SKLB023 blocks joint inflammation and cartilage destruction in arthritis models via suppression of nuclear factor-kappa B activation in macrophage

• Published in: PloS one Vol. 8; no. 2; p. e56349
• Main Authors: Xie, Caifeng, Ma, Liang, Liu, Juan, Li, Xiuxia, Pei, Heying, Xiang, Mingli, Chen, Lijuan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19-02-2013; Public Library of Science (PLoS)
• Subjects: Acetanilides - pharmacology; Acetanilides - therapeutic use; Analysis; Animal models; Animals; Ankle Joint - drug effects; Ankle Joint - immunology; Ankle Joint - pathology; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Arthritis; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - metabolism; Biology; Cartilage; Cartilage, Articular - drug effects; Cartilage, Articular - immunology; Cartilage, Articular - pathology; Cell activation; Cell Line; Collagen; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; Cytokines; Cytokines - blood; Deoxyribonucleic acid; Destruction; Disease; Disease Models, Animal; DNA; Female; Gene expression; Government agencies; Inflammation; Inflammation Mediators - blood; Inflammatory diseases; Interleukin 6; Kinases; Laboratory animals; Lipopolysaccharides - pharmacology; Macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Male; Medical schools; Medicine; Mice; Mice, Inbred DBA; Mitogen-Activated Protein Kinases - metabolism; Mitogens; NF-kappa B - metabolism; NF-κB protein; Nitric oxide; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; Pathogenesis; Penicillin; Peritoneum; Phosphorylation; Protein Processing, Post-Translational; Rats; Rats, Inbred Lew; Rheumatoid arthritis; Rheumatoid factor; Rodents; Signal transduction; Signal Transduction - drug effects; Thiazolidinediones - pharmacology; Thiazolidinediones - therapeutic use; Tissues; Tumor necrosis factor-α; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0056349

Rheumatoid arthritis (RA) is the most common arthritis and is mainly characterized by symmetric polyarticular joint disorders. Our previous study demonstrated a novel small molecule compound (Z)-N-(3-Chlorophenyl)-2-(4-((2,4-dioxothiazolidin-5-ylidene) methyl) phenoxy) acet-amide (SKLB023) showed potently anti-arthritic effects in a rat arthritis model, however, the underlying mechanisms for this are largely unknown. Both NF-κB and macrophages were reported to play important roles in the pathologic processes of RA. The purposes of this study were to indicate whether NF-κB and macrophages contributed to anti-arthritic effects of SKLB023 in two experimental arthritis models. Our results showed that SKLB023 could significantly improve joint inflammation and cartilage destruction both in adjuvant induced arthritis (AIA) and collagen-induced arthritis (CIA) models. We further found that the binding activation of NF-κB to DNA in joint tissues and RAW264.7 macrophages were suppressed by SKLB023. SKLB023 also inhibited the NF-κB activity in peritoneal macrophages by luciferase assay. Furthermore, the number of macrophages in synovial tissues was decreased after the treatment of different doses of SKLB023. The levels of TNF-α, IL-1β, and IL-6 in plasma, and the levels of TNF-α, NO, and IL-1β in peritoneal macrophages were down-regulated by SKLB023. Finally, SKLB023 attenuated the expression of iNOS and COX-2 in vivo and suppressed the phosphorylations of components of the mitogen-activated protein kinases (MAPKs). These observations identify a novel function for SKLB023 as an inhibitor of NF-κB in macrophages of RA, highlighting that SKLB023 was a potential therapeutic strategy for RA.