title: RhoA/ROCK-dependent pathway is required for TLR2-mediated IL-23 production in human synovial macrophages: suppression by cilostazol.
abstract: 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.
authors: Medical Research Center for Ischemic Tissue Regeneration, Pusan National University, Gyeongnam, South Korea.
authors: So Youn
authors: SY
authors: Park
authors: Sung Won
authors: SW
authors: Lee
authors: Won Suk
authors: WS
authors: Lee
authors: Byung Yong
authors: BY
authors: Rhim
authors: Seung Jin
authors: SJ
authors: Lee
authors: Sang Mo
authors: SM
authors: Kwon
authors: Ki Whan
authors: KW
authors: Hong
authors: Chi Dae
authors: CD
authors: Kim
mesh_terms: D036002:ADP Ribose Transferases / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D001905:Botulinum Toxins / Q000494:pharmacology; D016022:Case-Control Studies; D000077407:Cilostazol; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D053759:Interleukin-23 / Q000096:biosynthesis*; D007719:Knee Joint / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012016:Reference Values; D015398:Signal Transduction / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology; D013582:Synovial Fluid / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013682:Teichoic Acids / Q000378:metabolism / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology*; D013873:Thionucleotides / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000577:Amides; D053759:Interleukin-23; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009570:Nitriles; D011725:Pyridines; D013450:Sulfones; C495342:TLR2 protein, human; D013682:Teichoic Acids; D013777:Tetrazoles; D013873:Thionucleotides; D051195:Toll-Like Receptor 2; C066737:RHOA protein, human; C108830:Y 27632; C016957:adenosine-3',5'-cyclic phosphorothioate; C009900:lipoteichoic acid; D000242:Cyclic AMP; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D054460:rho-Associated Kinases; D001905:Botulinum Toxins; D020742:rhoA GTP-Binding Protein; D000077407:Cilostazol
keywords: CIA; Cilostazol; IL-23; LTA; RA; RA synovial macrophages; RhoA; TLR2; collagen induced arthritis; interleukin-23; lipoteichoic acid; rheumatoid arthritis; toll like receptor 2