title: SKLB023 blocks joint inflammation and cartilage destruction in arthritis models via suppression of nuclear factor-kappa B activation in macrophage.
abstract: 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.
authors: State Key Laboratory of Biotherapy, West China Medical School, Sichuan University, Chengdu, China.
authors: Caifeng
authors: C
authors: Xie
authors: Liang
authors: L
authors: Ma
authors: Juan
authors: J
authors: Liu
authors: Xiuxia
authors: X
authors: Li
authors: Heying
authors: H
authors: Pei
authors: Mingli
authors: M
authors: Xiang
authors: Lijuan
authors: L
authors: Chen
mesh_terms: D000083:Acetanilides / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000843:Ankle Joint / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D002358:Cartilage, Articular / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D018836:Inflammation Mediators / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000083:Acetanilides; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C582844:N-(3-chlorophenyl)-2-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)acetamide; D016328:NF-kappa B; D045162:Thiazolidinediones; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D020928:Mitogen-Activated Protein Kinases