• Tuberculosis and Respiratory Diseases
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• v.63 no.2
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• pp.145-153
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• 2007

Background: Asthma is a syndrome that is characterized by a variable degree of airflow obstruction, bronchial hyperresponsiveness, and airway inflammation. Colchicine is an inexpensive and safe medication with unique anti-inflammatory properties. IL-1Ra (Interleukin-1 receptor antagonist) mediates the anti-inflammatory effect in human inflammatory diseases, including asthma. This study examined whether IL-1Ra mediates the anti-inflammatory effect of colchicine in normal human bronchial epithelial cells (NHBE), RAW 264.7 cells (murine macrophage cell line), and a mouse lung. Methods: NHBE, RAW 264.7 cells and BALB/c mice were stimulated with colchicine, and the increase in the IL-1Ra level was estimated by ELISA, Western analysis and RT-PCR analysis. Results: Colchicine stimulated NHBE and RAW 264.7 cells to release IL-1Ra into the supernatant in a dose-and time-dependent manner. The major isoform of IL-1Ra in NHBE and RAW 264.7 cells is type I icIL-1Ra, and sIL-1Ra, respectively. IL-1Ra up-regulation was blocked by PD98059, a specific inhibitor in MAPK pathways. Colchicine also stimulated the secretion of IL-1Ra into the bronchoalveolar lavage (BAL) fluid of BALB/c mouse. Conclusion: Colchicine stimulates an increase in the IL-1Ra level both in vivo and in vitro, and might have an anti-inflammatory effect.

• Biomolecules & Therapeutics
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• v.26 no.4
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• pp.417-423
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• 2018

Extracellular interleukin 1 alpha (IL-$1{\alpha}$) released from keratinocytes is one of the endpoints for in vitro assessments of skin irritancy. Although cells dying via primary skin irritation undergo apoptosis as well as necrosis, IL-$1{\alpha}$ is not released in apoptotic cells. On the other hand, active secretion has been identified in interleukin-1 receptor antagonist (IL-1ra), which was discovered to be a common, upregulated, differentially-expressed gene in a microarray analysis performed with keratinocytes treated using cytotoxic doses of chemicals. This study examined whether and how IL-1ra, particularly extracellularly released IL-1ra, was involved in chemically-induced keratinocyte cytotoxicity and skin irritation. Primary cultured normal adult skin keratinocytes were treated with cytotoxic doses of chemicals (hydroquinone, retinoic acid, sodium lauryl sulfate, or urshiol) with or without recombinant IL-1ra treatment. Mouse skin was administered irritant concentrations of hydroquinone or retinoic acid. IL-1ra (mRNA and/or intracellular/extracellularly released protein) levels increased in the chemically treated cultured keratinocytes with IL-$1{\alpha}$ and IL-$1{\beta}$ mRNAs and in the chemically exposed epidermis of the mouse skin. Recombinant IL-1ra treatment significantly reduced the chemically-induced apoptotic death and intracellular/extracellularly released IL-$1{\alpha}$ and IL-$1{\beta}$ in keratinocytes. Collectively, extracellular IL-1ra released from keratinocytes could be a compensatory mechanism to reduce the chemically-induced keratinocyte apoptosis by antagonism to IL-$1{\alpha}$ and IL-$1{\beta}$, suggesting potential applications to predict skin irritation.

• IMMUNE NETWORK
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• v.8 no.1
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• pp.29-37
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• 2008

Interleukin-23 (IL-23) is a novel pro-inflammatory cytokine which has been implicated to play a pathogenic role in rheumatoid arthritis (RA). This study was undertaken to investigate the IL-23 inductive activity of the proinflammatory cytokine IL-17, $IL-1{\beta}$ and tumor necrosis factor (TNF-${\alpha}$) in RA synovial fluid mononuclear cells (SFMC). Expression of IL-23p19, IL-17, $IL-1{\beta}$ and TNF-${\alpha}$ in joint was examined by immunohistochemistry (IHC) of patients with RA and osteoarthritis (OA). The effects of IL-17 and $IL-1{\beta}$ on expression of IL-23p19 in human SFMC from RA patients were determined by reverse transcriptase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). IL-23p19 was expressed in the RA fibroblast like synoviocyte (FLS), but not from OA FLS. Similar to the protein expression, IL-23p19 mRNA could be detected by RT-PCR in RA SFMC. IL-17 and $IL-1{\beta}$ could induce RA SFMC to produce the IL-23p19. The effects of IL-17 were much stronger than $IL-1{\beta}$ or TNF-${\alpha}$. These responses were observed in a doseresponsive manner. In addition, IL-17 or $IL-1{\beta}$ neutralizing antibody down-regulated the expression of IL-23p19 induced by LPS in RA-SFMC. Our results demonstrate that IL-23p19 is overexpressed in RA synovium and IL-17 and $IL-1{\beta}$ appears to upregulate the expression of IL-23p19 in RA-SFMC.

• Biomolecules & Therapeutics
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• v.25 no.2
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• pp.149-157
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• 2017

The interleukin-1 receptor antagonist (IL-1RA) is a potential stroke treatment candidate. Intranasal delivery is a novel method thereby a therapeutic protein can be penetrated into the brain parenchyma by bypassing the blood-brain barrier. Thus, this study tested whether intranasal IL-1RA can provide neuroprotection and brain penetration in transient cerebral ischemia. In male Sprague-Dawley rats, focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 1 h. The rats simultaneously received 50 mg/kg human IL-1RA through the intranasal (IN group) or intraperitoneal route (IP group). The other rats were given 0.5 mL/kg normal saline (EC group). Neurobehavioral function, infarct size, and the concentration of the administered human IL-1RA in the brain tissue were assessed. In addition, the cellular distribution of intranasal IL-1RA in the brain and its effect on proinflammatory cytokines expression were evaluated. Intranasal IL-1RA improved neurological deficit and reduced infarct size until 7 days after MCAO (p<0.05). The concentrations of the human IL-1RA in the brain tissue 24 h after MCAO were significantly greater in the IN group than in the IP group (p<0.05). The human IL-1RA was confirmed to be co-localized with neuron and microglia. Furthermore, the IN group had lower expression of $interleukin-1{\beta}$ and tumor necrosis $factor-{\alpha}$ at 6 h after MCAO than the EC group (p<0.05). These results suggest that intranasal IL-1RA can reach the brain parenchyma more efficiently and provide superior neuroprotection in the transient focal cerebral ischemia.

• The Journal of Korean Medicine
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• v.25 no.2
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• pp.207-219
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• 2004

Objectives : We investigated to find the relationship between single-nucleotide polymorphism (SNP) of IL4R, IL-10 and bee venom therapy efficacy in patients with RA treated with bee venom for 8 weeks. Methods : Korean RA patients (n=114) and healthy subjects (n=109) were included in this prospective study. Korean bee venom was dissolved in saline (diluted 1:3000) and administrated into acupuncture points. Bee venom therapy was applied twice a week and continued for 8 weeks. The clinical response was evaluated using various assessments before and after treatment. Disease severity was measured by determining the number of tender joints and swollen joints. Laboratory studies included ESR, CRP, and rheumatoid factor. Genotyping for IL-4R and IL-10 polymorphism was done by pyrosequencing analysis. Results : 1. In IL4R genotypes, there was significant difference between RA ptitients tind controls group. 2. In IL4R genotypes, there was significant difference among Good, Mild and Bad responders to in RA patients, but in the frequency of alleles and carriers, there were no significant difference. 3. There was no significant difference between RA patients and controls group in IL-10 gene genotypes. 4. In IL-10 genotypes, there was no significant difference among Good, Mild and Bad responders to in RA patients. 5. There was no significant difference in the improvement of ESR, CRP and KHAQ scores after bee venom therapy in RA patients among the IL4R or IL-10 genotypes. Conclusions : In IL-4R genotypes, there was significant difference between RA patients and control group, and among Good, Mild and Bad responders in RA patients. However, in IL-10 genotypes, there was no significant difference between RA patients and controls group and among Good, Mild and Bad responders in RA patients.

• Restorative Dentistry and Endodontics
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• v.26 no.6
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• pp.451-463
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• 2001

목적 - Inflammatory cytokine으로 알려진 interleukin 1$\beta$, tumor necrosis factor $\alpha$는 치수 및 치근단질환에서 주요한 역할을 하며, 골흡수를 자극하고 골형성을 방해하는 것으로 알려져 왔다. 이들 cytokine은 주로 단핵세포/대식세포가 형성하는 것으로 알려져 왔으나 최근 연구에 의하면, PMN도 또한 이 런 cytokine들을 형성할 수 있다는 것이 보고되었다. 오랫동안 염증반응이나 면역반응에서 PMN의 역할이 주로 포식작용 을 통해 병원균을 제거하는 것이라고만 생각되어져 왔던 것을 생각하면, 새로운 발견이라 할 수 있다. 또, PMN은 IL-1ra도 생성하는 것으로 보고되었는데, IL-1ra란 IL-1의 생물학적 작용을 방해하는 인자이므로, IL-1과 밀접한 관련을 가지는 질환의 발전에 있어서 IL-1과 IL-1ra의 balance가 매우 중요한 역할을 할 것으로 생각된다 즉, IL-1ra는 IL-1$\beta$의 proinflammatory effect를 제한할 수 있는 negative feedback mechanism이라고 할 수 있다. 이 연구의 목적은 치수 및 치근단 조직의 감염에 있어서 주요 원인균인 Porphyromonas endodontalis의 LPS가 PMN의 IL-1$\beta$, TNF-$\alpha$, IL-1ra생성에 미치는 영향을 단백질과 mRNA 수준에서 관찰하는 것이다. 잘 알려진 non-oral bacterium인 E. coli의 LPS를 positive control로 사용하였으며, IL-1ra가 IL-1$\beta$의 생물학적 작용을 방해하는 작용을 관찰하기 위해, IL-1의 biological assay도 시행하였다. 방법 - P. endodontalis ATCC 35406을 혐기성 조건에서 배양하고, hot phenol-water extraction의 방법으로 LPS를 추출(crude LPS)한 후, 제조회사로부터 구입한 E. coli의 crude LPS와 함께 정제하였다. 건강한 자원자들을 대상으로 말초혈액을 채취한 후 dextran sedimentaion을 거쳐 Lymphoprep을 이용하여 PMN층을 분리하였다. 얻어진 세포들은 RPMI 1640 (supplemented with fetal bovine serum antibiotics)에 5$\times$$10^{6}$cells/ml이 되도록 resuspend시킨 후 각기 다른 농도 (0, 0.01, 0.1, 1 and 10$\mu$g/ml)의 LPS를 처리하여, 각기 다른 시간(Northern blot : 1, 2, 4시간 ELISA : 2, 6, 12, 18시간)동안 37$^{\circ}C$ in 5% $CO_2$ 의 조건으로 배양하였다. 상층액은 -7$0^{\circ}C$에 보관하였다가 추후에 ELISA를 이용한 단백질 농도 측정과 IL-1 biological assay에 사용되어졌으며, 배양된 세포로부터 RNA를 추출하여 Northern hybridization을 통해 mRNA expression을 관찰하였다. (중략)

• Childhood Kidney Diseases
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• v.9 no.2
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• pp.175-182
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• 2005

Purpose : Interleukin 1 receptor antagonist(IL-1ra) is an endogenous antiinflammatory agent that binds to IL-1 receptor and thus competitively inhibits the binding of IL-1$\alpha$ and IL-1$\beta$. Allele 2 in association with various autoimmune diseases has been reported. In order to evaluate the influence of IL-1ra gene VNTR polymorphism on the susceptibility to HSP and its possible association with disease severity, manifested by severe renal involvement and renal sequelae, we studied the incidence of carriage rate and allele frequency of the 2 repeats of IL-1ra allele 2($IL1RN^{*}2$) of the IL-1ra gene in children with HSP with and without renal involvement. Methods : The IL-1ra gene polymorphisms were determined in children with HSP with(n=40) or without nephritis(n=34) who had been diagnosed at Busan Paik Hospital and the control groups(n=163). Gene polymorphism was identified by PCR amplification of the genomic DNA. Results : The allelic frequency and carriage rate of $IL1RN^{*}1$ were found most frequently in patients with HSP and in controls. The allelic frequency of $IL1RN^{*}2$ was higher in patients with HSP compared to that of controls($4.7\%\;vs.\;2.5\%$, P=0.794). The carriage rate of $IL1RN^{*}2$ was higher In patients with HSP compared to that of controls($8.1\%\;vs.\;6.8\%$, P=0.916). The allelic frequency of $IL1RN^{*}2$ was higher in patients with HSP nephritis compared to that of HSP($5.3\%\;vs.\;2.9\%$, P=0.356). The carriage rate of $IL1RN^{*}2$ was higher in Patients with HSP nephritis compared to that of HSP($10.0\%\;vs.\;5.9\%$, P=0.523). Among 13 patients with heavy proteinuria(>1.0 g), 11 had $IL1RN^{*}1$, 1 had $IL1RN^{*}2$ and the others had $IL1RN^{*}4$. At the time of last follow up 4 patients had sustained proteinuria and their genotype was $IL1RN^{*}1$. Conclusion : The allelic frequency and carriage rate of $IL1RN^{*}1$ were found most frequently in patients with HSP and in controls. Our study suggests that the carriage rate and allele frequency of the 2-repeats of IL-1lra allele 2($IL1RN^{*}2$) of the IL-1ra gene may not be associated with susceptibility and severity of renal involvement in children with HSP (J Korean Soc Pediatr Nephrol 2005;9:175-182)

• Biomedical Science Letters
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• v.24 no.2
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• pp.94-101
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• 2018

Tuberculosis (TB) is infectious disease caused by Mycobacterium tuberculosis (MTB) infection. It is known that not only the property of microorganism but also the genetic susceptibility of infected patients is controlled. Interleukin 2 (IL-2) is a cytokine belonging to type 1 T helper (Th1) activity. In addition, IL-2, when infected with MTB, binds IL-2 receptor and promotes T cell replication and is involved in granuloma formation. The aim of this study was to investigate the genetic polymorphisms of the IL-2 receptor gene in tuberculosis patients and normal individuals. We analyzed 22 SNPs in three genes using the genotype data of 443 tuberculosis cases and 3,228 healthy controls from the Korea Association Resource for their correlation with tuberculosis case. IL2RA, IL2RB, and IL2RG genes were genotyped of 16, 4, and 2 SNPs, respectively. Among three genes, only IL2RA gene polymorphisms showed statistically significant association with tuberculosis case. 6 SNPs with high significance were identified in the IL2RA gene. In addition, the linkage disequilibrium (LD) structure of IL2RA gene was confirmed. SNP imputation of IL2RA gene was performed, it was confirmed that more SNPs were significant between case and control. If we look at the results of IL2RA gene analysis above, we can see that genetic polymorphism in the gene expressing $IL-2R{\alpha}$ will regulate the expression level of $IL-2R{\alpha}$, and the change in the immune system involved in $IL-2R{\alpha}$. In this study, genetic polymorphism that may affect host immunity suggests that susceptibility to tuberculosis may be controlled.

• Korean Journal of Food Science and Technology
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• v.47 no.1
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• pp.119-125
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• 2015

The aim of this study was to investigate the synergistic anti-inflammatory effect of rosmarinic acid (RA) and luteolin from perilla (Perilla frutescens L.) leaves in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. A combination of RA and luteolin more strongly inhibited the production of nitric oxide (NO), inducible NOS (iNOS), prostaglandin $E_2$ ($PGE_2$), and COX-2 than higher concentrations of RA or luteolin alone in LPS-stimulated RAW264.7 macrophages. The combined RA and luteolin synergistically inhibited the production of pro-inflammatory cytokines, such as tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$), interleukin-6 (IL-6), and interleukin-$1{\beta}$ (IL-$1{\beta}$), in LPS-stimulated RAW264.7 macrophages. Furthermore, combined RA and luteolin more strongly suppressed NF-${\kappa}B$ activation than RA or luteolin alone, by inhibiting the degradation of inhibitor of NF-${\kappa}B(I{\kappa}B)$-${\alpha}$ and nuclear translocation of the p65 subunit of NF-${\kappa}B$ in LPS-stimulated RAW264.7 macrophages. Collectively, these results suggest that RA and luteolin in combination exhibit synergistic effects in suppression of LPS-induced inflammation in RAW264.7 macrophages.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1994.04a
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• pp.207-207
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• 1994

I) 지금까지 만성골수성백혈병의 치료법으로서 골수이식이나 인터페론의 투여등이 시행되어왔으며 백혈병세포에서 Interleukin-1$\beta$(이하 IL-1$\beta$)이 자율적으로 생성됨이 보고 되어 이러한 질병의 진행에 IL-1$\beta$의 활성증가가 관련될것이라는 견해가 대두되어 왔다. 최근 단핵구성백혈병 환자의 소변에서 분리된 IL-1수용체 길항제(1L-1 receptor antagonist: IL-lRA)가 clonig되었고 인터페론치료에 저항하는 환자들의 치료에 IL-1RA 가 이용될수 있을것이라는 견해가 있다. 따라서 본 연구는 유전공학연구소가 분리 정제한 IL-1RA가 만성골수백혈병 환자로부터 유래한 K562세포주의 증식에 미치는 영향을 평가하고 알파인터페론과의 병용투여시의 상호작용에 관해 검토하였다.