Suppression of <scp>PU</scp>.1‐linked <scp>TLR</scp>4 expression by cilostazol with decrease of cytokine production in macrophages from patients with rheumatoid arthritis

Park, S Y; Lee, S W; Baek, Sun‐Yong; Lee, C W; Lee, W S; Rhim, Byung Yong; Hong, Ki Whan; Kim, C D

doi:10.1111/bph.12021

Cited by 44 publications

(32 citation statements)

References 35 publications

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“…Recently, we further reported that cilostazol significantly suppressed LPS-induced TLR4 expression by blocking PU.1 transcriptional activity in synovial macrophages obtained from RA patients. In addition, cilostazol suppressed IκBα degradation, the nuclear translocation of NF-κB p65, associated with reduced production of the cytokines TNF-α and IL-1β [17]. Furthermore, synovial inflammation and bone erosion were significantly inhibited by cilostazol treatment in a murine CIA model.…”

Section: Contents Lists Available At Sciencedirectmentioning

confidence: 88%

“…Yang and Karsenty [12] emphasized that PU.1 is absolutely required for macrophage differentiation. Furthermore, Park et al [17] found that cilostazol down-regulated LPS-stimulated PU.1-linked TLR4 expression and NF-κB signal pathways, and then suppressed inflammatory cytokine production in synovial macrophages from RA patients and markedly inhibited the severity of CIA in mice. In the present study, we observed that cilostazol inhibited RANKL-induced RANK expression by inhibiting PU.1, which is consistent with a previous report by Kwon et al [13].…”

Section: Discussionmentioning

confidence: 99%

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Suppression of RANKL-induced osteoclast differentiation by cilostazol via SIRT1-induced RANK inhibition

Park

Lee

Kim

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Osteoclasts are bone-specific multinucleated cells generated by differentiation of monocyte/macrophage hematopoietic lineages and degrade bone matrix by secretion of lytic enzymes. The regulation of osteoclast differentiation provides a potential strategy for treatment of bone-lytic damage. In this study, cilostazol, an inhibitor of type III phosphodiesterase, inhibited RANKL [receptor activator of nuclear factor kappa B (RANK) ligand]-induced RANK expression in bone marrow-derived monocyte/macrophage precursors (BMMs) and Raw 264.7 cells by inhibiting PU.1 via SIRT1 activation. RANKL-induced RANK expression was attenuated by cilostazol and rSIRT1 in Raw 264.7 cells, and these were blocked by sirtinol. In line with these, cilostazol elevated SIRT1 mRNA and protein levels in 12-24h and increased SIRT1 activity, and these effects were inhibited by sirtinol. Furthermore, the RANKL-induced nuclear expression of PU.1, a transcription factor required for macrophage differentiation, was suppressed by cilostazol. Additionally, marked RANKL-induced RANK immunofluorescence staining in Raw 264.7 cells was attenuated by cilostazol and rSIRT1, and both attenuations were prevented by sirtinol. Extensive RANK staining of knee synovial tissues in a mouse model of collagen-induced arthritis (CIA) was markedly reduced by cilostazol (30mg/kg/day). In line with these results, both RANKL- and M-CSF-induced differentiation of BMMs to multinucleated TRAP(+) giant cells and resorption pit formation were inhibited by cilostazol associated with a decrease in TRAP (a marker enzyme of osteoclasts) activity. In conclusion, cilostazol activates SIRT1, which suppresses the nuclear translocation of PU.1, and thus, inhibits RANKL-stimulated RANK expression and causes anti-osteoclast formation in BMMs in vitro and in their murine model of CIA.

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Section: Contents Lists Available At Sciencedirectmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Suppression of RANKL-induced osteoclast differentiation by cilostazol via SIRT1-induced RANK inhibition

Park

Lee

Kim

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Cilostazol has also been shown to inhibit IFN-α and TNF-α production from plasmacytoid dendritic cells in a dosedependent manner [14]. In addition, cilostazol has been reported to suppress TNF-α and IL-1β production in synovial macrophages from RA patients via inhibition of TLR4/MyD88/ NF-κB signaling pathways [15]. Moreover, cilostazol inhibits TLR2-induced IL-23 production in human synovial macrophages by suppressing the RhoA pathway via a cAMP-dependent pathway [16].…”

Section: Discussionmentioning

confidence: 99%

Cilostazol Suppresses IL-23 Production in Human Dendritic Cells via an AMPK-Dependent Pathway

Shi¹,

Yin²,

Liu³

et al. 2016

Cell Physiol Biochem

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Background/Aims: Cilostazol has been previously demonstrated to inhibit IL-23 production in human synovial macrophages via a RhoA/ROCK-dependent pathway. However, whether cilostazol affects IL-23 production in human dendritic cells remains largely unknown. The present study was designed to investigate this question and elucidate the possible underlying mechanisms. Methods: Human monocyte-derived dendritic cells (mo-DCs) were pretreated with or without cilostazol and then incubated with zymosan. Enzyme-linked immunosorbent assay (ELISA) and real time PCR analyses were used to measure IL-23 protein expression and RNA levels, respectively, whereas Western blotting was used to measure the expression and phosphorylation level of AMPK. Results: Our results demonstrated that cilostazol suppressed zymosan-induced IL-23 protein production in a concentration dependent manner without affecting dendritic cell viability. In addition, it was found that cilostazol suppressed the expression of the p19 and p40 subunits of IL-23. Moreover, cilostazol mimicked the effect of the AMPK agonist A-769662, as demonstrated by the fact that IL-23 production was also inhibited by A-769662, and the effect of cilostazol on IL-23 production was blocked by the AMPK antagonist Compound C. More importantly, Western blotting demonstrated that cilostazol led to an increased phosphorylation of AMPK. Conclusion: Collectively, our data suggest that cilostazol inhibits the production of IL-23 in human mo-DCs, potentially via the activation of AMPK. This suggests that cilostazol could be an effective anti-inflammatory agent in IL-23- and dendritic cell-related diseases.

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“…TLR4 responsiveness is reported to play a role in the pathogenesis of other autoimmune diseases besides SLE including coxsackievirus-induced autoimmune myocarditis [132] collagen-induced arthritis [133], primary biliary cirrhosis [134], experimental autoimmune uveitis (EAU) [135], antibody-mediated glomerulonephritis [136] and autoimmune destructive arthritis [137]. However, most data were in mice; data in humans are largely lacking.…”

Section: Tlr4 Responsiveness and Monocyte Activation In Other Autoimmmentioning

confidence: 99%

Sex differences in monocytes and TLR4 associated immune responses; implications for systemic lupus erythematosus (SLE)

Jiang¹,

Gilkeson²

2014

J Immunother Appl

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It has been shown that TLR7 and TLR9 signaling play a role in SLE pathogenesis. Our recent study revealed that estrogen receptor α knockout mice have impaired inflammatory responses to TLR3, TLR4, TLR7 and TLR9 ligand stimulation in DCs, B cells and whole spleen cells. These findings indicate that estrogen receptor mediated signaling may impact universal TLR responsiveness. Whether estrogen has a direct or indirect effect on TLR responsiveness by immune cells is not clear. There is evidence of a role of TLR4 in SLE disease pathogenesis, such as the kidney damage, the induction of CD40 and autoantibodies, the suppression of regulatory T cells, and the role of pro-inflammatory cytokines (e.g., IL-6, IL-1β, TNF-α) in SLE pathogenesis that can be induced by TLR4-mediated monocyte activation, suggesting that TLR4 and TLR4 responsiveness are also important for SLE disease. This review will focus on TLR4 responses and monocytes, which are understudied in systemic autoimmune diseases such as SLE.

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Suppression of PU.1‐linked TLR4 expression by cilostazol with decrease of cytokine production in macrophages from patients with rheumatoid arthritis

Cited by 44 publications

References 35 publications

Suppression of RANKL-induced osteoclast differentiation by cilostazol via SIRT1-induced RANK inhibition

Suppression of RANKL-induced osteoclast differentiation by cilostazol via SIRT1-induced RANK inhibition

Cilostazol Suppresses IL-23 Production in Human Dendritic Cells via an AMPK-Dependent Pathway

Sex differences in monocytes and TLR4 associated immune responses; implications for systemic lupus erythematosus (SLE)

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