PT  - JOURNAL ARTICLE
AU  - Joosten, Leo A B
AU  - Crişan, Tania O
AU  - Azam, Tania
AU  - Cleophas, Maartje C P
AU  - Koenders, Marije I
AU  - van de Veerdonk, Frank L
AU  - Netea, Mihai G
AU  - Kim, Soohyun
AU  - Dinarello, Charles A
TI  - 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
AID  - 10.1136/annrheumdis-2014-206966
DP  - 2016 Jun 01
TA  - Annals of the Rheumatic Diseases
PG  - 1219--1227
VI  - 75
IP  - 6
4099  - http://ard.bmj.com/content/75/6/1219.short
4100  - http://ard.bmj.com/content/75/6/1219.full
SO  - Ann Rheum Dis2016 Jun 01; 75
AB  - 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.