• IMMUNE NETWORK
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• v.11 no.4
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• pp.216-222
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• 2011

Background: The ligand for CD137 (CD137L; also called 4-1BBL) is mainly expressed on activated APCs such as dendritic cells, B cells and macrophages. Even though CD137L functions as a trigger of the CD137 signaling pathway for T cell activation and expansion, engagement of CD137L can deliver a signal leading to the production of proinflammatory cytokines in macrophages. Methods: We generated cell-permeable TAT-CD137L cytoplasmic domain fusion protein (TAT-CD137Lct) and examined its ability to initiate the CD137L reverse signaling pathway. Results: Treatment of TAT-CD137Lct induced the production of high levels of IL-6 and TNF-${\alpha}$ mRNAs and proteins in peritoneal macrophages. TAT-CD137Lct increased phosphorylation of Erk, p38 MAPK and Jnk, and activated transcription factors C/EBP and CREB. However, TAT-CD137Lct did not visibly affect the degradation of the inhibitor of NF-${\kappa}B$ ($IkB{\alpha}$). We further demonstrated that JNK activation was required for TAT-CD137Lct-induced production of TNF-${\alpha}$, while activation of Erk and p38 MAPK were involved in IL-6 and TNF-${\alpha}$ production. Conclusion: Our results suggest that TATCD137Lct is an effective activator for the CD137L reverse signaling pathway.

• Journal of Microbiology and Biotechnology
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• v.30 no.1
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• pp.85-92
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• 2020

One of the omega-3 essential fatty acids, docosahexaenoic acid (DHA), is a significant constituent of the cell membrane and the precursor of several potent lipid mediators. These mediators are considered to be important in preventing or treating several diseases. Resolvin D5, an oxidized lipid mediator derived from DHA, has been known to exert anti-inflammatory effects. However, the detailed mechanism underlying these effects has not yet been elucidated in human monocytic THP-1 cells. In the present study, we investigated the effects of resolvin D5 on inflammation-related signaling pathways, including the extracellular signal-regulated kinase (ERK)-nuclear factor (NF)-κB signaling pathway. Resolvin D5 downregulated the production of interleukin (IL)-6 and chemokine (C-C motif) ligand 5 (CCL5). Additionally, these inhibitory effects were found to be modulated by mitogen-activated protein kinase (MAPK) and NF-κB in lipopolysaccharide (LPS)-treated THP-1 cells. Resolvin D5 inhibited the LPS-stimulated phosphorylation of ERK and translocation of p65 and p50 into the nucleus, resulting in the inhibition of IL-6 and CCL5 production. These results revealed that resolvin D5 exerts anti-inflammatory effects in LPS-treated THP-1 cells by regulating the phosphorylation of ERK and nuclear translocation of NF-κB.

• BMB Reports
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• v.56 no.6
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• pp.359-364
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• 2023

KAI1/CD82, a membrane tetraspanin protein, can prevent various cancers and retinal disorders through its anti-angiogenic and anti-metastatic capacity. However, little is known about its anti-inflammatory effect and molecular mechanism. Therefore, the present study aimed to inLPSvestigate effect of a recombinant protein of the large extracellular domain of human KAI1 (Gly 111-Leu 228, rhKAI1) on lipopolysaccharides (LPS)-stimulated RAW264.7 macrophage-like cells and mouse bone marrow-derived macrophages (BMDM) and to identify its underlying mechanism. Our data showed that rhKAI1 suppressed expression levels of classically macrophages (M1) phenotype-related surface markers F4/80+CD86+ in LPS-stimulated BMDM and RAW264.7 cells. In addition, LPS markedly increased mRNA expression and release levels of pro-inflammatory cytokines and mediators such as interleukin (IL)-1β, IL-6, tumor necrosis factor-α, cyclooxygenase-2, nitric oxide and prostaglandin E2, whereas these increases were substantially down-regulated by rhKAI1. Furthermore, LPS strongly increased expression of NF-κB p65 in the nuclei and phosphorylation of ERK, JNK, and p38 MAPK. However, nuclear translocation of NF-κB p65 and phosphorylation of JNK were greatly reversed in the presence of rhKAI1. Especially, rhKAI1 markedly suppressed expression of toll-like receptor (TLR4) and prevented binding of LPS with TLR4 through molecular docking predict analysis. Importantly, Glu 214 of rhKAI1 residue strongly interacted with Lys 360 of TLR4 residue, with a binding distance of 2.9 Å. Taken together, these findings suggest that rhKAI1 has an anti-inflammatory effect on LPS-polarized macrophages by interacting with TLR4 and down-regulating the JNK/NF-κB signaling pathway.

• The Korean Journal of Physiology and Pharmacology
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• v.17 no.5
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• pp.427-433
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• 2013

Receptor activator of NF-${\kappa}B$ ligand (RANKL)-induced osteoclastogenesis is accompanied by intracellular $Ca^{2+}$ mobilization in a form of oscillations, which plays essential roles by activating sequentially $Ca^{2+}$/calmodulin-dependent protein kinase, calcineurin and NFATc1, necessary in the osteoclast differentiation. However, it is not known whether $Ca^{2+}$ mobilization which is evoked in RANKL-independent way induces to differentiate into osteoclasts. In present study, we investigated $Ca^{2+}$ mobilization induced by aluminum fluoride ($AlF_4^-$), a G-protein activator, with or without RANKL and the effects of $AlF_4^-$ on the osteoclastogenesis in primary cultured mouse bone marrow-derived macrophages (BMMs). We show here that $AlF_4^-$ induces intracellular $Ca^{2+}$ concentration ($[Ca^{2+}]_i$) oscillations, which is dependent on extracellular $Ca^{2+}$ influx. Notably, co-stimulation of $AlF_4^-$ with RANKL resulted in enhanced NFATc1 expression and formation of tartrate-resistant acid phosphatase (TRAP) positive multinucleated cells. Additionally, we confirmed that mitogen-activated protein kinase (MAPK) is also activated by $AlF_4^-$. Taken together, these results demonstrate that G-protein would be a novel modulator responsible for $[Ca^{2+}]_i$ oscillations and MAPK activation which lead to enhancement of RANKL-mediated osteoclastogenesis.

• Korean Journal of Clinical Laboratory Science
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• v.54 no.3
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• pp.201-208
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• 2022

Neuroinflammation is defined as a neurological inflammation within the brain and the spinal cord. In neuroinflammation, microglia are the tissue-resident macrophages of the central nervous system, which act as the first line of defense against harmful pathogens. Dexmedetomidine (Dex) has an anti-inflammatory effect in many neurological conditions. Additionally, the microRNA-30a-5p (miR-30a-5p) mimic has been proven to be effective in macrophages in inflammatory conditions. This study aimed to investigate the synergistic anti-inflammatory effects of both miR-30a-5p and Dex in lipopolysaccharide (LPS)-induced BV2 cells. This study showed that miR-30a-5p and Dex decreased nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) translocation in LPS-induced BV2 cells. MiR-30a-5p and Dex alleviated tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), LPS-induced phosphorylation c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinase (ERK) and p38. Also, the expression of the NOD-like receptor pyrin domain containing 3 inflammasome (NLRP3), cleaved caspase-1, and ASC was inhibited. Furthermore, LPS-stimulated nitric oxide (NO) production, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) expression were attenuated by Dex and miR-30a-5p. Our results indicate that a combination of Dex and miR-30a-5p, attenuates NF-κB activation, the mitogen-activated protein kinase (MAPK) signaling pathway, and inflammatory mediators involved in LPS-induced inflammation and inhibits the activation of the NLRP3 inflammasome in LPS-activated BV2 cells.

• Journal of Ginseng Research
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• v.41 no.2
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• pp.134-143
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• 2017

Background: The prevalence of allergic inflammatory diseases such as atopic dermatitis (AD), asthma, and allergic rhinitis worldwide has increased and complete recovery is difficult. Korean Red Ginseng, which is the heat-processed root of Panax ginseng Meyer, is widely and frequently used as a traditional medicine in East Asia. In this study, we investigated whether Korean Red Ginseng water extract (RGE) regulates the expression of proinflammatory cytokines and chemokines via the mitogen-activated protein kinases (MAPKs)/nuclear factor kappa B ($NF-{\kappa}B$) pathway in allergic inflammation. Methods: Compound 48/80-induced anaphylactic shock and 1-fluoro-2,4-dinitrobenzene (DNFB)-induced AD-like skin lesion mice models were used to investigate the antiallergic effects of RGE. Human keratinocytes (HaCaT cells) and human mast cells (HMC-1) were also used to clarify the effects of RGE on the expression of proinflammatory cytokines and chemokines. Results: Anaphylactic shock and DNFB-induced AD-like skin lesions were attenuated by RGE administration through reduction of serum immunoglobulin E (IgE) and interleukin (IL)-6 levels in mouse models. RGE also reduced the production of proinflammatory cytokines including $IL-1{\beta}$, IL-6, and IL-8, and expression of chemokines such as IL-8, thymus and activation-regulated chemokine (TARC), and macrophage-derived chemokine (MDC) in HaCaT cells. Additionally, RGE decreased the release of tumor necrosis $factor-{\alpha}$ ($TNF-{\alpha}$), $IL-1{\beta}$, IL-6, and IL-8 as well as expressions of chemokines including macro-phage inflammatory protein $(MIP)-1{\alpha}$, $MIP-1{\beta}$, regulated on activation, normal T cell expressed and secreted (RANTES), monocyte chemoattractant protein (MCP)-1, and IL-8 in HMC-1 cells. Furthermore, our data demonstrated that these inhibitory effects occurred through blockage of the MAPK and $NF-{\kappa}B$ pathway. Conclusion: RGE may be a useful therapeutic agent for the treatment of allergic inflammatory diseases such as AD-like dermatitis.

• Journal of Life Science
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• v.24 no.9
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• pp.973-980
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• 2014

This study was conducted to explore new nutraceutical resources from the plant kingdom possessing biological activities. To fulfill this purpose, the anti-oxidative and anti-inflammatory activities of Decaisnea insignis ethanol extract (DIEE) were evaluated. First, DIEE possessed potent scavenging activity against 1,1-diphenyl-2-picryl hydrazyl (DPPH), similar to ascorbic acid used as a positive control. Moreover, DIEE inhibited lipopolysaccharide (LPS)- and hydrogen peroxide ($H_2O_2$)-induced reactive oxygen species (ROS) in RAW 264.7 cells. Furthermore, DIEE induced the expression of an anti-oxidative enzyme, heme oxygenase 1 (HO-1), and its upstream transcription factor, nuclear factor-E2-related factor 2 (Nrf2), in a dose-dependent manner. The modulation of the HO-1 and Nrf2 expressions might be regulated by mitogen-activated protein kinases (MAPKs) and their upstream signaling pathways. On the other hand, DIEE suppressed LPS-induced nitric oxide (NO) formation without cytotoxicity. The inhibition of the NO formation was the result of the downregulation of inducible NO synthase (iNOS) by DIEE. The suppression of NO and iNOS by DIEE might be modulated by their upstream transcription factors, nuclear factor ${\kappa}B$ ($NF-{\kappa}B$), and activator protein 1 (AP-1) pathways. Taken together, these results provide important new insights that D. insignis possesses anti-oxidative and anti-inflammatory activities. Therefore, it might be utilized as a promising material in the field of nutraceuticals.

• International Journal of Internet, Broadcasting and Communication
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• v.12 no.2
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• pp.98-112
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• 2020

There is a strong connection between the diet rich in antioxidants and the decreased incidence of inflammatory bowel disease and cancerous diseases. Diets that are rich in anti-oxidants particularly include fruits and vegetables containing the high amounts of vitamin A-E, carotenoids, and minerals. The supercritical heat-treated radish extracts of the research result had an inhibitory effect on the development of aberrant crypt foci (ACF), namely, preneoplastic lesions having a potential to become cancer cells and reduced the number of the aberrant crypt foci (ACF) consisting of four or more aberrant crypts (AC) having high risk to become tumors by about half. The supercritical heat-treated radish extracts can reduce the incidence of preneoplastic lesions having a high risk of developing cancer by about 28 %. DSS-treated mice developed symptoms similar to those of human UC, such as severe bloody diarrhea and weight loss. Supercritical heat-treated radish extracts, as well as sulfasalazine, suppressed colonic length and mucosal inflammatory infiltration. In addition, supercritical heat-treated radish extracts treatment significantly reduced the expression of pro-inflammatory signaling molecules through suppression both mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-kB) signaling pathways, and prevented the apoptosis of colon. Moreover, supercritical heat-treated radish extracts administration significantly led to the up-regulation of anti-oxidant enzyme including SOD and Catalase.

• Journal of Acupuncture Research
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• v.32 no.3
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• pp.83-93
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• 2015

Objectives : The purpose of this study was to evaluate whether acupuncture at $SP_6$ attenuates esophageal inflammation on refluxed-induced esophagitis. Methods : Acupuncture at $SP_6$ was stimulated by acupuncture torsion technique for 30 seconds four times every hour after an operation induced reflux esophagitis(RE), and its effects were assessed in comparison with RE rats without acupuncture, and normal rats. Results : $SP_6$ acupuncture stimulation markedly ameliorated mucosal damage in the histological evaluation. Reflux-induced esophagitis rats exhibited the down-regulation of antioxidant-related protein expression levels such as heme oxygenase-1(HO-1) in the esophagitis; however, the associated levels with $SP_6$ acupuncture stimulation were significantly higher than those in RE rats without acupuncture stimulation. Moreover, $SP_6$ acupuncture stimulation significantly reduced the expression of inflammatory proteins through mitogen-activated protein kinase(MAPK)-related signaling pathways. The increased protein expressions of inflammatory mediators, cyclooxygenase-2(COX-2) and inducible nitric oxide synthase(iNOS), by nuclear factor-kappa B(NF-kB) activation were significantly suppressed through $SP_6$ acupuncture stimulation. Conclusions : Our findings support the therapeutic evidence for $SP_6$ acupuncture stimulation alleviating the development of esophagitis via regulating inflammation through the activation of the antioxidant pathway.

• Journal of Life Science
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• v.31 no.9
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• pp.818-826
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• 2021

5-Aminolevulinic acid phosphate (5-ALA-p) is a substance obtained by eluting 5-ALA (a natural delta amino acid) with aqueous ammonia, adding phosphoric acid to the eluate, and then adding acetone to confer properties suitable for use in photodynamic therapy applications. However, its pharmacological efficacy, including potential mechanisms of antioxidant and anti-inflammatory reactions, remains unclear. This study aimed to investigate the effects of 5-ALA-p on oxidative and inflammatory stresses in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Our data showed that 5-ALA-p significantly inhibited excessive phagocytic activity via LPS and attenuated oxidative stress in LPS-treated RAW 264.7 cells. Furthermore, 5-ALA-p improved mitochondrial biogenesis reduced by LPS, suggesting that 5-ALA-p restores mitochondrial damage caused by LPS. Additionally, 5-ALA-p significantly suppressed the release of nitric oxide (NO) and pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin (IL)-1β, and IL-6, which are associated with the inhibition of inducible NO synthase and respective cytokine expression. Furthermore, 5-ALA-p reduced the nuclear translocation of nuclear factor-kappa B (NF-κB) and inhibited phosphorylation of mitogen-activated protein kinases (MAPKs), indicating that the anti-inflammatory effect of 5-ALA-p is mediated through the suppression of NF-κB and MAPK signaling pathways. Based on these results, 5-ALA-p may serve as a potential candidate to reduce inflammation and oxidative stress.