Toll-Like Receptor 4 Agonists Mrp 8 And Mrp 14 Act As Endogenous Enhancers Of Msu-Crystal Induced Il-1 Secretion In Vitro And Reflect Disease Activity In Gout Patients In Vivo

Background Monosodium urate (MSU) crystal induced interleukin-1 (IL-1β) secretion is a critical pathogenic factor in the development of gout and serves as a therapeutic target in these patients. Nevertheless, without co-stimulation by a pro-IL-1β inducing factor, such as lipopolysaccharides, MSU alone does not induce IL-1β secretion in vitro . The endogenous Toll-like receptor 4 (TLR-4) agonists myeloid related protein (MRP) 8 and MRP14 play a significant role in human inflammatory and infectious diseases, reflect disease activity and have been shown to be an important pathogenic factor in murine arthritis models. Objectives To analyze the co-stimulatory properties of MRP8 and MRP14 that lead to enhancement of MSU crystal induced IL-1β secretion, verify their expression in gout patients and test their value as biomarkers in gout patients. Methods The co-stimulatory effects of MRP8 and MRP14 on MSU-induced IL-1β secretion were tested in vitro on primary human monocytes and macrophages, and on murine macrophages, with confirmation by ELISA and Western Blot. Furthermore MSU-induced release of MRPs from human neutrophils and monocytes was measured by ELISA. MRP8 and MRP14 was measured in paired serum and synovial fluid samples (n=15) and in synovial tissue (n=10) of gout patients. The relationship between disease activity and MRP expression was analyzed in the serum of acute and convalescent gout patients (each n=40). Results MRP8 and MRP14 were released by MSU-activated human neutrophils and monocytes and induced pro-IL-1β production in monocytes. MSU-induced IL-1β secretion was significantly increased by MRP co-stimulation in human and murine monocytes and macrophages. MRP was found in the synovia and synovial fluid of active gout patients and levels were significantly elevated compared to those in osteoarthritis patients. Moreover, the serum levels of MRPs in gout patients were positively associated with disease activity (mean ± 95% CI, acute: 2020±420 ng/ml, convalescent: 920±70 ng/ml, controls: 430±100 ng/ml; p Conclusions MRP8 and MRP14 are endogenous enhancers of MSU crystal-induced IL-1β secretion by induction of pro-IL-1β via TLR-4. These proteins are found at the site of inflammation in patients with acute gout and their serum levels reflect disease activity in these patients. These findings indicate a new role of endogenous TLR-4 ligands in the pathogenesis of gout. References [1]Martinon et al., Nature. 2006 Mar 9;440(7081):237-41. [2]Vogl et al., Nat Med. 2007 Sep;13(9):1042-9. [3]van Lent et al., Ann Rheum Dis. 2008 Dec;67(12):1750-8. Disclosure of Interest None Declared