Journal Article

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

Netea, Mihai G, Joosten, Leo A B, Cleophas, Maartje C P, van de Veerdonk, Frank L, Koenders, Marije I, Kim, Soohyun, Azam, Tania, Dinarello, Charles A, Crişan, Tania O

2016

Overview

ObjectivesIn 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.MethodsA 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.ResultsAAT-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.ConclusionsA 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.

• Subject: alpha 1-Antitrypsin - administration & dosage / alpha 1-Antitrypsin - pharmacology / alpha 1-Antitrypsin - therapeutic use / Animals / Arthritis, Experimental - drug therapy / Arthritis, Experimental - immunology / Arthritis, Experimental - pathology / Arthritis, Gouty - drug therapy / Arthritis, Gouty - immunology / Arthritis, Gouty - pathology / Cells, Cultured / Dose-Response Relationship, Drug / Drug Evaluation, Preclinical - methods / Gout Suppressants - administration & dosage / Gout Suppressants - pharmacology / Gout Suppressants - therapeutic use / Humans / Immunoglobulin Fc Fragments - administration & dosage / Immunoglobulin Fc Fragments - pharmacology / Immunoglobulin Fc Fragments - therapeutic use / Injections, Intra-Articular / Injections, Intraperitoneal / Interleukin 1 Receptor Antagonist Protein - biosynthesis / Interleukin-1beta - antagonists & inhibitors / Interleukin-1beta - metabolism / Lipopolysaccharide Receptors - analysis / Male / Mice, Inbred C57BL / Mice, Transgenic / Monocytes - drug effects / Monocytes - immunology / Recombinant Fusion Proteins - administration & dosage / Recombinant Fusion Proteins - pharmacology / Recombinant Fusion Proteins - therapeutic use