Affiliation:
1. Graduated Program in Pharmacology, Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo
2. Graduated Program in Pharmacology, Biochemistry and Molecular Biology Department, Federal University of Santa Maria (UFSM), Santa Maria, Rio Grande do Sul
3. Graduated Program in Pharmacology, Pharmacology Department, Federal University of Santa Catarina (UFSC), Florianopolis, Santa Catarina, Brazil
4. Graduated Program in Genetics and Biochemistry, Biotechnology Institute, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil
Abstract
AbstractObjectiveThe present study aimed to elucidate the mechanisms involved in MSU-induced IL-1β release in a rodent animal model of acute gout arthritis.MethodsPainful (mechanical and thermal hypersensitivity, ongoing pain and arthritis score) and inflammatory (oedema, plasma extravasation, cell infiltration and IL-1β release) parameters were assessed several hours after intra-articular injection of MSU (100 µg/articulation) in wild-type or knockout mice for Toll-like receptor 4 (TLR4), inducible nitric oxide synthase (iNOS), transient receptor potential (TRP) V1 and the IL-1 receptor (IL-1R). Also, wild-type animals were treated with clodronate, lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS) (TLR4 antagonist), spleen tyrosine kinase (SYK) inhibitor (iSYK), aminoguanidine (AMG, an iNOS inhibitor) or SB366791 (TRPV1 antagonist). Nitrite/nitrate and IL-1β levels were measured on the synovial fluid of wild-type mice, 2 h after intra-articular MSU injections, or medium from macrophages stimulated for MSU (1000 μg) for 2 h.ResultsIntra-articular MSU injection caused robust nociception and severe inflammation from 2 up to 6 h after injection, which were prevented by the pre-treatment with clodronate, LPS-RS, iSYK, AMG and SB366791, or the genetic ablation of TLR4, iNOS, TRPV1 or IL-1R. MSU also increased nitrite/nitrate and IL-1β levels in the synovial fluid, which was prevented by clodronate, LPS-RS, iSYK and AMG, but not by SB366791. Similarly, MSU-stimulated peritoneal macrophages released nitric oxide, which was prevented by LPS-RS, iSYK and AMG, but not by SB366791, and released IL-1β, which was prevented by LPS-RS, iSYK, AMG and SB366791.ConclusionOur data indicate that MSU may activate TLR4, SYK, iNOS and TRPV1 to induce the release of IL-1β by macrophages, triggering nociception and inflammation during acute gout attack.
Funder
São Paulo Research Foundation
Coordination for the Improvement of Higher Education Personnel
Brazilian National Council for Scientific and Technological Development
Publisher
Oxford University Press (OUP)
Subject
Pharmacology (medical),Rheumatology