Alpha-1-anti-trypsin-Fc fusion protein ameliorates gouty arthritis by reducing release and extracellular processing of IL-1beta and by the induction of endogenous IL-1Ra
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SourceAnnals of the Rheumatic Diseases, 75, 6, (2016), pp. 1219-1227
Article / Letter to editor
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Annals of the Rheumatic Diseases
SubjectRadboudumc 4: lnfectious Diseases and Global Health RIMLS: Radboud Institute for Molecular Life Sciences; Radboudumc 5: Inflammatory diseases RIMLS: Radboud Institute for Molecular Life Sciences
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)-1beta 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-1beta release from human blood monocytes and for inhibition of extracellular IL-1beta precursor processing. RESULTS: AAT-Fc markedly suppressed MSU/C16.0-induced joint inflammation by 85-91% (p<0.001). Ex vivo production of IL-1beta 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-1beta by 60% in transgenic mice expressing low levels of human AAT. In vitro, AAT-Fc reduced MSU/C16.0-induced release of IL-1beta from human blood monocytes and inhibited proteinase-3-mediated extracellular processing of the IL-1beta precursor into active IL-1beta. 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.
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