Direct regulation of IL-2 by curcumin

Oh, Jin-Gyo,Hwang, Da-Jeong,Heo, Tae-Hwe Elsevier 2018 Biochemical and biophysical research communication Vol.495 No.1

<P><B>Abstract</B></P> <P>Interleukin-2 (IL-2) is a crucial growth factor for both regulatory and effector T cells. Thus, IL-2 plays a critical role in the stimulation and suppression of immune responses. Recently, anti-IL-2 antibodies (Abs) have been shown to possess strong IL-2 modulatory activities by affecting the interaction between IL-2 and IL-2 receptors. In this study, we screened an herbal library to identify a compound that regulates IL-2, which resulted in the identification of curcumin as a direct binder and inhibitor of IL-2. Curcumin is a phytochemical with well-known anti-cancer properties. In this study, curcumin mimicked or altered the binding pattern of anti-IL-2 Abs against IL-2 and remarkably inhibited the interaction of recombinant IL-2 with the IL-2 receptor α, CD25. Interestingly, curcumin neutralized the biological activities of IL-2 both in vitro and in vivo. In this report, we elucidated the unsolved mechanism of the anti-cancer effect of curcumin by identifying IL-2 as a direct molecular target. Curcumin, as a small molecule IL-2 modulator, has the potential to be used to treat IL-2 related pathologic conditions.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Curcumin identified as a direct binding partner of IL-2. </LI> <LI> Binding between IL-2 and IL-2 receptor alpha is reduced by curcumin. </LI> <LI> Curcumin counteracts the side effect of IL-2, vascular leak syndrome. </LI> </UL> </P>

Allergen-Dependent Differences in ILC2s Frequencies in Patients With Allergic Rhinitis

Dachuan Fan,Xiangdong Wang,Min Wang,Yang Wang,Liang Zhang,Ying Li,Erzhong Fan,Feifei Cao,Koen Van Crombruggen,Luo Zhang 대한천식알레르기학회 2016 Allergy, Asthma & Immunology Research Vol.8 No.3

Purpose: Group 2 innate lymphoid cells (ILC2s) are a novel population of lineage-negative cells that induce innate type 2 responses by producing the critical Th2-type cytokines IL-5 and IL-13 in response to IL-25 and IL-33 stimulation. ILC2s accumulation in the peripheral blood of patients with allergic rhinitis (AR) is controversial; the precise role of ILC2s in the immunopathogenesis of AR is still not clear. We investigated the role of ILC2s in phenotypic AR sensitized to distinct allergens. Methods: Flow cytometric analysis of the peripheral blood of 7 healthy controls (HCs), 9 patients monosensitized to house dust mite (HDM), and 8 patients monosensitized to mugwort was performed to quantify ILC2s frequency. Peripheral blood mononuclear cells (PBMCs) were isolated from HDM-AR and mugwort-AR patients, and Lineage- and Lineage+ cells were separated using a fluorescence-activated cell sorter (FACS). IL-5 and IL-13 levels in the supernatants of PBMCs, and Lineage- and Lineage+ cells stimulated with IL-25 and/or IL-33 combined with IL-2 in vitro were assessed using the Milliplex magnetic bead kit. Results: The percentage of ILC2s was significantly elevated in HDM-AR patients compared to mugwort-AR patients and HCs, while no significant difference was found between mugwort-AR patients and HCs. IL-33±IL-25 plus IL-2 induced a significantly greater release of IL-5 and IL-13 in the PBMCs of HDM-AR patients compared to PBMCs of mugwort-AR patients. IL-25 plus IL-2 also induced a significantly greater release of IL-13 in the PBMCs of HDM-AR patients compared to PBMCs of mugwort-AR patients. Stimulation with IL-33 and/or IL-25 combined with IL-2 also induced a significantly greater IL-5 and IL-13 release from Lineage- cells compared to Lineage+ cells. Conclusions: AR patients sensitized to HDM or mugwort allergen have distinct phenotypic and functional profiles in ILC2s frequencies. ILC2s mediate major type 2 immunity in the development of HDM-AR and may be a potential therapeutic target.

급성 백혈병에서 혈청내 Soluble IL-2 Receptor 측정

김시찬,민유홍,이선주,한지숙,고윤웅 大韓血液學會 1993 大韓血液學會誌 Vol.28 No.2

Association of Genetic Polymorphism of IL-2 Receptor Subunit and Tuberculosis Case

Sang-In Lee,Hyun-Seok Jin,Sangjung Park 대한의생명과학회 2018 Biomedical Science Letters Vol.24 No.2

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-2Rα will regulate the expression level of IL-2Rα, and the change in the immune system involved in IL-2Rα. In this study, genetic polymorphism that may affect host immunity suggests that susceptibility to tuberculosis may be controlled.

화상환자에서 면역억제 기전

정태호,황일우,장수일,김문규,서정민,정치영,김정철 慶北大學校 醫科大學 1995 慶北醫大誌 Vol.36 No.4

목적 : 본 연구는 화상환자에서 면역이상의 기전을 조사코져 T-세포의 활성을 나타내는 가용성 interleukin-2 수용체(IL-2R), 대식세포의 활성을 나타내는 neopterin, tumor necrosis factor(TNF) 및 interleukin-6 (IL-6), 그리고 호중구의 활성을 반영하는 elastase-α1-antitrypsin을 측정하였다. 또한 lipopolysaccharide(LPS)가 이들 면역세포의 활성화에 미치는 영향을 조사하였다. 대상 및 방법 : 30예의 화상환자를 대상으로 화상후 1일, 7일, 14일, 21일, 28일에 각각 혈액을 채취하여 혈청중 가용성 IL-2R, TNF, IL-6, 그리고 elastase-α1-antitrypsin은 각각 효소면역법으로, 혈청중 neopterin은 radioimmunoassay법으로 측정하였다. LPS가 말초 단핵세포에 미치는 영향은 역전사 중합효소 연쇄반응을 통하여 각종 cytokines의 mRNA 발현을 측정하였다. 결과 : 화상환자에서 혈청중 가용성 IL-2R은 화상후 1일째부터 대조군에 비하여 유의성 있게 증가되어 7일과 14일째에 최고치를 나타냈으며 그 이후에는 다소 감소하였으나 대조군보다는 유의한 증가를 나타냈다. 화상환자를 중화상, 중등도화상, 경도화상으로 분류하여 혈청중 가용성 IL-2R 치를 비교해본 결과 중증 화상일수록 더욱 높은 치를 나타냈다. 화상환자에서 혈청중 neopterin 역시 화상후 1일째부터 증가되어 전 관찰기간 동안 대조군에 비해 유의한 높은 치를 나타냈다. 경도화상과 중등도 화상에서는 서로 유의한 차이를 보이지 않았으나 중환자에서는 경도 혹은 중등도 화상환자에 비해 유의한 증가를 보였다. 화상환자에서 혈청중 TNF 농도는 화상후 1일부터 증가되어 관찰전기간에 걸쳐 유의한 증가를 나타냈으며 중등도 화상환자에서 가장 높은 치를 보였다. 혈청중 IL-6치 역시 화상 전기간에 걸쳐 대조군보다 유의한 증가를 나타냈으며 중화상 환자에서 가장 높은 치를 나타냈다. 화상은 또한 혈청중 elastase-α1-antitrypsin 농도를 현저히 증가시켰다. 즉 화상후 1일에 elastase-α1-antitrypsin 농도는 정상인보다 5배 높았으며 그 이후 약 4주간 계속 높은 농도를 유지하다가 환자가 회복되면서 감소하는 경향을 나타내었다. 중등도화상 및 중화상환자의 혈청중 elastase-α1-antitrypsin 농도는 경도 화상환자에서 비해 유의한 증가를 보였다. 한편 화상환자에서 면역이상을 초래하는 주된 요인으로 여겨지는 lipopolysaccharide는 면역세포를 총체적으로 활성화시켜 IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, TNF, IFN-γ, TGF-β, GM-CSF, IL-2R의 유전자발현을 현저히 증가시켰다. 결론 : 화상환자에서 T-세포, 대식세포, 호중구의 활성화를 반영하는 가용성 IL-2R, neopterin, ,TNF, IL-6, elastase-α1-antitrypsin치가 혈중에 증가되어 있으며 화상의 정도가 심할수록 더 높았다. Cell-mediated immunity frequently becomes severely impaired after thermal injury. However, the cause of postburn immune dysfunction is unclear and controversy exists over both pathophysiology and clinical relevance of these abnormalities. This study was undertaken to investigate the immune responses in vivo of patients with burn. Levels of soluble IL-2R, a sensitive marker of T-cell activation, levels of serum TNF, IL-6, and neopterin, an index of macrophage activation, and levels of serum elastase-α1-antitrypsin, an index of neutrophil activation, were measured in serial serum samples taken from 30 burned patients. In patients with burn, soluble IL-2R levels were increased over a 4-week interval with peak concentrations reached during the 2nd week after burn. Patients with severe burn showed a higher soluble IL-2R levels than those with mild or moderate burn. In addition soluble IL-2R significantly correlated with burn size. The levels of serum neopterin were already increased at the first day following burn, and remained at a high level throughout the total period studied (28 days). Patients with severe burn showed significantly higher concentration of serum neopterin than mild or moderate burn. There was positive relationship between the burn sizes and the levels of neopterin. A significant positive correlation was also found between serum soluble IL-2R levels and neopterin levels in burn patients. Levels of serum TNF and IL-6 were also significantly increased over a 4-week interval in burn patients. The levels of serum elastase-α1-antitrypsin were also already increased at the first day following burn, and remained at a high level over a 4-week. Patients with moderate or severe burn showed significantly higher concentration of serum elastase-α1-antitrypsin than those with mild burn. There was no significant relationship between the burn extent and the level of elastase-α1-antitrypsin. LPS increased the transcription of all the cytokines we examined in peripheral mononuclear cells, i.e., IL-1α, IL-1β, IL-2, IL-4, IL-5_IL-6, IL-8, IL-10, TNF, TGF-β, GM-CSF, and IL-2R. We conclude that soluble IL-2R, neopterin, TNF, IL-6, and elastase-α1-antitrypsin might be useful parameters for monitoring of the clinical course in burn patients. Moreover, they indicate that T-cell, macrophage, and neutrophil activation might play the central role in the pathogenesis of the immuno-logic and metabolic disturbance that follows thermal injury.

고농도 포도당과 Angiotensin 2 및 차단제가 Angiotensin 2 차단제가 인체 메산지움 세포의 IL - 6 및 Fibronectin 생산에 미치는 영향

고경식(Kyung Sik Ko),임천규(Chun Gyoo Ihm),김희진(Hee Jin Kim),이태원(Tae Won Lee),김명재(Myung Jae Kim) 대한내과학회 2001 대한내과학회지 Vol.61 No.4

N/A Background: Diabetic nephropathy is a leading cause of end-stage renal disease and is characterized by activation of some growth factors (e.g., angiotensin 2, endotelin-1, IL-8, and TGF-β) and deposition of extracellular matrix proteins . Both ACE inhibit or s and AT 1 receptor blockers partially prevent renal hypertrophy in diabetes. Recently, IL-6 is thought to act as an autocrine growth fact or for the mesangial cells. Angiotensin 2 (Ang 2) is one of the non-inflammatory stimulators of IL-6 release from mesangial cells. IL-6 have been implicated in glomerulonephritis, including mesangioproliferative glomerulonephritis. IL-6 may be associated with renal damage, especially mesangioproliferative diabetic nephropathy. However, little is known about the pathogenetic relations between IL-6 and diabetic nephropathy. Methods: To evaluate the effects of high glucose concentration, Ang 2 and its blockers on IL-6 and fibronectin production, human mesangial cells were cultured in various conditions. Normal concentration (100 mg/dL) and high concentration of D-glucose (450 mg/dL), Ang 2 (10-7M), high glucose with Ang 2, captopril (10-6M), and losartan (10-6M) were added. After 48 hours, IL-6 and fibronectin concentration in the supernatant were measured by ELISA method. Results: The effects of various conditions on the production of IL-6 and fibronectin in cultured human mesangial cells were as follows: 1. The concentration of IL-6 in the supernatant was significantly low in high glucose group (9.9±0.2 pg/mL) compared to that in control group (18.0±6.2 pg/mL) (p<0.05), and there was no difference in the supernatant concentration of fibronectin between the groups of high glucose and control. 2. The concentration of IL-6 in the supernatant of Ang 2 group (28.0±5.0 pg/mL) was significantly higher than that in control group (18.0±6.2 pg/mL) (p<0.05), and there was no difference in the supernatant concentration of fibronectin between the groups of Ang 2 and control. 3. In the supernatant of high glucose with Ang 2 group, the concentration of IL-6 (20.0±4.0 pg/mL) was significantly higher than that of high glucose group (9.9±0.2 pg/mL) (p<0.05), and the concentration of fibronectin (3,100±50 pg/mL) was significantly higher than that of control group (2,840±290 pg/mL) (p<0.05). 4. The concentration of IL-6 in the supernatant was significantly lowered after the addition of captopril (10.7±1.8 pg/mL) and losartan (9.3±2.4 pg/mL) in high glucose with Ang 2 group (20.0±4.0 pg/mL) (p<0.05). 5. The concentration of fibronectin was significantly lowered after the addition of captopril (2,640±30 pg/mL) and losartan (2,440±230 pg/mL) in high glucose with Ang 2 group (3,100±50 pg/mL) (p<0.05). 6. There was no difference in the concentration of supernatant IL-6 and fibronectin between the groups of captopril and losartan. Conclusion: High glucose concentration decreases and Ang 2 increases the production of IL-6 by cultured human mesangial cells. Captopril and losartan decrease the production of IL-6 and fibronectin which have been stimulated by high glucose concentration and Ang 2. These drugs may be useful in the treatment of renal disease, especially diabetic nephropathy, in which Ang 2 and high blood glucose are cooperative in the progression of nephropathy. (Korean J Med 61:399-408, 2001)

결핵성 흉막염에서 Soluble Interleukin-2R, Interleukin-6 및 Adenosine Deaminase의 변화에 관한 연구

김종혁 ( Kim Jong Hyeog ),정복현 ( Jeong Bog Hyeon ),문승환 ( Mun Seung Hwan ),조호준 ( Jo Ho Jun ),이명구 ( Lee Myeong Gu ),현인규 ( Hyeon In Gyu ),정기석 ( Jeong Gi Seog ),남송현 ( Nam Song Hyeon ),류지소 ( Lyu Ji So ),조현찬 ( 대한내과학회 1993 대한내과학회지 Vol.44 No.2

흉막 질환을 진단하고 그 기전을 이해하는데 각종 면역학적 지표들이 이용되어 왔으며 특히 결핵성 흉막염은 T 임파구가 활성화도이 조력 T 임파구가 증가하고 sIL-2R, ADA 및 interferon gamma 등이 증가한다고 알려져 있다. 저자들은 이들 T 임파구의 산물인 sIL-2R, IL-6, ADA 등이 흉막질환의 감별 진단에 도움이 되는지를 살펴 보고 서로간의 상관관계를 조사하여 다음과 같은 결론을 얻었다. 1) 흉막액에서 sIL-2R 치는 결핵성에서 877±430pmol/L로 결핵성에서 증가되어 있었다. 2) 흉막액에서 IL-6 치는 결핵성에서 25,593±17,352pg/ml, 악성에서 5,800±3,485pg/ml로 유의한 차이를 보였고 농흉에서 74,080±48,569pg/ml로 가장 높게 나타났다. 3) 결핵성 흉막액내의 sIL-2R 치와 ADA 치는 서로 유의한 상관관계를 보이며 증가되어 있었다(r=0.5623, p=0.001). 4) 결핵성 흉막액의 sIL-2R 치는 IL-6가 증가함에 따라 상승하는 경향을 보였다. 이상의 결과로 흉막염에서 결핵과 악성 종양의 감별은 ADA, sIL-2R 및 IL-6 모두가 의미있는 지표들로 사료되며 결핵성에서 sIL-2R와 ADA 간의 유의한 상관관계가 있고 sIL-2R와 IL-6 간에도 동반상승의 경향을 보여 T 임파구에서 형성되는 이들 지표들이 결핵성 흉막 삼출액내에서 서로 연관성이 있음을 시사하였다. Background: The aim of this study is to evaluate the value of interleukin-6 (IL-6), Soluble interleukin-2 receptor (sIL-2R) and adenosine deaminase in diagnosing tuberculos pleurisy and in differentiating it from malignant pleural effusion, and to find out mutual relationships between the three parameters. Methods: We investigated the level of IL-6, sIL-2R and ADA in various pleural diseases. Included were 77 subjects with pleural effusion (57 bopsy proven tuberculous pleurisy, 9 malignant pleural effusion, 5 empyema, 4 parapneumonic effusion, 1 paragonimiasis and 1 pancreatitis). IL-6 was measured by Quantikine human IL-6 (R&D systems), sIL-2R by h-interleukin-2-receotor ELISA (Boehringer Manheim biochemica) and ADA by Giusti`s colorimetric method. Results: The level of IL-6 was significantly higher in tuberculous effusion (25,593±17,352 pg/ml) than that of malignant effusion (5,800±3,485 pg/ml, p < 0.001). IL-6 was also increased in empyema fluids (74,080±48, 569 pg/ml). The level of sIL-2R was significantly higher in tuberculous effuson (877±430 pmol/l) than that of 20 nontuberculous effusion (259±230 pmol/L, p<0.001). The level of ADA was also higher in tuberculous effusion (82.4±26.9 U/L) than that of nontuberculous effusion (18.8±11.6 U/L, p<0.001). Levels of both ADA and sIL-2R were lower in malignant effusion (16.4±9.66 U/L, 229+171 pmol/L) than those of tuberculous effusion. The sensitivity and specificity of IL-6 in discriminating tuberculosis from malignancy were 84% and 100% respectively (cut-off value: 10000 pg/ml). Those of sIL-2R were 87% and 77% (cut-off value: 350 pmol/L). ADA was most valuable in differentiating tuberculosis from malignancy, sensitivity and specificity of which were 100% (cut-off value: 40 U/L). The correlation coefficient of sIL-2R and IL-6 was 0.3822 (p=0.001). Conclusion: It was suggested that assay of IL-6, sIL-2R and ADA could play an implemental role in differential diagnosis of tuberculous pleural effusion. Increased level of the three parameters and significant correlations between them were suggestive of the involvement of activated T cells in tuberculous pleural effusion.

심근경색증에서 단핵구 배양후 측정한 Interleukin-2(IL-2)에 관한 연구

이충석,권영주 순천향의학연구소 1998 Journal of Soonchunhyang Medical Science Vol.4 No.2

연구배경 : 허혈성 심장병의 원인인 동맥의 죽상경화증 진행 과정에서 혈관 내피 세포 하층에 단핵구 침윤이 있으며 단핵구 가운데 T세포가 많이 관여하는 것으로 알려져있다. T세포의 활성도를 알기 위하여 T세포에서 분비되는 cytokine의 하나인 IL-2 측정이 활성도에대한 하나의 지표로도 사용될 수 있다. 불안정성 협심증이나 급성 심근경색증과 같은 급성 허혈성 심질환에서 IL-2와 같은 cytokine의 혈중 농도가 증가하고 cytokine의 농도 상승은 저산소증으로 인한 혈관 내피 세포에의한 cytokine 의 분비 증가와 활성화된 단핵구와도 관련이 있다. 본 연구는 급성 심근경색증에서 단핵구의 cytokine의 분비 능력을 알아보기 위하여 단핵구를 분리 배양하여 단핵구에서 분비된 IL-2를 측정하여 그 결과를 보고한다. 방법 : 급성 심근경색증으로 진단된 17명의 환자와 정상 대조군 7명을 대상으로 하였으며 심도자를 시행하여 상행 대동맥에서 20cc의 혈액을 채취한 후 단핵구를 원심분리하여 Concanavalin A를 첨가해 37oc에서 24시간 및 48시간 배양한 후 그 상층액에서 IL-2를 측정하였다. IL-2의 측정은 면역 혈청학적인 검사인 ELISA법으로 하였으며 정상 대조군과 급성 심근 경색증 군에서 배양전과 24시간 및 48시간 배양액 내의 IL-2 를 측정하였다. 결과 : 1. 정상 대조군에서는 Interleukin-2(IL-2)는 단핵구 배양 전에서는 14.35 ±1.13pg/mL, 배양 24시간 후에는 973.7±517.27 pg/mL,48시간 후에는 608.8±154.70 pg/mL 이었다. 반면 급성 심근경색증 환자에서는 배양 전 16.51±7.51 pg/mL, 배양 24시간 후 2182.1±1320.1 pg/mL, 48시간 후에는 2543.0±1167.8 pg/mL 이었다. 배양전 및 24시간 배양액의 IL-2는 정상 대조군과 급성 심근경색증 군 사이에 유의한 차이가 없었으나 48시간 배양액 에서는 급성 심근경색증 군에서 IL-2가 유의하게 높았다. 2. 침범된 관동맥 병변의 수에 따라 단일혈관 및 두혈관이상 질환으로나누고 이에 따른 IL-2의 농도를 정상 대조군과 관동맥 병변의 수에따른 비교에서 배양 전에는 유의한 차이가 없었으나 24시간 배양액에서는 두혈관이상 관동맥 질환에서 정상대조군 및 단일혈관 질환보다 유의하게 높았으며 48시간 배양액에서는 두혈관 및 단일혈관 관동맥질환 모두에서 정상 대조군 보다 유의하게 높았다. 3. 급성 심근경색증 환자에서 혈중효소중 총 Creatine phosphokinase (CK)상승 정도와 IL-2농도와의 상관관계를 비교해보면 배양 24시간 및 48시간 배양액 모두에서 IL-2의 농도는 총CK 농도가 높을 수록 IL-2의 농도도 유의하게 높았다. 결론 : 급성 심근경색증에서 단핵구의 IL-2의 분비능력은 배양 48시간 후에 증가 되었으며 관동맥 병변이 심할수록 단핵구의 활성화도 증가할 것으로 추정된다. Background: Mononuclear cells contribute to the promotion of release of cytokines in acute myocardial infarction. This study was designed to evaluate interleukin-2(IL-2) levels by mononuclear cells culture in patients with acute myocardial infarction. Methods: We measured IL-2 by mononuclear cells from 17 patients with acute myocardial infarction and 7 control subjects. Mononuclear cells were isolated and incubated with Concanavalin A for 24 hours and 48 hours. Secretions of IL-2 were measured by ELISA kit. Results: Levels of IL-2 by 48 hours incubation culture of mononuclear cells significantly increased in patients with acute myocardial infarction compared with control subjects. However, levels of IL-2 by 24 hours incubation culture of mononuclear cells did not increase in patients with acute myocardial infarction compared with control subjects. In the extent of coronary artery disease by 24 hours incubation culture of mononuclear cells, levels of IL-2 significantly increased in 2 vessels coronary artery disease when compared with control subjects. Also, levels of IL-2 by 48 hours incubation culture of mononuclear cells increased in 1 vessel and 2 vessels coronary artery disease when compared with control subjects. Levels of IL-2 by 24 hours and 48 hours incubation culture of mononuclear cells significantly correlated with levels of total creatine phophokinase in patients with acute myocardial infarction. Conclusion: Higher level of IL-2 by mononuclear cells culture in patients with acute myocardial infarction suggested that enhanced secretory capacity of cytokines of mononuclear cells in acute ischemic heart disease.

신증후 출혈열에서 Interleukin 2의 의의

김용섭,차대룡,변현주,권현민,권영주,조원용,김형규,원동준 대한내과학회 1992 대한내과학회지 Vol.42 No.2

신증후 출혈열(HFRS)은 바이러스에 의해 발생되는 출혈열의 일종으로 임상경과중 급성 신부전과 다량의 단백뇨를 발생하는 질환으로 단백뇨의 발생기전에 대해서는 이론이 많다. 최근 HFRS환자의 신조직검사상 신간질에 침윤된 T 임파구가 신기능 이상 및 단백뇨 발생과 어떠한 연관이 있을 것이란 연구결과가 있어 이에 저자들은 전형적인 HFRS의 임상소견을 보이고 급성 신부전의 임상경과를 보인 14예에서 핍뇨기와 이뇨기의 혈장과 소변에서 여러 가지 생화학적 지표와 RIA방법을 이용한 Interleukin 2(IL-2)를 측정하고 대조군의 IL-2와 비교하여 다음과 같은 결과를 얻었다. 1) HFRS 환자에서 24시간 단백뇨는 핍뇨기에서 731.6±106.9㎎/㎗보다 유의성이 있었으며(p=0.0009), 대조군의 36.5±8.6㎎/㎗ 보다도 유의성이 있었다(p<0.0000). 2) HFRS 환자의 혈장 IL-2는 핍뇨기와 이뇨기에서 각각 7.85±0.37f㏖/㎖, 7.19±0.29f㏖/㎖으로 유의성이 없었으나(p=0.13), 대조군의 5.89±0.14f㏖/㎖와는 각가 유의성이 있었다(p=0.005). 3) HFRS 환자의 핍뇨기에서 소변 IL-2는 5.07±1.06f㏖/㎎Cr으로 이뇨기의 0.35±0.05f㏖/㎎Cr (p=0.009)에 비해 유의성이 있었다. 4) HFRS 환자의 핍뇨기에서 혈장 IL-2와 24시간 단백뇨와는 정비례 관계를 보였으며(r=0.64, p<0.09), 크레아티닌 제거율과 소변 IL-2는 역비례 관계를 보였다. (r=-0.73, p<0.04) 이상의 결과로 볼 때 HFRS에서 신기능 이상의 병태생리와 신간질에 침윤된 T임파구에서 분비되는 IL-2와 유관할 것으로 생각되며, 또한 IL-2가 단백뇨에도 영향을 미칠것이라고 추측된다. Background. Recently renal biopsy findings in Hemorrhagic Fever with Renal Syndrome (HFRS) shows that T lymphocytes infiltrated in renal interstitium may associate with abnormal renal function and proteinuria. Therefore. to speculate the role of Interleukin 2 (IL-2) for proteinuria and renal function, author estimated IL-s in serum and urine in oliguric and diuretic phase of patients who were proved serologically and showed typically clinical manifestations of HFRS. Methods. Authors selected 14 patients who have classic manifestations of HFRS with acute renal failure during clinical course. The conventional studies were performed and serum and urine IL-2 were measured in oliguric and diuretic phase of HFRS with RIA. Also, above measurements wer performed in control group Results. 24 hours proteinuria in oliguric phase (731.6±106.9㎎/day) was significantly higher than in diuretic phase (499.9±275.2㎎/day) (p=0.0009) and also significantly higher than normal control group (36.5±8.6㎎/㎗) (p=0.0000). There was no significant difference in serum concentration of IL-2 between oliguric and diuretic phase (p=0.12), but there was significant difference compared with that of control group, respectively (p<0.01). The excretion of urine IL-2 of HFRS patients in oliguric phase (5.07±1.06f㏖/㎎Cr) were significantly higher than patients in diruretic phase (0.35±0.05f㏖/㎎Cr) an control group (0.78±0.27f㏖/㎎Cr) and control group (0.78±0.27f㏖/㎎Cr) (p<0.05). In oliguric phase of HFRS patients, serum IL-2 and 24 hours proteinuria showed positive correlation (r=0.64, P=0.09) and creatinine and urine IL-2 showed reverse correlation (r=-0.73, p=0.04). Conclusion. Authors consider that IL-2 have a significant role for proteinuria and renal function in the patient with HFRS.

담관계암종에서 c-met, c-erbB-2, COX-2, IL-6의 발현과 임상 의의

주현호 ( Hyun Ho Joo ),송은영 ( Eun Young Song ),진상화 ( Sang Hwa Jin ),오상훈 ( Sang Hoon Oh ),최영길 ( Young Kil Choi ) 대한소화기학회 2007 대한소화기학회지 Vol.50 No.6

목적: 담관계암종의 형성 및 발달과정에 c-met, c-erbB-2, COX-2, IL-6 발현이 관여한다고 알려져 있으나 아직 병리적으로 분명하지 않다. 담관계암종에서 c-met, c-erbB-2, COX-2, IL-6 발현과 임상인자간의 관계를 규명하고자 한다. 대상 및 방법: 수술로 적출된 총 114예의 담관계암 조직에서 c-met, c-erbB-2, COX-2 및 IL-6 발현을 면역조직화학 방법으로 조사하였다. 상기 표지자의 발현과 상호 연관성을 분석하였다. 결과: 담관암 112예 중 34예(30.4%)에서 c-met 발현이 관찰되었고, c-erbB-2 발현은 112예 중 5예(4.5%), COX-2 과 발현은 113예 중 53예(46.9%), IL-6 발현은 113예 중 68예 (60.2%)에서 관찰되었다. 담관암이 근육외측 결체 조직까지 침윤한 경우에 c-met 발현율이 높았고(p=0.0262), 림프절 전이가 없을 때 IL-6 발현율이 높았다(p=0.0325). c-erbB-2 발현을 보이거나 COX-2 발현만을 보일 때 림프절 전이가 많았다(p=0.0442). 결론: 담관암종 발생에 c-met 유전자 이상이 일부 관여하며, 종양의 침습과 연관성이 있을 것으로 추정한다. COX-2 및 IL-6 발현도 관여할 것으로 추정하나 C-erbB-2 유전자 이상은 관여하지 않을 것으로 생각한다. 따라서, 담관암의 c-met, COX-2 및 IL-6 발현을 동시에 조사하는 것이 담관암 환자의 임상 경과를 예측하는 데 도움을 줄 것으로 생각한다. Background/Aims: c-met, c-erbB-2, interleukin (IL)-6, and cyclooxygenase (COX)-2 expressions are considered to be implicated in the carcinogenesis and progression of cholangiocarcinoma, but the molecular pathogenesis of cholangiocarcinoma is still poorly understood. We aimed to analyze the expressions of each marker and their relationships with clinicopathologic factors. Methods: One hundred and fourteen tissue samples were obtained from surgically resected specimens from patients with billiary tract cancer. The expressions of c-met, c-erbB-2, COX-2, and IL-6 were examined by immunohistochemically. The expression of each marker and correlations between these markers and clinicopathologic factors were analyzed. Results: The expression rates of each maker were as follows: c-met 34/112 (30.4%), c-erbB-2 5/112 (4.5%), COX-2 53/113 (46.9%), and IL-6 68/113 (60.2%), respectively. c-met expression was more frequently observed in cases with invasion through the adjacent connective tissues (p=0.0263). IL-6 overexpression was more frequently observed in cases with absent lymph node metastasis (p=0.0325). Either c-erbB-2 expression or COX-2 expression was significantly associated with lymph node metastasis (p=0.0442). Conclusions: The expression of c-met was closely related to the invasiveness of cholangiocarcinoma. Co-expression of c-met, COX-2 and, IL-6 showed a significant correlation with invasiveness and lymph node metastasis and these could be useful marker to guide clinical outcome in patients with cholangiocarcinoma. (Korean J Gastroenterol 2007;50:370-378)