• Clinical and Experimental Pediatrics
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• v.56 no.4
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• pp.151-158
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• 2013

Purpose: We investigated the mRNA levels of peroxisome proliferator-activated receptor (PPAR)-${\alpha}$, PPAR-${\gamma}$, adipokines, and cytokines in the lung tissue of lean and obese mice with and without ovalbumin (OVA) challenge, and the effect of rosiglitazone, a PPAR-${\gamma}$ agonist. Methods: We developed 6 mice models: OVA-challenged lean mice with and without rosiglitazone; obese mice with and without rosiglitazone; and OVA-challenged obese mice with and without rosiglitazone. We performed real-time polymerase chain reaction for leptin, leptin receptor, adiponectin, vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-${\alpha}$, transforming growth factor (TGF)-${\beta}$, PPAR-${\alpha}$ and PPAR-${\gamma}$ from the lung tissue and determined the cell counts and cytokine levels in the bronchoalveolar lavage fluid. Results: Mice with OVA challenge showed airway hyperresponsiveness. The lung mRNA levels of PPAR${\alpha}$ and PPAR-${\gamma}$ increased significantly in obese mice with OVA challenge compared to that in other types of mice and decreased after rosiglitazone administeration. Leptin and leptin receptor expression increased in obese mice with and without OVA challenge and decreased following rosiglitazone treatment. Adiponectin mRNA level increased in lean mice with OVA challenge. Lung VEGF, TNF-${\alpha}$, and TGF-${\beta}$ mRNA levels increased in obese mice with and without OVA challenge compared to that in the control mice. However, rosiglitazone reduced only TGF-${\beta}$ expression in obese mice, and even augmented VEGF expression in all types of mice. Rosiglitazone treatment did not reduce airway responsiveness, but increased neutrophils and macrophages in the bronchoalveolar lavage fluid. Conclusion: PPAR-${\alpha}$ and PPAR-${\gamma}$ expressions were upregulated in the lung tissue of OVA-challenged obese mice however, rosiglitazone treatment did not downregulate airway inflammation in these mice.

• Journal of Microbiology and Biotechnology
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• v.27 no.8
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• pp.1529-1538
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• 2017

Klebsiella pneumoniae is an opportunistic and clinically significant emerging pathogen. We investigated the relative roles of Toll-like receptor (TLR) 2 and TLR4 in initiating host defenses against K. pneumoniae. TLR2 knockout (KO), TLR4 KO, TLR2/4 double KO (DKO), and wild-type (WT) mice were inoculated with K. pneumoniae. Mice in each group were sacrificed after either 12 or 24h, and the lungs, liver, and blood were harvested to enumerate bacterial colony-forming units (CFU). Cytokine and chemokine levels were analyzed using enzyme-linked immunosorbent assay and real-time PCR, and pneumonia severity was determined by histopathological analysis. Survival was significantly shortened in TLR4 KO and TLR2/4 DKO mice compared with that of WT mice after infection with $5{\times}10^3CFU$. TLR2 KO mice were more susceptible to infection than WT mice after exposure to a higher infectious dose. Bacterial burdens in the lungs and liver were significantly higher in TLR2/4 DKO mice than in WT mice. Serum $TNF-{\alpha}$, MCP-1, MIP-2, and nitric oxide levels were significantly decreased in TLR2/4 DKO mice relative to those in WT mice, and TLR2/4 DKO mice showed significantly decreased levels of $TNF-{\alpha}$, IL-6, MCP-1, and inducible nitric oxide synthase mRNA in the lung compared with those in WT mice. Collectively, these data indicate that TLR2/4 DKO mice were more susceptible to K. pneumoniae infection than single TLR2 KO and TLR4 KO mice. These results suggest that TLR2 and TLR4 play cooperative roles in lung innate immune responses and bacterial dissemination, resulting in systemic inflammation during K. pneumoniae infection.

• Journal of Life Science
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• v.31 no.10
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• pp.954-959
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• 2021

Apoptosis is an important mechanism that regulates cellular populations to maintain homeostasis, and the caspases, a family of cysteine proteases, are key mediators of the apoptosis pathway. Caspase-8 is an initiator caspase of the extrinsic apoptotic pathway, which is initiated by extracellular stimuli. Caspase-8 have two conserved domains, N-terminal tandem death effector domains (DED) and C-terminal two catalytic domain, which are important for this extrinsic apoptosis pathway. In extrinsic apoptosis pathway, death receptors which members of TNF superfamily are activated by binding of death receptor specific ligands from cell outside. After the activated death receptors recruit adaptor protein Fas-associated death domain protein (FADD), death domains (DD) of death receptor and FADD bind to each other and FADD combined with death receptor recruits procaspase-8, a precursor form of caspase-8. The DED of FADD and procaspase-8 bind to one another and FADD-bound procaspase-8 is activated by cleavage of the prodomain. This death receptor-FADD-caspase-8 complex called death inducing signaling complex (DISC). Cellular FLICE-inhibitory proteins (c-FLIPs) regulate caspase-8 activation by acting both anti- and pro-apoptotically, and caspase-8 activation initiates the activation of executioner caspases such as caspase-3. Finally activated executioner caspases complete the apoptosis by acting critically DNA degradation, nuclear condensation, plasma membrane blebbing, and the proteolysis of certain caspase substrates.

• The Korean Journal of Physiology and Pharmacology
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• v.19 no.2
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• pp.111-118
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• 2015

Osteoprotegerin (OPG), receptor activator of NF-${\kappa}B$ ligand (RANKL)/receptor activator of NF-${\kappa}B$ (RANK) axis, and TNF-related apoptosis-inducing ligand (TRAIL) participate in vascular calcification process including atherosclerosis, but their contributions under high glucose (HG) and phosphate (HP) condition for a long-term period (more than 2 weeks) have not been fully determined. In this study, we evaluated the effects of HG and HP levels over 2 or 4 weeks on the progression of vascular calcification in rat vascular smooth muscle cells (VSMCs). Calcium deposition in VSMCs was increased in medium containing HG (30 mmol/L D-glucose) with ${\beta}$-glycerophosphate (${\beta}$-GP, 12 mmol/L) after 2 weeks and increased further after 4 weeks. OPG mRNA and protein expressions were unchanged in HG group with or without ${\beta}$-GP after 2 weeks. However, after 4 weeks, OPG mRNA and protein expressions were significantly lower in HG group with ${\beta}$-GP. No significant expression changes were observed in RANKL, RANK, or TRAIL during the experiment. After 4 weeks of treatment in HG group containing ${\beta}$-GP and rhBMP-7, an inhibitor of vascular calcification, OPG expressions were maintained. Furthermore, mRNA expression of alkaline phosphatase (ALP), a marker of vascular mineralization, was lower in the presence of rhBMP-7. These results suggest that low OPG levels after long term HG and phosphate stimulation might reduce the binding of OPG to RANKL and TRAIL, and these changes could increase osteo-inductive VSMC differentiation, especially vascular mineralization reflected by increased ALP activity during vascular calcification.

• The Korean Journal of Physiology and Pharmacology
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• v.21 no.5
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• pp.495-507
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• 2017

The effect of clonidine administered intrathecally (i.t.) on the mortality and the blood glucose level induced by sepsis was examined in mice. To produce sepsis, the mixture of D-galactosamine (GaLN; 0.6 g/10 ml)/lipopolysaccharide (LPS; $27{\mu}g/27{\mu}l$) was treated intraperitoneally (i.p.). The i.t. pretreatment with clonidine ($5{\mu}g/5{\mu}l$) increased the blood glucose level and attenuated mortality induced by sepsis in a dose-dependent manner. The i.t. post-treatment with clonidine up to 3 h caused an elevation of the blood glucose level and protected sepsis-induced mortality, whereas clonidine post-treated at 6, 9, or 12 h did not affect. The pre-treatment with oral D-glucose for 30 min prior to i.t. post-treatment (6 h) with clonidine did not rescue sepsis-induced mortality. In addition, i.t. pretreatment with pertussis toxin (PTX) reduced clonidine-induced protection against mortality and clonidine-induced hyperglycemia, suggesting that protective effect against sepsis-induced mortality seems to be mediated via activating PTX-sensitive G-proteins in the spinal cord. Moreover, pretreatment with clonidine attenuated the plasma tumor necrosis factor ${\alpha}$ ($TNF-{\alpha}$) induced by sepsis. Clonidine administered i.t. or i.p. increased $p-AMPK{\alpha}1$ and $p-AMPK{\alpha}2$, but decreased p-Tyk2 and p-mTOR levels in both control and sepsis groups, suggesting that the up-regulations of $p-AMPK{\alpha}1$ and $p-AMPK{\alpha}2$, or down-regulations of p-mTOR and p-Tyk2 may play critical roles for the protective effect of clonidine against sepsis-induced mortality.

• Korean Chemical Engineering Research
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• v.47 no.4
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• pp.501-505
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• 2009

In this study, we evaluated the effect of soluble EPCR(Soluble Endothelial Protein C Receptor, sEPCR) on the anti-inflammatory activities by activated protein C(APC) in endothelium. We demonstrated that sEPCR inhibited the barrier protective activity, the inhibition of neutrophils adhesion toward endothelial cells and the inhibition of transendothelial migration by APC in endothelial cells. Interestingly, sEPCR also blocked the mechanism by which APC inhibited the expression of cell adhesion molecules(CAM) by TNF-alpha in endothelial cells. These results suggested that the anti-inflammatory activities of APC was inhibited by sEPCR which blocked the binding motifs of Gla domain of APC to membrane bound EPCR. This finding will provide the important evidence in the development of new medicine for the treatment of severe sepsis and inflammatory diseases and good clue for understanding unknown mechanisms by which APC showed the anti-inflammatory activities in endothelium.

• IMMUNE NETWORK
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• v.2 no.4
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• pp.223-226
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• 2002

Background: The type 2 deviated immunological state is predominant in lepromatous leprosy. Erythema nodosum leprosum (ENL) is an immune-complex mediated reaction that typically occurs in lepromatous leprosy. To date, the serum levels of tumor necrosis factor (TNF)-${\alpha}$, interleukin (IL)-2 receptor, IL-10, IL-$1{\beta}$, IL-1 receptor antagonist and monocyte chemoattractant protein-1 (MCP-1) were reported to be higher in lepromatous leprosy. TNF-${\alpha}$ is also known to be higher in ENL, which is reduced after thalidomide treatment. However the serum type 2 chemokine levels in lepromatous leprosy patients have not been reported. Methods: The serum levels of the type 2 chemokines such as thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC) and eotaxin together with IL-12 and IL-10 in the sera from leprosy patients were detected using an enzyme-linked solvent assay (ELISA) method. Results: The Serum TARC, MDC, eotaxin, IL-10 and IL-12 levels in lepromatous leprosy patients were not significantly different from the normal control levels. The serum levels were not significantly different between the paucibacillary group and multibacillary group. The serum TARC or MDC levels in the ENL patients were more reduced after a treatment containing thalidomide. Conclusion: The type 2 chemokines are not related to the severity of lepromatous leprosy. The larger reducing effect of the TARC or MDC levels in ENL patients by a treatment containing thalidomide suggests the potential role of these chemokines in the development of ENL and the therapeutic mechanism of thalidomide.

• Molecules and Cells
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• v.37 no.8
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• pp.585-591
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• 2014

The ${\beta}_2$ adrenergic receptor (ADRB2) is a G protein-coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder (COPD). Although a number of ADRB2 agonists have been developed for use in asthma therapy, indacaterol is the only ultra-long-acting inhaled ${\beta}_2$-agonist (LABA) approved by the FDA for relieving the symptoms in COPD patients. The precise molecular mechanism underlying the pharmacological effect of indacaterol, however, remains unclear. Here, we show that ${\beta}$-arrestin-2 mediates the internalization of ADRB2 following indacaterol treatment. Moreover, we demonstrate that indacaterol significantly inhibits tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$)-induced NF-${\kappa}B$ activity by reducing levels of both phosphorylated-IKK and -$I{\kappa}B{\alpha}$, thereby decreasing NF-${\kappa}B$ nuclear translocation and the expression of MMP-9, an NF-${\kappa}B$ target gene. Subsequently, we show that indacaterol significantly inhibits TNF-${\alpha}$/NF-${\kappa}B$-induced cell invasiveness and migration in a human cancer cell line. In conclusion, we propose that indacaterol may inhibit NF-${\kappa}B$ activity in a ${\beta}$-arrestin2-dependent manner, preventing further lung damage and improving lung function in COPD patients.

• The Korean Journal of Food And Nutrition
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• v.24 no.2
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• pp.268-272
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• 2011

전곡류의 섭취와 만성질환의 유병율은 음의 상관관계가 있는 것으로 알려져 있다. 본 연구에서는 선행 연구 결과, 지방축적억제능이 우수한 소재로 선정된 기장의 항염증능 여부를 검증하고자 하였다. 이를 위해 RAW264.7 세포에 기장열수분획($1\;{\mu}g/m\ell$ 및 $10\;{\mu}g/m\ell$)과 lipopolysaccharide(LPS)를 함께 처리한 후, 24시간 배양시켜 염증매개인자들의 분비량 및 mRNA 발현 정도를 측정하였다. 또한 LPS 자극에 대한 첫 번째 신호전달인자로 알려져 있는 interleukin-1 receptor associated kinase-4(IRAK-4)의 단백질 발현 정도를 측정하였다. 본 연구결과, 기장의 열수분획($10\;{\mu}g/m\ell$)은 LPS로 유도된 NO, $PGE_2$, TNF-${\alpha}$, IL-6 및 MCP-1의 생성량 및 mRNA 발현량을 유의적으로 억제하였다(p<0.05). 특히 이들 지표 중 pro-inflammatory cytokine인 TNF-${\alpha}$와 IL-6의 mRNA 발현량이 효과적으로 감소하였다(p<0.01). IRAK-4의 단백질 발현량 또한 유의적으로 감소하여 LPS 자극에 대한 기장열수분획의 항염증능은 toll-like receptor(TLR)를 통한 IRAK-4를 매개로 하는 신호전달체계 조절에 기인하는 것으로 사료된다.

• Parasites, Hosts and Diseases
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• v.46 no.3
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• pp.145-151
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• 2008

During Toxoplasma gondii infection, macrophages, dendritic cells, and neutrophils are important sources of pro-inflammatory cytokines from the host. To counteract the pro-inflammatory activities, T. gondii is known to have several mechanisms inducing down-regulation of the host immunity. In the present study, we analyzed the production of pro- and anti-inflammatory cytokines from a human myelomonocytic cell line, THP-1 cells, in response to treatment with T. gondii lysate or lipopolysaccharide (LPS). Treatment of THP-1 cells with LPS induced production of IL-12, TNF-$\alpha$, IL-8, and IL-10. Co-treatment of THP-1 cells with T. gondii lysate inhibited the LPS-induced IL-12, IL-8 and TNF-$\alpha$ expression, but increased the level of IL-10 synergistically. IL-12 and IL-10 production was down-regulated by anti-human toll-like receptor (TLR)-2 and TLR4 antibodies. T. gondii lysate triggered nuclear factor (NF)-${\kappa}B$-dependent IL-8 expression in HEK293 cells transfected with TLR2. It is suggested that immunosuppression induced by T. gondii lysate treatment might occur via TLR2-mediated NF-${\kappa}B$ activation.