title: Selective spleen tyrosine kinase inhibition delays autoimmune arthritis in mice.
abstract: Spleen tyrosine kinase (SYK) has an important role in immunoreceptor signaling, and SYK inhibition has accordingly attenuated immune-mediated injury in several models. Therefore, the present study examined the effect of SYK inhibition with the selective spleen tyrosine kinase inhibitor P505-15 in experimental rheumatoid arthritis (RA) using a murine model of collagen-induced arthritis (CIA). Treatment with the selective SYK inhibitor P505-15, a small molecule kinase inhibitor selective for SYK, led to a reduction in arthritis score and attenuated histological damage. P505-15 reduced cartilage destruction and macrophage infiltration in CIA mice. In addition, P505-15-treated mice showed lower circulating levels of type II-collagen immunoglobulin (Ig)G1 and IgG2 and pro-inflammatory cytokines. Importantly, P505-15 treatment markedly reduced the interleukin 1β-stimulated inflammatory response in human RA synovial cells. Given these encouraging results, a key function for SYK in the development of RA was identified, highlighting that SYK may be a potential therapeutic target for human RA.
authors.affiliation: Department of Joint Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, P.R. China.
authors.forename: Zuofu
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Hyperbaric Oxygen, Yantai Yuhuangding Hospital, Yantai, Shandong 264000, P.R. China.
authors.forename: Chunni
authors.initials: C
authors.lastname: Cao
authors.affiliation: Department of Joint Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, P.R. China.
authors.forename: Shui
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Joint Surgery, Yantai Yuhuangding Hospital, Yantai, Shandong 264000, P.R. China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000818:Animals; D000843:Ankle Joint / Q000473:pathology; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D002356:Cartilage / Q000187:drug effects / Q000473:pathology; D002478:Cells, Cultured; D024043:Collagen Type II / Q000276:immunology; D003514:Cyclohexylamines / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D000072377:Syk Kinase; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: C571149:4-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-2-(2-aminocyclohexylamino)pyrimidine-5-carboxamide; D024043:Collagen Type II; D003514:Cyclohexylamines; D016207:Cytokines; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse