Monosodium urate crystals stimulate IL-6 production via TAK1 and induce pulmonary vascular dysfunction

Abstract

Uric acid (UA), the product of purine catabolism, is released from injured or infected cells. Beyond maximal solubility, UA precipitates into monosodium urate (MSU) crystals which cause inflammation by activating the innate immune system. UA levels are increased in several respiratory diseases associated with hypoxemia including ARDS, pulmonary hypertension or COPD. The aim of this study was to analyse the effects of MSU crystals on vascular function in isolated pulmonary arteries (PA). PA smooth muscle cells (SMC) were incubated for 24h in the absence (Ctrl) or presence of MSU crystals (250μg/ml). IL-6 levels were determined by ELISA and contractile responses analysed in human PA mounted in a wire myograph. Exposure to MSU crystals for 24h significantly increased IL-6 release by rat PASMCs (Ctrl=0.4±0.1; MSU=2.2±0.7 ng/ml). Induction of IL-6 by MSU crystals was inhibited by the TAK1 inhibitor 5Z-7-oxozeaenol but was not affected by the TLR4 antagonist TAK242 or the pan-caspase inhibitor Z-VAD-FMK. Furthermore, MSU crystals also stimulated human PASMCs to release IL-6 (Ctrl=2±1; MSU=7±2 ng/ml), markedly impaired hypoxic pulmonary vasoconstriction (HPV) and reduced the relaxant responses to acetylcholine while preserving the contractile responses to endothelin-1 in human PA. In summary, MSU crystals induce endothelial dysfunction, impair HPV and stimulate the release of IL-6 by PASMCs through a mechanism which involves TAK-1 activation. These findings suggest that MSU crystals might contribute to the development of pulmonary vascular dysfunction and arterial hypoxemia in conditions associated with high levels of UA. Supported by Spanish MINECO 2011-28150 and ISCIII CP12/03304.