흰쥐 경골의 신연 골형성술에서 염증성 싸이토카인의 발현

황일웅(Il Ung Hwang),조태준(Tae-Joon Cho),최인호(In Ho Choi),정진엽(Chin Youb Chung),유원준(Won Joon Yoo),김은희(Eun Hee Kim) 대한정형외과학회 2004 대한정형외과학회지 Vol.39 No.1

목적: 본 연구의 목적은 신연 골형성술에서의 염증성 싸이토카인의 발현 양상을 일반 골절 치유 과정과 비교하는 것이다. 대상 및 방법: 흰쥐 경골의 단순 골절 치유 모델과 신연 골형성술 모델을 대상으로 3주에 걸쳐서 단계적으로 골 조직을 채취하였다. 총 리보핵산을 추출하고 각종 염증성 싸이토카인 발현의 시간적 변화를 검사하였다. 수술 후 7일과 9일째에 조직에서 면역조직화학 검사를 통해서 IL-6의 공간적 발현 양상을 조사하였다. 결과: IL-1β, IL-6는 단순 골절 치유 과정에서 수술 후 1일째에 발현이 절정에 달하였다가 3일째부터 발현이 감소하여 수술 전 상태로 회복되었다. IL-1β는 신연 골형성술 중 신연 기간에도 발현의 변화가 없었으나 IL-6은 신연을 시작함에 따라 다시 발현이 증가하는 양상을 보였다. 면역조직화학 검사장 IL-6은 골수 세포 뿐 아니라 연골세포, 골모세포 그리고 신연 간격의 미성숙 간엽세포에서 발현이 확인되었다. 결론: 신연 변형력에 의한 IL-6의 발현이 유도되는 것을 확인하였으며, 이는 조절된 염증 반응이 신연 골형성술 과정에서 신생골 형성에 부분적으로 기여할 가능성을 시사하는 것으로 생각된다. Purpose: The purposes of this study were to investigate the expression pattern of pro-inflammatory cytokines during distraction osteogenesis and to compare these with expression during simple fracture healing. Materials and Methods: Regenerated bones from the rat tibia subjected distraction osteogenesis and simple fracture healing models were harvested over three-week periods. Temporal expressions of mRNA of pro-inflammatory cytokines were investigated by RNase protection assay. Immunohistochemical studies for IL-6 were performed in postoperative day 7 and 9 tissue section specimens. Results: IL-1β and IL-6 produced detectable signals, while IL-1α, TNF α and TNF β did not. The mRNA expressions of IL-1β and IL-6 were markedly upregulated on postoperative day 1 and then subsided to the preoperative level. IL-1β mRNA expression remained the same even when distraction began. However, IL-6 mRNA expression was reactivated during the distraction phase. Immunohistochemical study revealed the expressions of IL-6 not only at the transitional zone of the transchondroid ossification, in young osteoblasts lining newly formed trabeculae and in hematopoietic cells in the marrow but also in primitive mesenchymal cells at the distraction gap. Conclusion: Distraction strain re-induced IL-6 expression during distraction osteogenesis, which suggests that well-controlled inflammatory reaction might contribute to active new bone formation in distraction osteogenesis.

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 17 (IL-17) Increases the Expression of Toll-like Receptor-2, 4, and 9 by Increasing IL-1β and IL-6 Production in Autoimmune Arthritis

LEE, JUN-HEE,CHO, MI-LA,KIM, JU-IN,MOON, YOUNG-MEE,OH, HYE-JWA,KIM, GEUN-TAE,RYU, SUN,BAEK, SEUNG-HOON,LEE, SUN-HEE,KIM, HO-YOUN,KIM, SUNG-IL The Journal of Rheumatology 2009 The Journal of rheumatology Vol.36 No.4

<B>Objective.</B><P>To examine the effect of interleukin 17 (IL-17) on the expression of Toll-like receptor (TLR)-2, 4, and 9 in collagen-induced arthritis (CIA) in mice.</P><B>Methods.</B><P>On Days 28 and 32 after induction of CIA in mice, phosphate-buffered saline (PBS group) or IL-17 (IL-17 group) was injected into both knee joints. On Day 35, mice were sacrificed. The severity of knee joint arthritis, synovial inflammation, and bone destruction was measured by a scoring system using macrography and histological analysis. Synovial expression of TLR-2, 4, 9, IL-17, IL-1ß, tumor necrosis factor-α (TNF-α), and IL-6 was determined by real-time PCR and immunohistochemistry. Synoviocytes of CIA mice were cultured with IL-17 and with neutralizing antibodies to cytokine, and the expression of TLR-2, 4, 9, IL-1ß, TNF-α, and IL-6 was determined by real-time RT-PCR.</P><B>Results.</B><P>In CIA mice, knee arthritis scores, synovial inflammation, bone destruction scores, and expression of synovial TLR-2, 4, and 9, IL-17, IL-1ß, TNF-α and IL-6 were higher in the IL-17 and PBS groups than in normal DBA1 mice. These variables were also significantly higher in the IL-17 group than in the PBS group. In CIA synoviocytes, IL-17 increased the expression of TLR-2, 4, and 9, and this effect was significantly alleviated by neutralizing antibodies to IL-17, IL-1ß, and IL-6.</P><B>Conclusion.</B><P>IL-17 aggravates joint inflammation and destruction, and increases the synovial expression of TLR-2, 4, and 9 by increasing IL-1ß and IL-6. These results imply that the IL-17-induced increase in expression of TLR-2, 4, and 9, and IL-1ß and IL-6 production are involved in the IL-17-induced aggravation of arthritis.</P>

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)

류마티스 관절염 동물 모델에서 활막의 RANKL/OPG mRNA 발현 비율 및 IL-17의 효과

이준희 ( Jun Hee Lee ),김근태 ( Geun Tae Kim ),류선 ( Sun Ryu ),김주인 ( Ju In Kim ),백승훈 ( Seung Hoon Baek ),김성일 ( Sung Il Kim ) 대한류마티스학회 2006 대한류마티스학회지 Vol.13 No.2

Objective: To investigate the synovial mRNA expression of receptor activator of NFκB (RANK), RANK ligand (RANKL), osteoprotegerin (OPG) and RANKL/OPG mRNA expression ratio, and to evaluate the effects of IL-17 in experimental rheumatoid arthritis (RA) model. Methods: After induction of collagen-induced arthritis (CIA) by type II collagen in DBA1 mice, mice were anesthetized at day 28 and a small aperture in the skin of the knee was performed. Mice, in which arthritis of knee was present, were selected and divided into 3 groups, and phosphate-buffered saline (PBS group), IL-17 (IL-17 group) or anti-IL-17 monoclonal antibody (anti-IL-17 group) was injected to both knee joint at day 28 and 32. At day 35, mice were sacrificed and synovium of knee joints were isolated. Synovial mRNA expression of RANKL, RANK and OPG was assessed by real-time RT-PCR and immunohistochemical stain. Results: Synovial RANKL and RANK mRNA expressions were significantly different among IL-17, PBS, anti-IL-17 and normal group (IL-17>PBS>anti-IL-17>normal group), and synovial OPG mRNA expressions in PBS, IL-17 and anti-IL-17 group were significantly high than those in normal group, however, there was no significant difference among IL-17, PBS and anti-IL-17 group. RANKL/OPG mRNA ratio was significantly different among these groups (IL-17>PBS>anti-IL-17>normal group). In immunohistochemical stain, RANKL, RANK and OPG-positive cells were expressed at synovium. Conclusion: Synovial RANKL/OPG mRNA ratio was enhanced in CIA, and IL-17 induced higher RANKL/OPG ratio in the synovium of CIA, which was blocked by anti-IL-17 antibody. These results suggest that RANKL/OPG mRNA ratio play an important roles on bone destruction, and IL-17 may be actively involved in bone destruction by enhancing RANKL/OPG ratio in CIA model.

IL-17A induces osteoblast differentiation by activating JAK2/STAT3 in ankylosing spondylitis

Jo, Sungsin,Wang, Sung Eun,Lee, Young Lim,Kang, Suman,Lee, Bitnara,Han, Jinil,Sung, Il-Hoon,Park, Ye-Soo,Bae, Sang-Cheol,Kim, Tae-Hwan BioMed Central 2018 Arthritis research & therapy Vol.20 No.-

<P><B>Background</B></P><P>IL-17A has recently emerged as a potential target that regulates the extensive inflammation and abnormal bone formation observed in ankylosing spondylitis (AS). Blocking IL-17A is expected to inhibit bony ankylosis. Here, we investigated the effects of anti IL-17A agents in AS.</P><P><B>Methods</B></P><P>TNFα, IL-17A, and IL-12/23 p40 levels in serum and synovial fluid from patients with ankylosing spondylitis (AS), rheumatoid arthritis (RA), osteoarthritis (OA), or healthy controls (HC) were measured by ELISA. Bone tissue samples were obtained at surgery from the facet joints of ten patients with AS and ten control (Ct) patients with noninflammatory spinal disease. The functional relevance of IL-17A, biological blockades, Janus kinase 2 (JAK2), and non-receptor tyrosine kinase was assessed in vitro with primary bone-derived cells (BdCs) and serum from patients with AS.</P><P><B>Results</B></P><P>Basal levels of IL-17A and IL-12/23 p40 in body fluids were elevated in patients with AS. JAK2 was also highly expressed in bone tissue and primary BdCs from patients with AS. Furthermore, addition of exogenous IL-17A to primary Ct-BdCs promoted the osteogenic stimulus-induced increase in ALP activity and mineralization. Intriguingly, blocking IL-17A with serum from patients with AS attenuated ALP activity and mineralization in both Ct and AS-BdCs by inhibiting JAK2 phosphorylation and downregulating osteoblast-involved genes. Moreover, JAK2 inhibitors effectively reduced JAK2-driven ALP activity and JAK2-mediated events.</P><P><B>Conclusions</B></P><P>Our findings indicate that IL-17A regulates osteoblast activity and differentiation via JAK2/STAT3 signaling. They shed light on AS pathogenesis and suggest new rational therapies for clinical AS ankylosis.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (10.1186/s13075-018-1582-3) contains supplementary material, which is available to authorized users.</P>

The Correlation of Serum IL-12B Expression With Disease Activity in Patients With Inflammatory Bowel Disease

Lee, Hye Won,Chung, Sook Hee,Moon, Chang Mo,Che, Xiumei,Kim, Seung Won,Park, Soo Jung,Hong, Sung Pil,Kim, Tae Il,Kim, Won Ho,Cheon, Jae Hee Williams & Wilkins Co 2016 Medicine Vol.95 No.23

<▼1><P>Supplemental Digital Content is available in the text</P></▼1><▼2><P><B>Abstract</B></P><P>Genetic variants in <I>IL12B</I>, encoding the p40 subunit common in interleukin-12 (IL-12) and interleukin-23, were identified as the susceptibility loci for inflammatory bowel disease (IBD). This study aimed to identify the correlation of serum IL-12B expression with disease activity in patients with IBD and evaluate the possibility of IL-12B as a biomarker for assessing inflammatory status in IBD.</P><P>A total of 102 patients with IBD, including 38, 32, and 32 patients with Crohn's disease (CD), ulcerative colitis (UC), and intestinal Behçet's disease (intestinal BD), respectively, were included. The clinical and laboratory data from the patients were collected at the time of serum IL-12B measurement. Serum IL-12B levels were measured using an enzyme-linked immunosorbent assay.</P><P>The median IL-12B levels in patients with CD, UC, and intestinal BD were significantly higher than those in controls (1.87, 2.74, and 2.73 pg/mL, respectively, vs. 1.42 pg/mL, all <I>P</I> <0.05). IL-12B concentrations were associated with disease activity in patients with UC and intestinal BD but not in those with CD. IL-12B levels were increased with increasing disease activity in patients with UC (<I>P</I> <0.001). Likewise, patients with active intestinal BD had higher IL-12B levels than those without active disease (<I>P</I> = 0.008). IL-12B levels were correlated with the endoscopic disease activity of UC (<I>P</I> = 0.002) and intestinal BD (<I>P</I> = 0.001) but not that of CD.</P><P>Serum IL-12B levels were significantly correlated with clinical and endoscopic disease activity in patients with UC and intestinal BD, suggesting its potential use as a biomarker for assessing disease activity in these patients.</P></▼2>

Interleukin-17이 배양된 류마티스관절염 활막세포에서 vascular endothelial growth factor 생성에 미치는 영향

곽임수 ( Ihm Soo Kwak ),남태수 ( Tae Soo Nam ),나하연 ( Ha Yeon Rha ),서정탁 ( Jeung Tak Suh ),김유선 ( Yoo Sun Kim ),김성일 ( Sung Il Kim ) 대한류마티스학회 2001 대한류마티스학회지 Vol.8 No.3

Objective: To investigate the the effects of interleukin-17 (IL-17) on the production of vascular endothelial growth factor (VEGF) from cultured rheumatoid arthritis synoviocytes. Methods: Fibroblast-like synovial cells(FLS) were prepared from the synovial tissues of rheumatoid arthritis patients and cultured in the presence of IL-17, IL-17 with or without transforming growth factor-β(TGF-β), tumor necrosis factor-α(TNF-α) and interleukin-1β(IL-1β). VEGF levels were determined in the culture supernatants by sandwitch ELISA. Results: Stimulation of FLS by serial concentration of IL-17, TGF-β, TNF-α, IL-1β increased the production of VEGF by 2.1-2.7, 2.2-3.0, 2.0-2.9, 2.3-3.1 fold over the constitutive levels of unstimulated FLS. Stimulation of FLS by IL-17 with TGF-β or TNF-α or IL-1β also increased the production of VEGF according to culture periods by 1.6-1.8, 1.1-1.9, 1.5-1.7 fold over the levels stimulated with TGF-β or TNF-α or IL-1β, respectively. This results indicated that IL-17 increased the effect of TGF-β, TNF-α, IL-1β on FLS, leading synergistic enhancement of VEGF production. Conclusion: IL-17 may be involved in the neovascularization in rheumatoid synovitis by enhancing the production of VEGF.

A novel role for bone-derived cells in ankylosing spondylitis: Focus on IL-23

Jo, Sungsin,Koo, Bon San,Lee, Bitnara,Kwon, Eunji,Lee, Young Lim,Chung, Heekyoung,Sung, Il-Hoon,Park, Ye-Soo,Kim, Tae-Hwan Elsevier 2017 Biochemical and biophysical research communication Vol. No.

<P><B>Abstract</B></P> <P>The main aim of this study are to explore the role of bone-derived cells (BdCs) in ankylosing spondylitis (AS) and determine the underlying molecular mechanisms of IL-23 production. Primary BdCs were isolated from diced bone of facet joints obtained during surgery from seven AS patients and seven disease control (Ct) patients. Osteoblastic activity of BdCs was assessed by measuring their alkaline phosphatase activity and by alizarin red staining. Osteoblast and endoplasmic reticulum (ER) stress-related genes were assessed by quantitative PCR, immunoblotting, immunofluorescence, and immunohistochemistry. In addition, expression of IL-23 in response to BIX (selective BIP inducer X)-induced ER stress was evaluated by qPCR and ELISA. Protein interaction and binding to IL-23 promoter were confirmed by Immunoprecipitation and Chromatin immunoprecipitation, respectively. Transcript levels of genes involved in osteoblast function, as well as of the ER stress marker were higher in the AS group than the Ct group, and elevated RUNX2, BiP and IL-23 expression were observed in the BdCs, serum, and bone biopsies from the AS group. BIX-induced ER stress stimulated osteoblastic activity and IL-23 secretion by upregulating RUNX2 expression. Furthermore, in AS BdCs, RUNX2 interacted with C/EBPβ to bind to IL-23 promoter and RUNX2 knockdown suppressed IL-23 secretion. These finding may provide a molecular mechanism involved in sustained ER stress in AS BdCs stimulates the activation of RUNX2 and C/EBPβ genes, leading to IL-23 production.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Bones and its-derived cells from patients with AS showed an increase in ER stress. </LI> <LI> IL-23 cytokine was significantly higher in AS patients than in healthy controls. </LI> <LI> Inducing ER stress in AS exhibited an increase of bone-related genes. </LI> <LI> Inducing ER stress in AS was accompanied with augmentation of IL-23 cytokine. </LI> <LI> ER stress-induced RUNX2 is involved in IL-23 secretion and bone-related genes. </LI> </UL> </P>

일반논문 : 향수의 민족학 -1930~1940년대 동경 간행 한글 시집 연구 2-

박태일 ( Tae Il Park ) 현대문학이론학회 2015 現代文學理論硏究 Vol.0 No.60

1930∼1940년대 동경에서 나온 한글 시집은 열두 권이다. 이 글은 그들 가운데서‘향수’의 정서를 집중적으로 담고 있는 시집 네 권을 대상으로 그 ‘향수’(nostalgia)의양상을 살피기 위한 목표로 쓰였다. 전한촌은 아나키스트 항왜 투쟁에 몸담았던 이다. 그의 『무궤열차』(1934)에 나타나는 향수는 집단적인 정위 장소 동경에 대한 이념 주체의 배타적인 장소감을 바탕으로, 위대한 새 ‘조선’의 도래를 향한 이념 대결의 공간이었다. 박일권의 『나그내』(1936)에서 향수는 이방인으로서 겪는 개별적인 경험 주체의 동경에 대한 비판적 장소감 속에서 그러한 현실을 벗어날 수 있는 유사 중심 장소, 위안과 탈주의 친밀 공간이었다. 김인걸의 『세월』(1936)과 김동일의 『흐름』(1940)에 담긴향수는 생존과 생활의 최소 조건마저 갖추지 힘들었던 개별적인 회고 주체가 과거 기억을 거듭 재구성하는 실존적 내면 공간이었다. 1930∼1940년대는 제국주의의 억압이극에 이르렀던 때다. 이 시기 동경 간행 한글 시집이 보여 준 이러한 세 가지 모습의 향수는 가난과 차별 속에서 다수 재왜동포가 겪었던 민족적 우울의 표현적 등가물이라는 적극적인 뜻을 지닌다. Twelve books of poetry were published in Tokyo from 1930‘s to 1940’s. Among them, 4 books that contain emotion of nostalgia are the main concern of this study. Jeon Han Chon took part in the anarchist anti-Japanese struggle. The emotion of nostalgia represented in his book of trackless train(1934) was eager for the advent of the great new Korea. Comfort and escape from the reality was the core of the emotion of nostalgia shown in Park Il Gwon‘s wayfarer(1936). In Kim In Girl’s times(1936) and Kim Dong Il’s stream(1940), nostalgia is the inner space that repeatedly reconstructs past memory. Supperssion by imperialism reached anextreme in 1930’S∼1940’s. Poverty and discrimination deepened more and more at that time. Three aspects of nostalgia listed above contain expression of ethnic depression that many of korean residents in japan would comfront. This is the active meanig of their emotion of nostalgia.