RhoA/ROCK-dependent pathway is required for TLR2-mediated IL-23 production in human synovial macrophages: Suppression by cilostazol

• Published in: Biochemical pharmacology Vol. 86; no. 9; pp. 1320 - 1327
• Main Authors: Park, So Youn, Lee, Sung Won, Lee, Won Suk, Rhim, Byung Yong, Lee, Seung Jin, Kwon, Sang Mo, Hong, Ki Whan, Kim, Chi Dae
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.11.2013
• Subjects: ADP Ribose Transferases - pharmacology; Amides - pharmacology; Animals; antigen-presenting cells; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; blood; Botulinum Toxins - pharmacology; cAMP-dependent protein kinase; Case-Control Studies; Cilostazol; Cyclic AMP - analogs & derivatives; Cyclic AMP - pharmacology; drugs; Humans; IL-23; immune response; Interleukin-23 - biosynthesis; Knee Joint - drug effects; Knee Joint - metabolism; Lipopolysaccharides - metabolism; Lipopolysaccharides - pharmacology; macrophages; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Mice, Inbred DBA; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; Nitriles - pharmacology; patients; Pyridines - pharmacology; RA synovial macrophages; Reference Values; rheumatoid arthritis; rho-Associated Kinases - metabolism; RhoA; rhoA GTP-Binding Protein - metabolism; Signal Transduction - drug effects; Sulfones - pharmacology; synovial fluid; Synovial Fluid - cytology; Synovial Fluid - drug effects; Synovial Fluid - metabolism; Teichoic Acids - metabolism; Teichoic Acids - pharmacology; Tetrazoles - pharmacology; Thionucleotides - pharmacology; TLR2; Toll-Like Receptor 2 - metabolism; LTA; CIA; Cilostazol; IL-23; RA synovial macrophages; RhoA; RA; TLR2; toll like receptor 2; rheumatoid arthritis; interleukin-23; collagen induced arthritis; lipoteichoic acid
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2013.08.017

IL-23 is produced by antigen presenting cells and plays critical roles in immune response in rheumatoid arthritis. In this study, we investigated whether the RhoA/Rho-kinase pathway is required to elevate TLR2-mediated IL-23 production in synovial macrophages from patients with rheumatoid arthritis (RA), and then examined the suppressive effect of cilostazol on these pathways. IL-23 production was elevated by lipoteichoic acid (LTA), a TLR2 ligand, and this elevation was more prominent in RA macrophages than in those from peripheral blood of normal control. LTA increased the activation of RhoA in association with increased the nuclear translocation of NF-κB and its DNA-binding activity. Pretreatment of RA macrophages with the pharmacological inhibitors exoenzyme C3 (RhoA), Y27632 (Rho-kinase) or BAY11-7082 (NF-κB) inhibited IL-23 production by LTA. Inhibition of the RhoA/Rho-kinase pathway by these drugs attenuated NF-κB activation. Cilostazol suppressed the TLR2-mediated activation of RhoA, decreased NF-κB activity with down-regulated IL-23 production, and these effects were reversed by Rp-cAMPS, as an inhibitor of cAMP-dependent protein kinase. The expression of IL-23, which colocalized with CD68(+) cells in knee joint of CIA mice, was significantly attenuated by cilostazol along with the decreased severity of arthritis. Taken together, the RhoA/Rho-kinase pathway signals TLR2-stimulated IL-23 production in synovial fluid macrophages via activation of NF-κB. Thus it is summarized that cilostazol suppresses TLR2-mediated IL-23 production by suppressing RhoA pathway via cAMP-dependent protein kinase activation.