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.

A Novel Small-Molecule Inhibitor Targeting the IL-6 Receptor β Subunit, Glycoprotein 130

Hong, Soon-Sun,Choi, Jung Ho,Lee, Sung Yoon,Park, Yeon-Hwa,Park, Kyung-Yeon,Lee, Joo Young,Kim, Juyoung,Gajulapati, Veeraswamy,Goo, Ja-Il,Singh, Sarbjit,Lee, Kyeong,Kim, Young-Kook,Im, So Hee,Ahn, Sun The American Association of Immunologists, Inc. 2015 JOURNAL OF IMMUNOLOGY Vol.195 No.1

<P>IL-6 is a major causative factor of inflammatory disease. Although IL-6 and its signaling pathways are promising targets, orally available small-molecule drugs specific for IL-6 have not been developed. To discover IL-6 antagonists, we screened our in-house chemical library and identified-LMT-28, a novel synthetic compound, as a candidate IL-6 blocker. The activity, mechanism of action, and direct molecular target of LMT-28 were investigated. A reporter gene assay showed that LMT-28 suppressed activation of STAT3 induced by IL-6, but not activation induced by leukemia inhibitory factor. In addition, LMT-28 downregulated IL-6-stimulated phosphorylation of STAT3, gp130, and JAK2 protein and substantially inhibited IL-6-dependent TF-1 cell proliferation. LMT-28 antagonized IL-6-induced TNF-alpha production in vivo. In pathologic models, oral administration of LMT-28 alleviated collagen-induced arthritis and acute pancreatitis in mice. Based on the observation of upstream IL-6 signal inhibition by LMT-28, we hypothesized IL-6, IL-6R alpha, or gp130 to be putative molecular targets. We subsequently demonstrated direct interaction of LMT-28 with gp130 and specific reduction of IL-6/IL-6R alpha complex binding to gp130 in the presence of LMT-28, which was measured by surface plasmon resonance analysis. Taken together, our data suggest that LMT-28 is a novel synthetic IL-6 inhibitor that functions through direct binding to gp130.</P>

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>

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.

폐포 대식세포 및 단핵구가 Interleukin-2 Enhanced Natural Killer 및 LAK Activity에 미치는 영향

조철호 ( Jo Cheol Ho ),김병일 ( Kim Byeong Il ),김세규 ( Kim Se Gyu ),천선희 ( Cheon Seon Hui ),김형중 ( Kim Hyeong Jung ),장준 ( Jang Jun ),안철민 ( An Cheol Min ),김성규 ( Kim Seong Gyu ),이원영 ( Lee Won Yeong ),윤정구 ( Yun J 대한내과학회 1992 대한내과학회지 Vol.42 No.5

저자들은 폐포 대식세포 및 말초혈액내의 단핵구가 NK 활성도 및 LAK 활성도에 미치는 영향을 보기위하여, 임파구에 여러 가지 농도(0, 100 : 1, 10 : 1, 1 : 1)의 폐포 대식세포와 단핵구를 넣어 IL-2 enhanced NK 활성도 및 LAK 활성도를 비교하여 다음과 같은 결과를 얻었다. 1) 여러 가지 농도의 단해구는 IL-2 enchanced NK 활성도 및 LAK 활성도에 영향을 미치지 않았다. 2) 동량의 페포대식세포(임파구 : 폐포 대식세포= 1 : 1)는 IL-2 enhanced NK 활성도를 의의있게 억제하였으나(p<0.05), 소량의 폐포대식세포(임파구 : 폐포 대식세포-10 : 1과 100 : 1)는 IL-2 enhanced NK 활성도를 억제하지 못하였다. 3) 임팍와 폐포 대식세포의 비율이 1 : 1과 10 : 1에서는 LAK 활성도를 의의있게 억제하였으나, 소량의 폐포대식세포(임파구 : 폐포 대식세포=100 : 1)는 LAK 활성도를 억제하지 못하였다(p<0.05). 이상의 결과로 IL-2 enhanced NK 활성도 및 LAK 활성도는 폐포 대식세포의 양에 비례하여 억제되었으나, 말초혈액내의 단핵구에 의해서는 영향받지 않는 것을 알 수 있었다. Alveolar macrophages (AM) are thought to function as primary effector cells against tumors growing in the lung. Systemic administration of lymphokine activated killer (LAK) cells and IL-2 resulted in partial antitumor response in patients with advanced cancer. LAK activity is influenced by various factors. We studied the effects of AM and blood monocytes from healthy donors on IL-2 enhanced NK activity against K-562 cells and LAK activity against Raji cells utilizing a 4h ^(51)Cr release assay. The following results were obtained: 1) The addition of different doses of human blood monocytes showed no suppression or enhancement of IL-2 enhanced NK and LAK activity. 2) The addition of high dose of AM (Lymphocyte: AM=1:1) significantly suppressed IL-2 enhanced NK activity. Smaller doses of AM (Lymphocyte: AM= 10:1and 100:1) did not suppress IL-2 enhanced NK activity. 3) The addition of high dose of AM (Lymphocyte: AM = 1:1 and 10:1) significantly suppressed LAK activity. The smallest dose of AM (Lymphocyte: AM= 100:1) did not suppress LAK activity. In conclusion, IL-2 enhanced NK and LAK activity were dose-dependently suppressed by human alveolar macrophages. However IL-2 enhanced NK and LAK activity were not suppressed by blood monocytes.

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>

Glucocorticoid-induced tumor necrosis factor receptor–related protein co-stimulation facilitates tumor regression by inducing IL-9–producing helper T cells

Kim, Il-Kyu,Kim, Byung-Seok,Koh, Choong-Hyun,Seok, Jae-Won,Park, Jun-Seok,Shin, Kwang-Soo,Bae, Eun-Ah,Lee, Ga-Eun,Jeon, Hyewon,Cho, Jaebeom,Jung, Yujin,Han, Daehee,Kwon, Byoung S,Lee, Ho-Young,Chung, Nature Publishing Group, a division of Macmillan P 2015 Nature medicine Vol.21 No.9

<P>T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) elicits antitumor activity in various tumor models; however, the underlying mechanism of action remains unclear. Here we demonstrate a crucial role for interleukin (IL)-9 in antitumor immunity generated by the GITR agonistic antibody DTA-1. IL-4 receptor knockout (Il4ra(-/-)) mice, which have reduced expression of IL-9, were resistant to tumor growth inhibition by DTA-1. Notably, neutralization of IL-9 considerably impaired tumor rejection induced by DTA-1. In particular, DTA-1-induced IL-9 promoted tumor-specific cytotoxic T lymphocyte (CTL) responses by enhancing the function of dendritic cells in vivo. Furthermore, GITR signaling enhanced the differentiation of IL-9-producing CD4(+) T-helper (T(H)9) cells in a TNFR-associated factor 6 (TRAF6)- and NF-kappa B-dependent manner and inhibited the generation of induced regulatory T cells in vitro. Our findings demonstrate that GITR co-stimulation mediates antitumor immunity by promoting T(H)9 cell differentiation and enhancing CTL responses and thus provide a mechanism of action for GITR agonist-mediated cancer immunotherapies.</P>

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.

Decreased Pattern-Recognition Receptor-Mediated Cytokine mRNA Expression in Obese Children With Otitis Media With Effusion

Kim, Youn Jung,Cha, Sung Ho,Lee, Ho Yun,Lee, Sun Kyu,Chung, Hee Yong,Yeo, Joon Hyung,Kim, Young Il,Yeo, Seung Geun Korean Society of Otorhinolaryngology-Head and Nec 2014 Clinical and Experimental Otorhinolaryngology Vol.7 No.1

<P><B>Objectives</B></P><P>To assess innate and humoral immune responses in middle ear effusion of obese pediatric patients with otitis media with effusion (OME).</P><P><B>Methods</B></P><P>We evaluated 219 children with OME, of whom 21 were obese and 198 were non-obese. We compared the expression in middle ear effusion of mRNAs encoding toll-like receptors (TLR) 2, 4, 5, and 9; nucleotide-binding oligomerization domains (NOD) 1 and 2; retinoic acid-inducible gene (RIG)-I; interleukins (IL)-6, -10, and -12; interferon (IFN)-γ; and tumor necrosis factor (TNF)-α mRNAs. We also compared the expression of immunoglobulins IgG, IgA, and IgM and the bacterial detection rate in the two groups.</P><P><B>Results</B></P><P>TLR2-mediated expression of IL-6 mRNA, TLR4-mediated expression of IL-6 and IL-10 mRNA, TLR5-mediated expression of IL-6, IL-10, and TNF-α mRNA, TLR9-mediated expression of IL-6 mRNA, and NOD2-mediated expression of IL-6, IL-12, and TNF-α mRNA were significantly lower in obese than in non-obese children (<I>P</I><0.05). However, concentrations of IgG, IgA, and IgM in middle ear effusion were lower in obese than in non-obese children, but none of these differences was significant (<I>P</I>>0.05).</P><P><B>Conclusion</B></P><P>Mean body mass index was higher and pattern-recognition receptor-mediated cytokine mRNA expression was lower in obese than in non-obese children with OME.</P>

Chronological changes in inflammatory cytokines immunoreactivities in the mouse hippocampus after systemic administration of high dosage of tetanus toxin.

Yan, Bing Chun,Park, Joon Ha,Kim, In Hye,Shin, Bich Na,Ahn, Ji Hyeon,Yoo, Ki-Yeon,Lee, Deuk-Sik,Kim, Myong Jo,Kang, Il-Jun,Won, Moo-Ho Springer-Verlag 2012 Experimental brain research Vol.223 No.2

<P>Tetanus toxin (TeT) is an exotoxin and has a capacity for neuronal binding and internalization. In the present study, we compared changes in the immunoreactivities and protein levels of interleukin (IL-) 2 as a pro-inflammatory cytokine and IL-4 as an anti-inflammatory cytokine in the hippocampus proper (HP) and dentate gyrus (DG) after systemic treatment of 10 or 100?ng/kg TeT into mice. In this study, we could not find any neuronal damage or loss in any subregions of the hippocampus after TeT treatment. In the control groups, strong IL-2 immunoreactivity was shown in the stratum pyramidal (SP) of the HP and in the granule cell layer (GCL) of the DG. At 6?h post-treatment, IL-2 immunoreactivity was hardly detected in the SP and GCL; however, strong IL-2 immunoreactivity was shown in the stratum oriens of the HP in both the groups. Thereafter, intermediate IL-2 immunoreactivity was shown in the SP and GCL. On the other hand, intermediate IL-4 immunoreactivity was detected in the SP and GCL of the control groups. At 6?h post-treatment, IL-4 immunoreactivity in the SP and GCL was apparently increased. Thereafter, IL-4 immunoreactivity was lower than that at 6?h post-treatment. In brief, IL-2 and 4 immunoreactivities were easily detected in SP and GCL in the controls and dramatically decreased and increased at 6?h post-treatment, respectively.</P>