• International Journal of Oral Biology
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• 제38권1호
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• pp.37-42
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• 2013

Receptor activator of NF-${\kappa}B$ ligand (RANKL) is an essential cytokine for osteoclast differentiation, activation and survival. T lymphocytes such as $T_{17}$ cells, a subset of T helper cells that produce IL-17, play an important role in rheumatoid arthritic bone resorption by producing inflammatory cytokines and RANKL. It has not yet been clearly elucidated how T cell activation induces RANKL expression. T cell receptor activation induces the activation of nuclear factor of activated T cell (NFAT) and expression of its target genes. In this study, we examined the role of NFAT in T cell activation-induced RANKL expression. EL-4, a murine T lymphocytic cell line, was used. When T cell activation was induced by phorbol 12-myristate 13-acetate (PMA) and ionomycin, RANKL expression increased in a time-dependent manner. In the presence of cyclosporin, an inhibitor of NFAT activation, this PMA/ionomycin-induced RANKL expression was blocked. Overexpression of either NFATc1 or NFATc3 induced RANKL expression. Chromatin immunoprecipitation results demonstrated that PMA/ionomycin treatment induced the binding of NFATc1 and NFATc3 to the mouse RANKL gene promoter. These results suggest that NFATc1 and NFATc3 mediates T cell receptor activation-induced RANKL expression in T lymphocytes.

• Molecules and Cells
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• 제40권10호
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• pp.752-760
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• 2017

A2B adenosine receptor (A2BAR) is known to be the regulator of bone homeostasis, but its regulatory mechanisms in osteoclast formation are less well-defined. Here, we demonstrate the effect of A2BAR stimulation on osteoclast differentiation and activity by RANKL. A2BAR was expressed in bone marrow-derived monocyte/macrophage (BMM) and RANKL increased A2BAR expression during osteoclastogenesis. A2BAR stimulation with its specific agonist BAY 60-6583 was sufficient to inhibit the activation of ERK1/2, p38 MAP kinases and $NF-{\kappa}B$ by RANKL as well as it abrogated cell-cell fusion in the late stage of osteoclast differentiation. Stimulation of A2BAR suppressed the expression of osteoclast marker genes, such as c-Fos, TRAP, Cathepsin-K and NFATc1, induced by RANKL, and transcriptional activity of NFATc1 was also inhibited by stimulation of A2BAR. A2BAR stimulation caused a notable reduction in the expression of Atp6v0d2 and DC-STAMP related to cell-cell fusion of osteoclasts. Especially, a decrease in bone resorption activity through suppression of actin ring formation by A2BAR stimulation was observed. Taken together, these results suggest that A2BAR stimulation inhibits the activation of ERK1/2, p38 and $NF-{\kappa}B$ by RANKL, which suppresses the induction of osteoclast marker genes, thus contributing to the decrease in osteoclast cell-cell fusion and bone resorption activity.

• IMMUNE NETWORK
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• 제13권2호
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• pp.55-62
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• 2013

Swiprosin-1 exhibits the highest expression in $CD8^+$ T cells and immature B cells and has been proposed to play a role in lymphocyte biology through actin remodeling. However, regulation of swiprosin-1 gene expression is poorly understood. Here we report that swiprosin-1 is up-regulated in T cells by PKC pathway. Targeted inhibition of the specific protein kinase C (PKC) isotypes by siRNA revealed that $PKC-{\theta}$ is involved in the expression of swiprosin-1 in the human T cells. In contrast, down-regulation of swiprosin-1 by A23187 or ionomycin suggests that calcium-signaling plays a negative role. Interestingly, swiprosin-1 expression is only reduced by treatment with $NF-{\kappa}B$ inhibitors but not by NF-AT inhibitor, suggesting that the $NF-{\kappa}B$ pathway is critical for regulation of swiprosin-1 expression. Collectively, these results suggest that swiprosin-1 is a $PKC-{\theta}$-inducible gene and that it may modulate the late phase of T cell activation after antigen challenge.

• Biomolecules & Therapeutics
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• 제27권1호
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• pp.92-100
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• 2019

Ginger, one of worldwide consumed dietary spice, is not only famous as food supplements, but also believed to exert a variety of remarkable pharmacological activity as herbal remedies. In this study, a ginger constituent, 12-dehydrogingerdione (DHGD) was proven that has comparable anti-inflammatory activity with positive control 6-shogaol in inhibiting LPS-induced interleukin (IL)-6, tumor necrosis factor $(TNF)-{\alpha}$, prostaglandin (PG) $E_2$, nitric oxide (NO), inducible NO synthase (iNOS) and cyclooxygenase (COX)-2, without interfering with COX-1 in cultured microglial cells. Subsequent mechanistic studies indicate that 12-DHGD may inhibit neuro-inflammation through suppressing the LPS-activated $Akt/IKK/NF-{\kappa}B$ pathway. Furthermore, 12-DHGD markedly promoted the activation of NF-E2-related factor (Nrf)-2 and heme oxygenase (HO)-1, and we demonstrated that the involvement of HO-1 on the production of pro-inflammatory mediators such as NO and $TNF-{\alpha}$ by using a HO-1 inhibitor, Zinc protoporphyrin (Znpp). These results indicate that 12-DHGD may protect against neuro-inflammation by inhibiting $Akt/IKK/I{\kappa}B/NF-{\kappa}B$ pathway and promoting Nrf-2/HO-1 pathway.

• 한방안이비인후피부과학회지
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• 제25권1호
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• pp.12-21
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• 2012

Background and Objectives : Allergic rhinitis is one of the most common diseases in the otorhinolaryngology area. in oriental clinic, Hyunggaeyungyo-tang(HYT) has been used as a primary prescription to treat allergic rhinitis. However, there have been no studies so far performed on the effect of this HYT use. The purpose of this study was find out therapeutic effects of its exclusive use on the rat with allergic rhinitis. Material and Methods : Thirty BALB/c mice were divided into three group : normal group(NOR), control group(CON) inoculated with allergic rhinitis and sample group(SAM) treated with the HYT extract after it was treated the same as the control group. Rats were sensitized intraperitoneally with ovalbumin solution 4times at intervals of 2 days. After that time, rats in SAM were administered by HYT to treat the inflammation. Results : 1. The number of eosinophil in SAM noticeably decreased than CON and this decrease had probability. The inhibition of eosinophil distribution. The infiltration of eosinophil in SAM noticeably decreased than CON. 2. The damaged mucosa as disruption of cilia in respiratory cell, vacant mucose secreting cell and infiltration of inflammation intricate cells in CON were increased than NOR, but SAM same as normal configuration. Decrease of icthing and sneezing intricate neurotransmitter (substance P). Decrease of angiogenesis intricate cytokine(MIP-2). 3. Transcription factor(NF-${\kappa}B$ p65) was decreased. 4. Transcription factor inhibitor(p-$I{\kappa}B$) was decreased. 5. Inflammation cytokine(iNOS) was decreased. Conclusion : The results suggest that HYT is significantly effective in the treatment of inflammation caused by allergic rhinitis through the suppression of NF-${\kappa}B$ activation and iNOS production.

• 한국자원식물학회지
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• 제31권3호
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• pp.211-217
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• 2018

Hibiscus syriacus (H. syriacus) as the national flower of Korea has been used as the herbal medicine in Asia. In this study, we evaluated the anti-inflammatory effect of 70% ethanol extracts from the root of Hibiscus syriacus (RHS-E70) and elucidated the potential signaling pathway in LPS-stimulated RAW264.7 cells. RHS-E70 dose-dependently suppressed NO production by inhibiting iNOS and IL-${\beta}$ expression in LPS-stimulated RAW264.7 cells. RHS-E70 inhibited the phosphorylation and degradation of $I{\kappa}B-{\alpha}$, which contributed to the inhibition of p65 nuclear accumulation and NF-${\kappa}B$ activation. Furthermore, RHS-E70 suppressed the phosphorylation of ERK1/2 and p38, which results in the inhibition of ATF2 phosphorylation and subsequent nuclear accumulation. These results indicate that RHS-E70 may exert anti-inflammatory activity by inhibiting NF-${\kappa}B$ and MAPK/ATF2 signaling. From these findings, RHS-E70 has potential to be a candidate for the development of chemopreventive or therapeutic agents for the inflammatory diseases.

• 한국식품과학회지
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• 제43권1호
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• pp.110-113
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• 2011

음식 알러지는 만성적인 장애를 일으킬 수 있는 즉각적이며 잠재적으로 생명을 위협하는 반응이다. 이 중 계란은 알러지 위험성이 높은 물질로, 아이들에게 음식 알러지를 유발하는 흔한 물질로 알려져 있다. 계란 알러젠 중에서 계란 흰자 단백질인 OVA이 주요한 알러젠으로 알려져 있다. 우리는 이번 연구에서 OVA이 염증 및 면역 반응에 중요한 역할을 한다고 알려져 있는 $NF-{\kappa}B$ 활성화와 COX-2와 iNOS 발현에 어떠한 영향을 미치는지를 알아보았다. OVA은 $NF-{\kappa}B$ 활성화와 COX-2와 iNOS의 발현을 증가시켰다. 이러한 연구는 앞으로 계란 알러젠에 의한 알러지 작용기전 규명 및 알러지 치료제 개발에 중요한 역할을 할 것으로 기대한다.

• Biomolecules & Therapeutics
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• 제22권1호
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• pp.10-16
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• 2014

Derivatives of caffeic acid have been reported to possess diverse pharmacological properties such as anti-inflammatory, anti-tumor, and neuroprotective effects. However, the biological activity of methyl p-hydroxycinnamate, an ester derivative of caffeic acid, has not been clearly demonstrated. This study aimed to elucidate the anti-inflammatory mechanism of methyl p-hydroxycinnamate in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. Methyl p-hydroxycinnamate significantly inhibited LPS-induced excessive production of pro-inflammatory mediators such as nitric oxide (NO) and $PGE_2$ and the protein expression of iNOS and COX-2. Methyl p-hydroxycinnamate also suppressed LPS-induced overproduction of pro-inflammatory cytokines such as IL-$1{\beta}$ and TNF-${\alpha}$. In addition, methyl p-hydroxycinnamate significantly suppressed LPS-induced degradation of $I{\kappa}B$, which retains NF-${\kappa}B$ in the cytoplasm, consequently inhibiting the transcription of pro-inflammatory genes by NF-${\kappa}B$ in the nucleus. Methyl p-hydroxycinnamate exhibited significantly increased Akt phosphorylation in a concentration-dependent manner. Furthermore, inhibition of Akt signaling pathway with wortmaninn abolished methyl p-hydroxycinnamate-induced Akt phosphorylation. Taken together, the present study clearly demonstrates that methyl p-hydroxycinnamate exhibits anti-inflammatory activity through the activation of Akt signaling pathway in LPS-stimulated RAW264.7 macrophage cells.

• Biomolecules & Therapeutics
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• 제20권6호
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• pp.532-537
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• 2012

Avicularin, quercetin-3-${\alpha}$-L-arabinofuranoside, has been reported to possess diverse pharmacological properties such as anti-inflammatory and anti-infectious effects. However, the underlying mechanism by which avicularin exerts its anti-inflammatory activity has not been clearly demonstrated. This study aimed to elucidate the anti-inflammatory mechanism of avicularin in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. Avicularin significantly inhibited LPS-induced excessive production of pro-inflammatory mediators such as nitric oxide (NO) and $PGE_2$ and the protein levels of iNOS and COX-2, which are responsible for the production of NO and $PGE_2$, respectively. Avicularin also suppressed LPS-induced overproduction of pro-inflammatory cytokine IL-$1{\beta}$. Furthermore, avicularin significantly suppressed LPS-induced degradation of $I{\kappa}B$, which retains NF-${\kappa}B$ in the cytoplasm, consequently inhibiting the transcription of pro-inflammatory genes by NF-${\kappa}B$ in the nucleus. To understand the underlying signaling mechanism of anti-inflammatory activity of avicularin, involvement of multiple kinases was examined. Avicularin significantly attenuated LPS-induced activation of ERK signaling pathway in a concentration-dependent manner. Taken together, the present study clearly demonstrates that avicularin exhibits anti-inflammatory activity through the suppression of ERK signaling pathway in LPS-stimulated RAW 264.7 macrophage cells.

• IMMUNE NETWORK
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• 제9권3호
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• pp.90-97
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• 2009

Background: CD147, as a cellular receptor for cyclophilin A (CypA), is a multifunctional protein involved in tumor invasion, inflammation, tissue remodeling, neural function, and reproduction. Recent observations showing the expression of CD147 in leukocytes indicate that this molecule may have roles in inflammation. Methods: In order to investigate the role of CD147 and its ligand in the pathogenesis of atherosclerosis, human atherosclerotic plaques were analyzed for the expression pattern of CD147 and CypA. The cellular responses and signaling molecules activated by the stimulation of CD147 were then investigated in the human macrophage cell line, THP-1, which expresses high basal level of CD147 on the cell surface. Results: Staining of both CD147 and CypA was detected in endothelial cell layers facing the lumen and macrophage-rich areas. Stimulation of CD147 with its specific monoclonal antibody induced the expression of matrix metalloproteinase (MMP)-9 in THP-1 cells and it was suppressed by inhibitors of both ERK and NF-${\kappa}B$. Accordingly, the stimulation of CD147 was observed to induce phosphorylation of ERK, phosphorylation-associated degradation of $I{\kappa}B$, and nuclear translocation of NF-${\kappa}B$ p65 and p50 subunits. Conclusion: These results suggest that CD147 mediates the inflammatory activation of macrophages that leads to the induction of MMP-9 expression, which could play a role in the pathogenesis of inflammatory diseases such as atherosclerosis.