Positive and negative roles of interleukin-6 in bone metabolism , inflammation and cell differentiation : application in oriental medical research

Lee, Dong Kyu,Kang, Dong Hwi,Kim, Dong Il,Lee, Tae Kyun,Park, Young Guk,Kim, Cheorl Ho 대한한의학회 부인과학회 2000 大韓韓方婦人科學會誌 Vol.13 No.2

Interleukin 6 (IL-6)은 여러종류의 세포에서 분화 및 주화인자로 작용하는 사이토카인이다. 사람 IL-6의 분자구조는 21에서 28 kDa의 분자량을 갖는 하나의 폴리펩타이드 단백질로서 N-형과 O-형당부가반응과 세린잔기에 인산화를 수반하여 수식되어 있다. 이 사이토카인은 수성의 28-아미노산 자기로 구성된 시그날배열을 가진 212 아미노산의 전구체 단백질로서 생합성된다. IL-6와 가장 밀접한 분자구조를 갖는 물질로는 granulocyte colony-stimulating factor (G-CSF)가 있으며 사람 IL-6의 유전자는 염색체 7p21에 암호화되어 있다. IL-6는 IL-6수용체 (80 kDa subunit, IL-6Ra)의 a-사슬의 세포의 영역과 상호작용을 거쳐 세포표면에 결합하게 되며 이렇게 생성된 결합체는 gp130수용체와 상호작용하며, 이때 gp130 subunit는 JAK/STAT signaling cascade의 계속적인 활성화능력을 보유하도록 리간드-의존적인 2량화 형성이 유도된다. IL-6Ra의 세포내 영역도메인은 신호전달반응에 아무런 역할을 하지 않으며 IL-6Ra의 세포막통과와 세포질도메인이 결여된 수용성 IL-6수용체도 마찬가지로 IL-6와 반웅하며 상승제로서 가능을 하게 된다. 이러한 광범위한 발현과 효과 때문에 IL-6생성의 생체내에서의 부적절한 발현과 조절은 중요한 생리적인 변화를 야기시킨다. 본 총설에서는 생리적이고 병태생리적인 조건에서의 IL-6의 역할과 기능을 검토하였으며 한의학에서의 면역, 천식, 골대사, 당뇨, 암, 순환기계질환, 신경계질환의 약물개발과 기전해석의 수단으로서 검토하였다. Interleukin 6 (IL-6) is a cytokine that functions as a trophic and differentiating factor in cells of many types. Human IL-6 is a single-chain protein with a molecular mass ranging from 21 to 28 kDa. IL-6 is modified by N- and O-glycosylations, as well as by phosphorylation on serine residues. The cytokine is synthesized as a precursor protein of 212 amino acids with a hydrophobic 28-residue signal sequence. Its closest homolog is granulocyte colony-stimulating factor (G-CSF). The gene for human IL-6 is located on chromosome 7p21. IL-6 binds to the cell surface via an interaction with the extracellular region of the a-chain of the IL-6 receptor (80 kDa subunit, IL-6Ra). This complex then associates with the gp130 receptor. The gpl30 subunit undergoes ligand-dependent dimerization with subsequent activation of the JAK/STAT signaling cascade. The intracellular domain of IL-6Ra does not play a role in signal transduction. The soluble IL-6 receptor, which lacks the transmembrane and cytoplasmic domain of IL-6Ra, is also responsive to IL-6 and acts as an agonist. Because of its wide-ranging expression and effects, the inappropriate expression and modulation of IL-6 production has important physiological consequences. Presently, it was examined that role of IL-6 under physiological and pathophysiological conditions, and its feasibility as a drug discovery target are meaningful in fields of oriental medical research.

Interleukin-1B(1L-1B) polymorphisms and gastric mucosal levels of IL-Iβ cytokine in Korean patients with gastric cancer

Chang, Young-Woon,Jang, Jae-Young,Kim, Nam-Hoon,Lee, Jae Won,Lee, Hyo Jung,Jung, Woon Won,Dong, Seok-Ho,Kim, Hyo-Jong,Kim, Byung-Ho,Lee, Joung-Il,Rin Chang KYUNG HEE UNIVERSITY MEDICAL CENTER 2006 고황의학상 수상논문집 Vol.21-22 No.-

Interleukin-1B and IL-1 receptor antagonist gene polymorphisms are associated with an increased risk of gastric cancer (GC) in Caucasian populations. However, recent studies could not find any association between IL-1B-511T polymorphism and the risk of GC in Asians. We tested for an association between IL-1 loci polymorphisms with increased gastric mucosal levels of IL-1β and an increased risk of developing GC in a Korean population. Polymorphisms of IL-1A-889, IL-1B-31, IL-1B-511 and IL-1RN were genotyped in 434 controls and 234 patients with GC. Mucosal IL-1β cytokine was measured using an ELISA. The frequencies of IL-1A, IL-1B-511, IL-1B-31 and IL-1RN were not statistically different between controls and all patients with GC. After subclassification of GC, only patients with intestinal-type GC showed a higher frequency of IL-1B-31T homozygotes (OR = 2.2; 95% CI = 1.1-4.3) compared with controls. Risk was also significantly increased in these patients for IL-1B-31T homozygotes compared with patients with diffuse-type GC (OR = 3.4; 95% CI = 1.5-7.7). As in Caucasian populations, linkage disequilibrium between IL-1B-31 and IL-1B-511 was nearly complete, but the pattern of haplotype related to the risk of GC (IL-1B-31T/IL-1B-511C) was opposite (IL-1B-511T/IL-1B-31C). Mucosal IL-1β levels in H. pylori-infected GC patients were higher in patients homozygous for IL-1B-31T compared with IL-1B-31C/T and IL-1B-31C/C. Thus, the combined effects of H. pylori infection and IL-1B-31T/IL-1B-511C polymorphisms with enhanced mucosal IL-1β production contributed to the development of intestinal-type GC in this Korean population.

위암에서 Helicobacter pylori cagA, vacA, iceA 유전자와 숙주 Interleukin-1β및 Interleukin-1 수용체 길항제 유전자 다형성

이성훈 ( Seong Hun Lee ),김태오 ( Tae Oh Kim ),이동현 ( Dong Hyun Lee ),박원일 ( Won Il Park ),김광하 ( Gwang Ha Kim ),허정 ( Jeong Heo ),강대환 ( Dae Hwan Kang ),송근암 ( Geun Am Song ),조몽 ( Mong Cho ) 대한내과학회 2006 대한내과학회지 Vol.71 No.1

Background: Both Helicobacter pylori (H. pylori) cagA, vacA, iceA genotype and host IL-1B/IL-1RN polymorphisms play a role in determining the clinical consequences of H. pylori infection. This study aimed to investigate whether there might be any combinations of H. pylori cagA, vacA, iceA genotype and host IL-1B/IL-1RN polymorphisms that are particularly associated with the occurrence of gastric carcinoma in Korean patients. Methods: This study population was comprised of 239 patients with H. pylori infection: 122 with gastric carcinoma and 117 with gastritis only. DNA was isolated from gastric biopsy sample and H. pylori cagA, vacA and iceA genotype were determined by PCR. IL-1B-511 polymorphisms were genotyped by PCR-RFLP and IL-1RN polymorphisms were analyzed with variable number of tandom repeat after PCR. Results: H. pylori cagA, vacA, and iceA genotype were not associated with an increased risk for gastric carcinoma. IL-1B-511*T carriers and IL-1RN*2 carriers did not show increased risk for gastric carcinoma. On combination of bacterial/host genotypes, cagA+/IL-1B-511*T carriers and cagA+/IL-1RN*2 carriers, vacA s1/IL-1B-511*T carriers, vacA s1/IL-1RN*2 carriers, vacA m1/IL-1B-511*T carriers, vacA m1/IL-1RN*2 carriers, iceA1/IL-1B-511*T carriers, iceA1/IL-1RN*2 carriers showed no increased risk of gastric carcinoma. Conclusions: Combined H. pylori cagA, vacA, iceA genotype and host IL-1B/IL-1RN polymorphisms shows no increased risk of gastric carcinoma. Therefore, it seems other endogenous or exogenous factors may play more important role in the development of gastric carcinoma in Korean.(Korean J Med 71:24-37, 2006)

Effects of Carthamus tinctorius L. seed extracts on regulation of cellular proliferation, prostaglandin E₂synthesis and plasminogen activator activity in the mouse calvarial bone cells

Lee,Dong-Young,Bae,Man-Jong,Kim,Dong-Il,Lee,Tac-Kyun,Nam,Kyung-Soo,Lee,Dong-Kyu,Kim,Cheorl-Ho 경산대학교 생명자원개발연구소 2000 생명자원과 산업 Vol.4 No.-

Medicinal extracts of Honghwain (Carthamus tinctorius L. seed) (CTE) was tested for whether they could inhibit IL-1β-induced PGE₂productional. Cell viability was not significaltly affected by treatment with the indicated concentration of the extracts. The CTE extracts were shown to havethe inhibitory effects against the synthesis of PGE₂. we also examined the effect of the pretreatment with a various concentrations of the CTE extracts then treated the PGE₂-induction agents. Pretreatment of the CTE extracts for 1 h, which by itself had little effect on cell survival, did not enhance the synthesis of PGE₂. Furthermore, the CTE extracts were shown to have the the protective effects against plasminogen dependent fibrinolysis induced by the bone resorption agents of IL-1β. Pretreatment of the CTE extracts for 1 h did not enhance the plasminogen dependent fibrinolysis. Finally, calcitonin showed the inhibitory activity the IL-1β-stimulated bone resorption in the mouse calvarial bone cells having both of the osteoblast and osteoclast cells. Seemingly, pretreatment of the CTE extracts for 1 h reduced the bone resorption. These results clearly indicated that calcitonin and CTE extracts play key roles in inhibition of the osteoclast-mediated bone resorption, and also indicated that the CTE-water extracts are highly stable and applicable to clinical uses in osteoporosis.

Increased serum interleukin-10 level in Kawasaki disease

Kim, Dong Soo,Lee, Hong Kyu,Noh, Geun Woong,Lee, Soon Il,Lee, Ki Young Yonsei University, College of Medicine 1996 Yonsei medical journal Vol.37 No.2

정신분열병과 22번 염색체 인터루킨-2 수용체 β-chain 유전자의 연관성

김용구,이민수,김 인,곽동일,서광윤 大韓神經精神醫學會 1998 신경정신의학 Vol.37 No.3

연구배경 : 정신분열병이 유전적이라고 제시하는 많은 역학 연구와 유전자 연구에도 불구하고, 이 질환의 유전방식과 질병유전자는 밝혀져 있지 않다. 본 연구에서는 정신분열병과 22번 염색체 장완의 11.2-12부위에 위치한 Interleukin-2수용체 β chain 유전자간에 유전적 연합을 조사하고자 정신분열병 환자 93명과 정상대조군 97명 대상으로 중합효소연쇄반응을 이용하여 Interleukin-2 수용체 β chain (IL-2Rβ) 유전자의 다형성 분포를 조사하였다. 연구방법 : 환자군은 DSM-Ⅲ-R 진단기준에 따라 임상아형(망상형, 붕괴형, 미붕괴형, 잔류형)으로 분류하였다. 음성 및 양성 정신분열병으로 분류하기위해 Positive and Negative Syndrome Scale(PANSS)을 사용하였다. Genomic DNA를 전혈 임파구에서 추출한 후, IL-2Rβ 유전자좌를 분석하기 위해 dinucleotide(GT)n 염기배열순서를 중합효소연쇄반응을 이용하여 증폭시켰다. 연구결과 : IL-1Rβ의 대립유전자는 모두 8가지 종류이고, guanine-thymine의 반복된 149 염기쌍을 시작으로 151, 153, 155, 157, 159, 161, 163 염기쌍의 형태를 보였다. 정신분열병 환자군과 정상대조군간에 도형접합체 및 이형접합체 빈도의 유의한 차이는 없었다. 환자군과 정상대조군의 대립유전자 분포의 빈도는 통계적으로 유의한 차이가 없었다. 더욱이 각각의 대립유전자 분포에서도 양군간 유의한 차이는 없었다. 또한 동질의 아형으로 분류해 보기위해 임상아형, 양성 및 음성증상군, 가족력의 유무에 따라 비교적 동질적인 표현형을 가진 집단으로 나눈 후 대립유전자 분포를 비교해 보았으나 통계적으로 유의한 차이를 보이지 않았다. 결 론 : 본 연구에서는 Interleukin-2 수용체 β chain 유전자가 정신분열병의 병인론에 관련된다는 가설을 지지할 만한 긍정적 소견을 얻지 못했다. Background : While a significant genetic predisposition to schizophrenia has been proposed, the mode of inheritance or nature of etiological factors is unknown. Previous reports of a genome-wide survey for schizophrenia susceptibility genes have indicated a possible region of linkage on chromosome 22. In order to test the possibility that the interleukin-2 receptor β chain(IL-2Rβ) gene on chromosome 22 is of etiological importance in schizophrenia, a case-control association study was conducted. Methods : Subjects were ninety-three schizophrenic patients with a diagnosis of schizophrenia by DSM-Ⅲ-R criteria and ninety-seven normal controls, Schizophrenic patients were divided by clinical phenotypes such as DSM-Ⅲ-R diagnostic subtypes, positive and negative symptoms, and family history so as to increase the homogeneity of schizophrenics. Genomic DNA was extracted from whole blood lymphocytes according to standard procedures. The DNA was used to study a dinucleotide repeat in the IL-2Rβ gene. To reveal the dinucleotide polymorphism. genomic DNA of subjects was amplified by polymerase chain reactions(PCR). Results : At the IL-2Rβ gene locus, all the previously reported alleles(eight different alleles) of a dinucleotide polymorphism were identified. There was no significant difference between number of heterozygosity in schizophrenic patients and in normal controls. There was no significant difference in the distribution of frequencies of alleles between schizophrenics and normal controls. In addition, there was no significant difference in the allele frequencies among subtypes of schizophrenic patients according to DSM-Ⅲ-R diagnostic subtypes, positive and negative symptoms, and family history. Conclusion : The present study did not detect a difference in frequencies of alleles of a dinucleotide polymorphism at the IL-2Rβ gene locus between schizophrenic patients and normal controls. These results do not supports an evidence that IL-2Rβ gene plays, a major role in the etiology of schizophrenia.

Free Paper Session : Upper Gastrointestinal Tract 1 ; Prevalence And Risk Factors For Atrophic Gastritis And Intestinal Metaplasia

( Na Young Kim ),( Dong Ho Lee ),( Joo Sung Kim ),( Hyun Chae Jung ),( In Sung Song ),( Kyung Phil Kang ),( Jung Hoon Lee ),( Jae Il Chung ),( Hyun Cheul Choi ),( Taek Man Nam ),( Sang Hyup Lee ),( Yo 대한소화기학회 2007 SIDDS Vol.9 No.-

Background/Aims: The prevalence of gastric cancer and Helicobacter pylori (Hp) infection is high in Korea. This study was performed to evaluate the prevalence rate of atrophic gastritis (AG) and intestinal metaplasia (IM) and their risk factors in the aspect of Hp virulence factors, environmental and host factors in normal population. Methods: The subjects consisted of 389, 135 H. pylori-negative and 254 H. pylori-positive. AG and IM were scored histologically by the Sydney classification in the antrum and body, respectively. Prevalence rate and bacterial factors such as cagA, vacA m1, m2, and oipA; environmental factors such as smoking, alcohol drinking; host factors such as genetic polymorphisms for IL-IB-511, IL-IRN, TNF-A, IL-10-592, IL-10-819, IL-10-1082, IL-8-251, IL-6-572, GSTP1, and p53 codon 72 were evaluated. Risk factors were calculated by multiple logistic regression analysis. Results: The prevalence rate of AG increased from 25%, 0% in the age of 20s, 45% and 22% in the 40s and 50% and 35% in the over 70s in the antrum and body, respectively (p<0.001). In case of IM it increased from 11.1% and 6.4% in the 30s up to 43% and 43% in over 70s in the antrum and body, respectively, (p<0.001). The positive rates of AG and IM were significantly higher in the Hp-positive than in the Hp-negative subjects. Multivariate analysis showed that the risk factors for AG were Hp infection, age ≥60, cagA and vacA m1 positive. In case of IM the risk factors were Hp infection, age ≥60, smoking, spicy food, occupation (unemployed or non professional vs. professional), IL6-572 G carrier over C/C and IL10-592 C/A vs. A/A. Conclusions: The prevalence rate of AG and IM increased proportional to age. The most risk factor for AG and IM was Hp infection. Bacterial factors were important for AG but environmental and host factors were rather important in case of IM.

Inflammatory Endotypes of Chronic Rhinosinusitis in the Korean Population: Distinct Expression of Type 3 Inflammation

Min Jin-Young,Kim Jin Youp,성충만,Kim Seon Tae,조현진,문수진,Cho Sung-Woo,Hong Sang Duk,Ryu Gwanghui,Cho Kyoung Rai,Kim Young Hyo,Park Soo-Kyoung,Kim Dong-Kyu,Lee Dong Hoon,Heo Sung Jae,Lee Ki-Il,Kim Su Jin,Le 대한천식알레르기학회 2023 Allergy, Asthma & Immunology Research Vol.15 No.4

Purpose: Cluster analyses on inflammatory markers of chronic rhinosinusitis (CRS) in Asians from multicenter data are lacking. This multicenter study aimed to identify the endotypes of CRS in Koreans and to evaluate the relationship between the endotypes and clinical parameters. Methods: Nasal tissues were obtained from patients with CRS and controls who underwent surgery. The endotypes of CRS were investigated by measuring interleukin (IL)-5, interferon (IFN)-γ, IL-17A, IL-22, IL-1β, IL-6, IL-8, matrix metalloproteinase-9, eotaxin-3, eosinophil cationic protein, myeloperoxidase (MPO), human neutrophil elastase (HNE), periostin, transforming growth factor-β1, total immunoglobulin E (IgE), and staphylococcal enterotoxin (SE)-specific IgE. We performed hierarchical cluster analysis and evaluated the phenotype, comorbidities, and Lund-Mackay computed tomography (LM CT) score in each cluster. Results: Five clusters and 3 endotypes were extracted from 244 CRS patients: cluster 1 had no upregulated mediators compared to the other clusters (mild mixed inflammatory CRS); clusters 2, 3, and 4 had higher concentrations of neutrophil-associated mediators including HNE, IL-8, IL-17A, and MPO (T3 CRS); and cluster 5 had higher levels of eosinophil-associated mediators (T2 CRS). SE-specific IgE was undetectable in T3 CRS and had low detectable levels (6.2%) even in T2 CRS. The CRS with nasal polyps (CRSwNP) phenotype and LM CT scores showed no significant differences between T2 and T3 CRS, while the incidence of comorbid asthma was higher in T2 CRS than T3 CRS. In T3 clusters, higher levels of neutrophilic markers were associated with disease severity and CRSwNP phenotype. Conclusions: In Koreans, there is a distinct T3 CRS endotype showing a high proportion of CRSwNP and severe disease extent, along with T2 CRS.

Threshold Rigidity Values for the Asbestos-like Pathogenicity of High-Aspect-Ratio Carbon Nanotubes in a Mouse Pleural Inflammation Model

Lee, Dong-Keun,Jeon, Soyeon,Han, Youngju,Kim, Sung-Hyun,Lee, Seonghan,Yu, Il Je,Song, Kyung Seuk,Kang, Aeyeon,Yun, Wan Soo,Kang, Sung-Min,Huh, Yun Suk,Cho, Wan-Seob American Chemical Society 2018 ACS NANO Vol.12 No.11

<P>The qualitative and quantitative evaluation of the physicochemical parameters associated with the pathogenicity of high-aspect-ratio nanomaterials is important for comprehensive regulation efforts and safety-by-design approaches. Here, we report quantitative data on the correlations between the rigidity of these nanomaterials and toxicity endpoints <I>in vitro</I> and <I>in vivo</I>. As measured by new ISO standards published in 2017, rigidity shows a strong positive correlation with inflammogenic potential, as indicated by inflammatory cell counts and IL-1β (a biomarker for frustrated phagocytosis) levels in both the acute and chronic phases. <I>In vitro</I> experiments using differentiated THP-1 cells find that only highly rigid multiwalled carbon nanotubes (MWCNTs) and asbestos fibers lead to piercing and frustrated phagocytosis. Thus, this study suggests a bending ratio of 0.97 and a static bending persistence length of 1.08 as threshold rigidity values for asbestos-like pathogenicity. However, additional research using MWCNTs with rigidity values that lie between those of non-inflammogenic (<I>D</I><SUB>b</SUB> = 0.66 and SBPL = 0.87) and inflammogenic fibers (<I>D</I><SUB>b</SUB> = 0.97 and SBPL = 1.09) is required to identify more accurate threshold values, which would be useful for comprehensive regulation and safety-by-design approaches based on MWCNTs.</P> [FIG OMISSION]</BR>

Silibinin polarizes Th1/Th2 immune responses through the inhibition of immunostimulatory function of dendritic cells

Lee, Jun Sik,Kim, Sang Gap,Kim, Hyung Keun,Lee, Tae-Hyung,Jeong, Young-Il,Lee, Chang-Min,Yoon, Man-Soo,Na, Yong Jin,Suh, Dong-Soo,Park, Nam Cheol,Choi, In-hak,Kim, Gi-Young,Choi, Yung Hyun,Chung, Hae Liss 2007 Journal of Cellular Physiology Vol.210 No.2

<P>Silibinin is the primary active compound in silymarin. It has been demonstrated to exert anti-carcinogenic effects and hepato-protective effects. However, the effects of silibinin on the maturation and immunostimulatory activities exhibited by dendritic cells (DCs) remain, for the most part, unknown. In this study, we have attempted to determine whether silibinin can influence surface molecule expression, dextran uptake, cytokine production, capacity to induce T-cell differentiation, and the signaling pathways underlying these phenomena in murine bone marrow-derived DCs. Silibinin was shown to significantly suppress the expression of CD80, CD86, MHC class I, and MHC class II in the DCs, and was also associated with impairments of LPS-induced IL-12 expression in the DCs. Silibinin-treated DCs proved highly efficient with regard to Ag capture via mannose receptor-mediated endocytosis. Silibinin also inhibited the LPS-induced activation of MAPKs and the nuclear translocation of the NF-κB p65 subunit. Additionally, silibinin-treated DCs evidenced an impaired induction of Th1 response, and a normal cell-mediated immune response. These findings provide new insight into the immunopharmacological functions of silibinin, especially with regard to their impact on the DCs. These findings expand our current understanding of the immunopharmacological functions of silibinin, and may prove useful in the development of therapeutic adjuvants for acute and chronic DC-associated diseases. J. Cell. Physiol. 210: 385–397, 2007. © 2006 Wiley-Liss, Inc.</P>