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>

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.

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>

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)

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.

Expression of TLR2, TLR4, and TLR9 in dermatomyositis and polymyositis

Kim, Geun-Tae,Cho, Mi-La,Park, Young-Eun,Yoo, Wan Hee,Kim, Jung-Hee,Oh, Hye-Jwa,Kim, Dae-Sung,Baek, Seung-Hoon,Lee, Sun-Hee,Lee, Jun-Hee,Kim, Ho-Youn,Kim, Sung-Il Springer-Verlag 2010 CLINICAL RHEUMATOLOGY Vol.29 No.3

<P>The aim of this study was to investigate the expressions of Toll-like receptor (TLR) 2, TLR4, TLR9, and their correlations with the expression of cytokines that are associated with activation of CD4<SUP>+</SUP> T cells and inflammation including interferon γ (IFNγ), interleukin 4 (IL4), interleukin 17 (IL17), and tumor necrosis factor α (TNFα) in muscle tissues of patients with dermatomyositis (DM) and polymyositis (PM). The expressions of TLR2, TLR4, TLR9, IFNγ, IL4, IL17, and TNFα were measured by real-time reverse transcription–polymerase chain reaction in muscle tissues from 14 patients with DM and PM (nine patients with DM, five patients with PM) and three controls. The expressions of TLR2, TLR4, and TLR9 were also localized with immunohistochemistry. The expression levels of TLR2, TLR4, TLR9, IFNγ, IL4, IL17, and TNFα were significantly high in patients with DM and PM compared with those in the controls, and the expression levels of TLR4 and TLR9 had significant positive correlations with the expressions of IFNγ, IL4, IL17, and TNFα. Immunohistochemistry showed that TLR2, TLR4, and TLR9 were expressed by infiltrating cells of perimysium in DM, whereas they were expressed by infiltrating cells of endomysium in PM. These results suggest that the involvement of TLR4 and TLR9 in immunopathogenesis of DM and PM might be connected with activation of CD4<SUP>+</SUP> T cells.</P>

15-deoxy- <b>Δ_12,14</b> -prostaglandin J <b>₂</b> Down-Regulates Activin-Induced Activin Receptor, Smad, and Cytokines Expression via Suppression of NF- <b><i><i><i>κ</i></i></i></b> B and MAPK Signaling in HepG2 Cells

Park, Seung-Won,Cho, Chunghee,Cho, Byung-Nam,Kim, Youngchul,Goo, Tae Won,Kim, Young Il Hindawi Publishing Corporation 2013 PPAR research Vol.2013 No.-

<P>15-Deoxy-Δ<SUP>12,14</SUP>-prostaglandin J<SUB>2</SUB> (15d-PGJ<SUB>2</SUB>) and activin are implicated in the control of apoptosis, cell proliferation, and inflammation in cells. We examined both the mechanism by which 15d-PGJ<SUB>2</SUB> regulates the transcription of activin-induced activin receptors (ActR) and Smads in HepG2 cells and the involvement of the nuclear factor-<I><I>κ</I></I>B (NF-<I><I>κ</I></I>B) and mitogen-activated protein kinase (MAPK) pathways in this regulation. Activin A (25 ng/mL) inhibited HepG2 cell proliferation, whereas 15d-PGJ<SUB>2</SUB> (2 <I><I>μ</I></I>M and 5 <I><I>μ</I></I>M) had no effect. Activin A and 15d-PGJ<SUB>2</SUB> showed different regulatory effects on ActR and Smad expression, NF-<I><I>κ</I></I>B p65 activity and MEK/ERK phosphorylation, whereas they both decreased IL-6 production and increased IL-8 production. When co-stimulated with 15d-PGJ<SUB>2</SUB> and activin, 15d-PGJ<SUB>2</SUB> inhibited the activin-induced increases in ActR and Smad expression, and decreased activin-induced IL-6 production. However, it increased activin-induced IL-8 production. In addition, 15d-PGJ<SUB>2</SUB> inhibited activin-induced NF-<I><I>κ</I></I>B p65 activity and activin-induced MEK/ERK phosphorylation. These results suggest that 15d-PGJ<SUB>2</SUB> suppresses activin-induced ActR and Smad expression, down-regulates IL-6 production, and up-regulates IL-8 production via suppression of NF-<I><I>κ</I></I>B and MAPK signaling pathway in HepG2 cells. Regulation of ActR and Smad transcript expression and cytokine production involves NF-<I><I>κ</I></I>B and the MAPK pathway via interaction with 15d-PGJ<SUB>2</SUB>/activin/Smad signaling.</P>

Skin-active Compounds in Syzygium Formosum Leaf Extract

( Jong-tae Park ),( Khanh Hong Thi Hoang ),( Nan-young Lee ),( Jong-il Park ),( Chang-kyu Lee ),( Jaehan Kim ) 한국피부장벽학회 2021 한국피부장벽학회지 Vol.23 No.2

Phenolic compounds and triterpenoids are secondary metabolites of the plant that have among the compounds the beneficial functionalities of anti-bacterial, anti-oxidative, anti-allergic, or anti-inflammatory. Syzygium formosum (SF) leaves have long been used in traditional medicine by the Vietnamese for the treatment of skin-related diseases such as rashes, atopic dermatitis, and psoriasis. To understand the underpinning pharmacological mechanism of skin relief functionality, the quantitative profile of phytochemicals in the leaf extract has been performed. Twenty phytochemical components including eight flavonoids, three phenolic acids, and nine triterpenoids were identified and quantitatively analyzed from the SF leaves. The dominant flavonoids of the SF leaves were found to be catechin, myricetin-3-O-rhamnoside, and quercetin-3-O-arabinoside. Gallic acid was the most abundant phenolic acid. Among triterpenoids, asiatic acid, corosolic acid, and betulinic acid were identified as major compounds ranging from 12.21 - 49.41, 14.12 - 22.50, and 19.23 - 26.94 mg/g dry leaf, respectively. The total triterpenoid content in the ethanolic extract of the SF batches ranged from 62.60 - 109.54 mg/g dry leaf which was 10 - 20 fold higher than that in Centella asiatica (CA) leaves. In ultraviolet B induced keratinocyte inflammation model, SF extract which was prepared industrial scale significantly reduced pro-inflammatory cytokines (IL-1β, IL-6, and IL-8) and COX-2, while commercial CA extract affected much less changes. Furthermore, SF extract induced significant increase of COL1α1 gene expression in human dermal fibroblast cells. Our results proved that Syzygium leaf extract with high content of biologically active compounds could be a superior bioactive ingredient in cosmetic and pharmaceutical industries.

재북 시기 백석의 번역 문학 연구

박태일(Park, Tae-il) 한국문학회 2020 韓國文學論叢 Vol.84 No.-

이 글은 재북 시기 백석의 번역 문학에 관한 실증적 점검을 통해 기존 정보의 잘못을 바로잡고 기워 온전한 문헌지를 마련하기 위해 이루어졌다. 논의는 세 가지다. 첫째, 이제까지 알려진 재북 시기 백석 번역 문학은 낱책 경우, 실물 확인이 어렵거나 백석 저술이 아닌 것이 7권이다. 낱글 경우는 중복 기록이나 글 이름, 잡지 이름, 낸 해달날 기록 잘못이 20군데에 이른다. 그들을 바루고 확정한 재북 시기 백석 번역 문학은 낱책 32종 32권과 낱글 43회 51편이다. 둘째, 현재 알려진 번역가 백석의 가명은 여섯이다. 그 가운데서 번역물의 무거운 비중이나 범위, 적확하고 창의적인 문체로 보아 박일파와 리세희는 백석과 동일인임을 획정한다. 나머지 넷은 번역 태도나 말씨, 활동 시기로 볼 때 백석과 엮기 어렵다. 셋째, 이 글에서 발굴한 백석의 번역 작품은 백석 기명과 박일파·리세희 기명으로 나온 낱책 13종 26권, 낱글 22회 26편이다. 그 안에는 북한 바깥 연변과 모스크바 출판본도 포함된다. 이들을 기존 확정분에 더하면 현재까지 갈무리한 재북 시기 백석 번역의 총량은 낱책 50종 58권, 낱글 66회 71편이다. 북한 초기 문학사에서 최대 번역가로서 백석의 걸음걸이가 뚜렷하다. 새로 마련한 문헌지를 바탕으로 백석의 번역 문학론으로 들어서는 문이 활짝 열리기 바란다. This study was conducted to correct empirical foundations for the translation literature Baek Seok had achieved while living in North Korea. The discussion is three. First, the translation literature of Baek Seok, which was previously known, has many problems. In the case of a book, it is difficult to confirm the actual publication, or it cannot be seen as a white-seat publication. In a magazine article, duplicate records, names and publication dates were sometimes misplaced. If they were corrected immediately, 32 books and 51 individual writings were translated by Baek Seok, who lived in North Korea. Second, the aliases of Baek Seok are known to be all six. Given the high weight, scope, and creative style of the translation, Park Il-pa and Ri Se-hui are the same people as Baek Seok. The remaining four are hardly white stones in translation attitudes, tone and period of activity. Third, there are 26 books and 26 individual writings that have been translated under the name of Baek Seok. And there are 26 books and 15 separate writings under the pseudonym of Park Il-pa and Lee Se-hee. In addition, there are 11 types of books published outside of North Korea. Therefore, the total amount of Baek Seok’s translation is confirmed by adding new excavations to the previously known ones. Soon there will be 57 books and 85 individual writings. It is clear that Baek Seok is North Korea s biggest translator. Hopefully, based on the newly created literature in this paper, a deep study of the translation literature of Baek Seok will be followed.