular; D007274:Injections, Intraperitoneal; D053590:Interleukin 1 Receptor Antagonist Protein / Q000096:biosynthesis*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000515:alpha 1-Antitrypsin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D006074:Gout Suppressants; C507764:Il1rn protein, mouse; D007141:Immunoglobulin Fc Fragments; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D018950:Lipopolysaccharide Receptors; D011993:Recombinant Fusion Proteins; D000515:alpha 1-Antitrypsin; C000619260:alpha-1-anti-trypsin-IgG1 Fc fusion protein
keywords: Cytokines; Gout; Inflammation; Treatment