• IMMUNE NETWORK
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• 제24권3호
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• pp.21.1-21.16
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• 2024

IL-1, a pleiotropic cytokine with profound effects on various cell types, particularly immune cells, plays a pivotal role in immune responses. The proinflammatory nature of IL-1 necessitates stringent control mechanisms of IL-1-mediated signaling at multiple levels, encompassing transcriptional and translational regulation, precursor processing, as well as the involvement of a receptor accessory protein, a decoy receptor, and a receptor antagonist. In T-cell immunity, IL-1 signaling is crucial during both the priming and effector phases of immune reactions. The fine-tuning of IL-1 signaling hinges upon two distinct receptor types; the functional IL-1 receptor (IL-1R) 1 and the decoy IL-1R2, accompanied by ancillary molecules such as the IL-1R accessory protein (IL-1R3) and IL-1R antagonist. IL-1R1 signaling by IL-1β is critical for the differentiation, expansion, and survival of Th17 cells, essential for defense against extracellular bacteria or fungi, yet implicated in autoimmune disease pathogenesis. Recent investigations emphasize the physiological importance of IL-1R2 expression, particularly in its capacity to modulate IL-1-dependent responses within Tregs. The precise regulation of IL-1R signaling is indispensable for orchestrating appropriate immune responses, as unchecked IL-1 signaling has been implicated in inflammatory disorders, including Th17-mediated autoimmunity. This review provides a thorough exploration of the IL-1R signaling complex and its pivotal roles in immune regulation. Additionally, it highlights recent advancements elucidating the mechanisms governing the expression of IL-1R1 and IL-1R2, underscoring their contributions to fine-tuning IL-1 signaling. Finally, the review briefly touches upon therapeutic strategies targeting IL-1R signaling, with potential clinical applications.

• IMMUNE NETWORK
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• 제5권1호
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• pp.16-22
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• 2005

Background: IL-18 was originally cloned as a IFN-${\gamma}$ inducing factor in primed T cells. In synergy with IL-12, IL-18 has been shown to induce strikingly high levels of IFN-${\gamma}$ production by T cells and to enhance Th1 development. Also this cytokine exerts induction of Th2 development through IL-4 induction. Methods: Resting $CD4^+$ T cells were sorted by negative selection and activated by anti-CD3 plus anti-CD28 Ab. Expression of IL-12 binding sites, IL-18 binding sites, IL-18R ${\alpha}$, and GATA-3 mRNA were analysed by FACS and RT-PCR, respectively. Results: Resting $CD4^+$ T cells expressed IL-18R ${\alpha}$ chain but not IL-18 binding sites, suggesting a lack of IL-18R ${\beta}$ expression. IL-18R ${\alpha}$ was maintained on the Th1 and Th2 committed cells. IL-18 binding sites were induced on the Th1 but not Th2 cells. Exposure of these cells to IL-18 led to up-regulation of GATA-3 mRNA expression only in Th2 committed cells. To elucidate the relationship between IL-18R ${\alpha}$ expression and GATA-3 induction by IL-18, Th1 and Th2 committed cells were further cultured in medium with or without IL-12 for 2 days. IL-12 binding sites were maintained on the Th1 and Th2 cells regardless of IL-12 treatment, but IL-18R a expression was rapidly down-regulated on the IL12-untreated Th2 cells which did not induce GATA-3 mRNA expression followed by IL-18 stimulation. Conclusion: IL-12 supports expression of IL-18R ${\alpha}$ and GATA-3 mRNA expression was induced by IL-18 through IL-18R ${\alpha}$ without expression of IL-18 binding site in Th2 cells.

• Journal of Periodontal and Implant Science
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• 제24권1호
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• pp.155-164
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• 1994

치조골흡수는 만성치주질환의 전형적인 증상이다. 골흡수에 작용하는 여러 요인들 중에서도, 특히 최근에 들어서 몇몇 cytokine들에 대한 관심이 높아지고 있는데, interleukin-1(IL-1), tumor necrosis factor(TNF) 및 interleukin-6(IL-6) 등이 치주질환의 진행과정에서 중요한 치조골흡수요인으로 제안되고 있다. 본 연구의 목적은 신생쥐의 골조직 배양실험을 통해서 recombinant human $interleukin-1{\beta}$ ($rHuIL-1{\beta}$), recombinant human tumor necrosis $factor-{\alpha}$($rHuTNF-{\alpha}$) 및 recombinant human interleukin-6(rHuIL-6) 의 골흡수 유도효과를 알아보고, cyclooxygenase 억제제인 indomethacin과 recombinant murine $interferon-{\gamma}$($rMurIFN-{\gamma}$)가 이들 cytokine의 골흡수 유도능력에 미치는 영향을 알아봄으로써 이들 cytokine의 작용기구에 대해서 알아보고자 하는데 있다. 생후 1-2일된 쥐에게 $1{\mu}Ci^{45}CaCl_2$를 피하주사하고 4일 후에 쥐를 희생시켜 $^{45}Ca$ 로 표지된 두개골을 얻어 24시간 전배양 후, 각 cytokine ($rHuIL-1{\beta}$, $rHuTNF-{\alpha}$ 및 rHuIL-6)과 cytokine 및 첨가약제 (indomethacin 및 $rMurIFN-{\gamma}$)가 함유된 배지로 교환하여 48시간 배양한다. 골흡수 유도효과는 두개골에서 48시간의 배양 중 유리되는 $^{45}Ca$의 방사능 정도로 평가하였다. 본 연구를 통해 다음과 같은 결과를 얻었다. 1. $rHuIL-1{\beta}$ ($10^{-12}-10^{-9}M$) 및 $rHuTNF-{\alpha}$ ($10^{-10}-10^{-8}M$)는 농도변화에 따르는 골흡수 유도효과를 보였으나 , rHuIL-6 ($10^{-10}-10^{-8}M$)는 유의할 만한 효과를 보이지 않았다. 2. Indomethacin ($10^{-6}M$)은 $rHuIL-1{\beta}$ 및 $rHuTNF-{\alpha}$의 골흡수 유도작용에 유의할 만한 억제효과를 나타내지 않았다. 3. $rMurIFN-{\gamma}$ (1000 U/ml) 은 $rHuIL-1{\beta}$ 및 $rHuTNF-{\alpha}$의 골흡수 유도작용에 유의한 억제효과를 나타내었다. 본연구를 통해 치주질환 환자의 치주조직에서 검출되는 $IL-1{\beta}$ 및 $TNF-{\alpha}$가 치조골 흡수에 중요한 역할을 할 것으로 생각된다.

• 한국수정란이식학회지
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• 제31권4호
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• pp.323-333
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• 2016

Pro-inflammatory cytokines, interleukin-$1{\beta}$(IL1B), IL6, and tumor necrosis factor-alpha (TNF), are known to play important roles in regulating the endometrial function in the uterus during the estrous cycle and pregnancy in several species. However, the expression and function of these cytokines and their receptors in the uterine endometrium during the estrous cycle have not been studied in pigs. Thus, this study determined the expression and regulation of IL1B, IL6, TNF and their respective receptors, IL1R1, IL1RAP, IL6R, GP130, TNFRSF1A, and TNFRSF1B during the estrous cycle in pigs. To analyze levels of each gene expression in the uterine endometrium we obtained from endometrial tissues on Days 0, 3, 6, 9, 12, 15, and 18 of the estrous cycle. Real-time RT-PCR analysis showed that levels of IL1B, IL1RAP, IL6R, GP130, TNF, TNFRSF1A, and TNFRSF1B mRNAs were highest on Day 15 or 18 of the estrous cycle, which corresponds to the proestrus period. Levels of IL1R1 were highest on Day 0, while levels of IL6 were biphasic with high levels on Day 6 and Day 15. The abundance of IL1B, IL6, IL6R, and TNF mRNAs was decreased by progesterone, while levels of GP130 were increased by progesterone in endometrial tissue explants. These results showed that expression of pro-inflammatory cytokines and their receptors changed stage-specifically during the estrous cycle and regulated by progesterone in the uterine endometrium in pigs, suggesting that these pro-inflammatory cytokines may be involved in the regulation endometrial function during the estrous cycle in pigs.

• Molecules and Cells
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• 제40권3호
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• pp.222-229
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• 2017

Adipose-derived stem cells (ADSCs) were previously considered to have an anti-inflammatory effect, and Interleukin-$1{\beta}$ ($IL-1{\beta}$) was found to be a pro-inflammatory factor in chondrocytes, but the mechanism underlying ADSCs and $IL-1{\beta}$ is unclear. In this study, we investigate whether P2X7 receptor (P2X7R) signalling, regulated by microRNA 373 (miR-373), was involved in the ADSCs and $IL-1{\beta}$ mediated inflammation in osteoarthritis (OA). Chondrocytes were collected from 20 OA patients and 20 control participants, and ADSCs were collected from patients who had undergone abdominal surgery. The typical surface molecules of ASDCs were detected by flow cytometry. The level of nitric oxide (NO) was determined by Griess reagent. Concentrations of prostaglandin E2 (PGE2), interleukin 6 (IL-6), matrix metallopeptidase 3 (MMP-3) were detected by enzyme-linked immunosorbent assay (ELISA). The expressions of IL-6, MMP-3, miR-373 and P2X7R were determined by real-time polymerase chain reaction (PCR), and Western blot was used to detect the protein expression of P2X7R. The typical potential characters of ADSCs were verified. In chondrocytes or OA tissues, the miR-373 expression level was decreased, but the P2X7R expression was increased. $IL-1{\beta}$ stimulation increased the level of inflammatory factors in OA chondrocytes, and ADSCs co-cultured with $IL-1{\beta}$-stimulated chondrocytes decreased the inflammation. OA chondrocytes transfected with the miR-373 inhibitor increased the inflammation level. The miR-373 mimic suppressed the inflammation by targeting P2X7R and regulated its expression, while its effect was reversed by overexpression of P2X7R. $IL-1{\beta}$ induced inflammation in OA chondrocytes, while ADSCs seemed to inhibit the expression of P2X7R that was regulated by miR-373 and involved in the anti-inflammatory process in OA.

• Parasites, Hosts and Diseases
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• 제29권4호
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• pp.381-388
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• 1991

정상 BALB/c 마우스의 복강에서 분리한 대식세포를 조제 림포카인 및 재조합 림포카인 (rGM-CSF, rIL-2, rIL-4, $rIFN-{\gamma}$)으로 18 시간 반응시켜 활성화시키고 대식세포 $1{\times}10^5$ 개와 $methyl-[^3H]-thymidine$으로 표지된 질트리코모나스 $1{\times}10^4$ 개를 10:1 비율로 넣고 18 시간 동안 $37^{\circ}C$, 5% $CO^2$ 항온항습기에서 반응시킨 다음 상청액 $100{\;}{\mu}l$씩을 scintillation cocktail 2ml에 넣어 방사능을 측정하여 세포독성을 관찰하고 nitrite 생산량을 측정하였다. rIL-2 40U/m1나 $rIFN-{\gamma}$ 100U/ml로 활성화시킨 대식세포는 대조군 보다 높은 세포독성을 보였으나 2개의 림포카인을 촌합시켰을때 낮은 세포독성을 보였다. rIL-4를 rGM-CSF, rIL-2 및 $rIFN-{\gamma}$와 각각 혼합시켰을 때 각 림포카인에 의한 대식세포의 세포독성은 감소되었다. 조제 림포 카인에서 IL-2에 대한 항체는 세포독성을 현저히 감소시켰다. Nitrite 생산량은 $rIFN-{\gamma}$ 및 rIL-4 각각으로 대식세포를 활성화시켰을 때 세포독성 정도와 비례되었고, rIL-2와 $rIFN-{\gamma}$을 혼합 시켰을 때 nitrite 생산량이 높고 증식이 억제되었으나 세포독성은 낮았다. 이러한 결과로 보아 rIL-2 및 $rIFN-{\gamma}$는 각각 단독으로도 대식세포를 활성화시켜 질트리모나스에 세포독성을 나타내며 rIL-4 는 세포독성을 억제시키는 것으로 생각되며, nitrite 생산량은 세포독성과 반드시 비례하지 않으나 nitric oxide가 질트리코모나스의 증식을 억제하는 것으로 생각된다.

• 대한의생명과학회지
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• 제13권3호
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• pp.183-187
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• 2007

Monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) playa key role in development of atherosclerosis. To take into account the atherogenic properties of MCP-1 and IL-8 and its influence on insulin resistance, we examined circulating levels of MCP-1 and IL-8 in adults. We recruited 292 subjects (84 males and 208 females) aged between 29 and 79 years. MCP-1 and IL-8 levels were measured by enzyme-linked immunosorbent assay. Age, total cholesterol, HDL-cholesterol, and LDL-cholesterol levels were significantly higher in female subjects (P<0.01, respectively), but diastolic blood pressure (BP) was significantly lower in female subjects compared to male subjects. MCP-1 and IL-8 levels were tended to increase with age, the highest in their seventies. MCP-1 (P=0.05) and IL-8 (P<0.01) levels were higher in males than in females. MCP-1 was positively correlated with age (r=0.17, P<0.05), IL-8 (r=0.26, P<0.01), fasting insulin (r=0.30, P<0.01), and HOMA-IR (r=0.29, P<0.01). In linear regression analysis, age was found to be independent factor associated with MCP-1 adjusted by age, BMI, fasting glucose, triglyceride, and systolic BP. In conclusion, age was found to be independent factor associated with MCP-1. It is possible that an increase of MCP-1 in adults with age may be risk to atherosclerosis and diabetic properties.

• 대한수의학회지
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• 제45권4호
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• pp.501-505
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• 2005

Immu-Forte composed of chitosan, ${\beta}-glucan$, manno-oligosaccharide and pangamic acid was evaluated for its effectiveness as a nonspecific immunostimulator in mice. The effects of Immu-Forte were determined by analysis of cytokines using ELISA and phenotype of leukocyte subpopulations using monoclonal antibodies specific to mouse leukocyte differentiation antigens and flow cytometry. All T cells, all B cells, CD4 T cells, CD8 T cells, macrophages, IL-2, IL-4, IL-12 and IFN-r in Immu-Forte A-treated group increased in 1 months posttreatment and were significantly higher (p < 0.05) than that of control at 1 months posttreatment. All T cells, all B cells, CD4 T cells, CD8 T cells, macrophages and IL-2 in Immu-Forte EX-treated low and middle dose groups increased in 1 months posttreatment and were significantly higher (p < 0.05) than that of control at 1 months posttreatment. In the Immu-Forte soybean-treated group, NK cells and IL-4 were significantly higher in middle dose-treated group, and IL-2, IL-4 and IFN-r were significantly higher in low dose-treated group. In the Immu-Forte F-treated group, all T cells, all B cells, CD4 T cells, CD8 T cells, macrophages, NK cells, IL-2, IL-4, IL-12 and IFN-r in high dose-treated group and all T cells, all B cells, CD4 T cells, CD8 T cells, macrophages, IL-2, IL-4, IL-12 and IFN-r in middle dose-treated group and NK cells, IL-2, IL-4, IL-12 and IFN-r in low dose-treated group were significantly higher (p < 0.05) than that of control at 1 months posttreatment. In conclusion, this study has demonstrated that Immu-Forte had an immunostimulatory effect on mice through proliferation and activation of mouse immune cells.

• IMMUNE NETWORK
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• 제24권1호
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• pp.1.1-1.6
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• 2024

IL-18 binding protein (IL-18BP) was originally discovered in 1999 while attempting to identify an IL-18 receptor ligand binding chain (also known as IL-18Rα) by subjecting concentrated human urine to an IL-18 ligand affinity column. The IL-18 ligand chromatography purified molecule was analyzed by protein microsequencing. The result revealed a novel 40 amino acid polypeptide. To isolate the complete open reading frame (ORF), various human and mouse cDNA libraries were screened using cDNA probe derived from the novel IL-18 affinity column bound molecule. The identified entire ORF gene was thought to be an IL-18Rα gene. However, IL-18BP has been proven to be a unique soluble antagonist that shares homology with a variety of viral proteins that are distinct from the IL-18Rα and IL-18Rβ chains. The IL-18BP cDNA was used to generate recombinant IL-18BP (rIL-18BP), which was indispensable for characterizing the role of IL-18BP in vitro and in vivo. Mammalian cell lines were used to produce rIL-18BP due to its glycosylation-dependent activity of IL-18BP (approximately 20 kDa). Various forms of rIL-18BP, intact, C-terminal his-tag, and Fc fusion proteins were produced for in vitro and in vivo experiments. Data showed potent neutralization of IL-18 activity, which seems promising for clinical application in immune diseases involving IL-18. However, it was a long journey from discovery to clinical use although there have been various clinical trials since IL-18BP was discovered in 1999. This review primarily covers the discovery of IL-18BP along with how basic research influences the clinical development of IL-18BP.

• Tuberculosis and Respiratory Diseases
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• 제53권3호
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• pp.294-308
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• 2002

연구배경 :결핵은 세포 매개성 면역반응이 병태생리에 중요한 역할을 하는 감염성 질환이다. 결핵균 항원으로 T 림프구가 활성화되면 여러 종류의 cytokine을 분비하며 T 림프구의 분화와 증식, 대식세포의 활성화를 촉진한다. 본 연구에서는 결핵의 중증도, 숙주의 면역상태 및 예후를 반영하는 지표로서 활성화된 T 림프구에서 만들어지는 IL-2의 수용성 수용체인 sIL-2R와 IFN-$\gamma$를 측정하였고 활성화된 대식세포에서 분비되는 neopterin을 측정하여 임상적 유용성을 판정하고자 하였다. 대상 및 방법 :활동성 폐결핵 환자 39명, 결핵성 림프절염 환자 6명의 치료전과 정상 대조군 10명에서 혈청 sIL-2R, neopterin, IFN-$\gamma$를 측정하였고, 결핵성 흉막염 환자 22명에서 치료전 혈청과 흉막액에서 각각 sIL-2R, ADA, neopterin을 측정하였다. 폐결핵 환자 39명을 ATS guidelines에 따라 중증도를 분류하였고, 사망한 1명과 결핵요양소로 전원된 2명을 제외한 36명에서 초치료 2개월 후 혈청 sIL-2R, neopterin과 IFN-$\gamma$를 측정하였다. 결 과 : 1) sIL-2R과 IFN-$\gamma$는 결핵환자에서 대조군에 비하여 증가된 경향을 보였다(p>0.05). Neopterin은 대조군 $4949{\pm}1242.l$ pg/ml, 폐결핵 $29.67{\pm}2132.8$ pg/ml, 결핵성 림프절엽 $3013{\pm}1877.3$ pg/ml, 결핵성 흉막염이 $2035{\pm}1216.4$ pg/ml로 결핵환자에서 대조군에 비하여 감소되는 경향을 보였으며, 폐결핵군과 결핵성 흉막염군에서는 통계적으로 유의하게 감소되어 있었다(p<0.05). 2) 폐결핵의 중증도가 심할수록 sIL-2R와 IFN-$\gamma$는 증가하였고, neopterin은 감소하였다(p<0.01). 3) 폐결핵 환자 36명에서 치료 후 측정한 sIL-2R는 $1071{\pm}l139.4$ U/ml에서 $1023{\pm}1920.9$ U/ml로(p>0.05), IFN-$\gamma$는 $41{\pm}52.8$ pg/ml에서 $22{\pm}23.9$ pg/ml로 각각 감소하였고 (p<0.05), neopterin은 $3158{\pm}2272.6$ pg/ml에서 $3737{\pm}2307.5$ pg/ml로 증가하였다(p>0.05). 이러한 결과는 경증군과 중등증군에 비해 중증군에서 현저한 변화를 보였고 임상적 경과와 상관성을 보였다. 4) 결핵성 흉막염 환자 22명에서 sIL-2R와 ADA는 혈청에 비하여 흉막액에서 유의하게 높은 값을 보였으나(p<0.01), neopterin은 차이가 없었다(p>0.05). 결 론 : 이상의 결과를 바탕으로 특히 중증군에서 치료 후에 sIL-2R, IFN-$\gamma$와 neopterin을 추적 관찰하면 숙주의 면역반응상태, 임상적 중증도 및 치료 반응성을 예측하는데 도움이 될 것으로 생각된다. 또한 결핵성 흉막염 환자에서는 국소적인 변역반웅의 활성화로 흉막액내의 면역학적 지표의 측정이 혈청 검사보다 특이적이며, 흉막액의 sIL-2R의 측정이 결핵성 흉막염의 진단에 유용할 것으로 생각된다.