Impact of interleukin-21 in the pathogenesis of primary Sjogren's syndrome: increased serum levels of interleukin-21 and its expression in the labial salivary glands

Kang, Kwi Young,Kim, Hyun-Ok,Kwok, Seung-Ki,Ju, Ji Hyeon,Park, Kyung-Su,Sun, Dong-Il,Jhun, Joo Yeon,Oh, Hye Jwa,Park, Sung-Hwan,Kim, Ho-Youn BioMed Central 2011 ARTHRITIS RESEARCH AND THERAPY Vol.13 No.5

<P><B>Introduction</B></P><P>Interleukin (IL)-21 is a cytokine that controls the functional activity of effector T helper cells and the differentiation of Th17 cells, and promotes B-cell differentiation. To test whether IL-21 participates in the pathogenesis of primary Sjögren's syndrome (SS), serum IL-21 level was measured and IL-21 expression in the labial salivary glands (LSG) was examined.</P><P><B>Methods</B></P><P>Serum IL-21 levels in 40 primary SS, 40 rheumatoid arthritis (RA), and 38 systemic lupus erythematosus (SLE) patients and 20 healthy controls were measured. Serum IL-21 levels of SS patients were assessed for correlations with laboratory data, including anti-nuclear antibody, anti-Ro/La antibodies, globulin, immunoglobulin (Ig) class, and IgG subclass. LSGs from 16 primary SS and 4 controls with sicca symptoms were evaluated for IL-21 and IL-21 receptor (IL-21R) expression by immunohistochemistry. Confocal microscopy was performed to further characterize the IL-21 positive cells.</P><P><B>Results</B></P><P>Primary SS patients had significantly higher serum IL-21 levels than controls, and these increments correlated positively with levels of IgG, IgG1. Serum IgG1 levels correlated with anti-Ro antibody titers. Immunohistochemical analyses showed that lymphocytic foci and the periductal area of the LSGs from SS patients expressed high levels of IL-21 and lower levels of IL-21R, whereas the control LSGs showed minimal expression of both antigens. The more the lymphocyte infiltrated, IL-21expression in LSGs showed a tendency to increase. Confocal microscopic analyses revealed that IL-21 expressing infiltrating lymphocytes in the LSGs of SS patients also expressed CXCR5.</P><P><B>Conclusions</B></P><P>Primary SS is associated with high serum IL-21 levels that correlate positively with serum IgG, especially IgG1, levels. The expression of IL-21 is increased as more lymphocytes infiltrated in LSGs. These observations suggest that IL-21 may play an important role in primary SS pathogenesis.</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.

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)

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.

The Effect of Human Placental Extract on Rheumatoid Arthritis in an Animal Model

Jeong Dong Park,신희석,Sang-Il Lee,A Ram Kim,Jong Moon Park,Sang-Yeop Shin,Jun Hwa Shin,Seung Won Moon,Hyun Park,오민균 대한재활의학회 2012 Annals of Rehabilitation Medicine Vol.36 No.2

Objective To assess the effi cacy of human placental extract (HPE) in an animal model of rheumatoid arthritis (RA). Method We used (i) KRN C57BL/6 TCR transgenic x NOD mice (KBx/N) serum transfer arthritis and (ii) collageninduced arthritis (CIA) mice to evaluate the effi cacy of HPE (1 ul or 100 ul, intra-peritoneal, three times per week)on RA. Incidence, severity of arthritis, and hind-paw thickness were quantifi ed. Joint destruction was analyzed using modifi ed mammographic imaging. Histopathological analysis for infl ammation, cartilage, and osteoclasts was performed using Hematoxylin-eosin (H-E), safranin-O, and tartrate-resistant acidic phosphatase (TRAP). ELISAs were used for detection of various cytokines in serum and joint tissue. Results Th ere were no signifi cant diff erences in incidence of arthritis, clinical scores of arthritis, and hind-paw thickness between HPE-treated and vehicle-treated groups for up to 2 weeks in the KBx/N serum transfer arthritis model. Histopathological analysis also showed no diff erences 2 weeks after treatment. Levels of TNF-α, IL-1β, IL-6, IL-10, and RANKL in serum and joint tissues were similar in all groups. Furthermore, there were no diff erences in clinical, radiological, and histological parameters between HPE-treated and vehicle-treated group for 3 weeks in the CIA model. Conclusion Systemic treatment with HPE has no benefi cial eff ects on arthritis in animal models of RA. Th erefore,indiscreet use of HPE in RA should be forbidden.

대전시 도시숲의 식생 및 토양특성에 관한 연구

김동일 ( Dong Il Kim ),박관수 ( Gwan Soo Park ),김길남 ( Gil Nam Kim ),김현숙 ( Hyoun Sook Kim ),이항구 ( Hang Goo Lee ),박범환 ( Beom Hwan Park ),이상진 ( Sang Jin Lee ),강길남 ( Kil Nam Kang ) 한국환경복원기술학회(구 한국환경복원녹화기술학회) 2011 한국환경복원기술학회지 Vol.14 No.2

This study was conducted to suggest appropriate methods for management of urban forest after investigating the present condition and problems of urban forests by analyzing vegetation and soil properties in urban forests in the Daejeon. On the basis of our research, Pinus rigida dominate Gyejoksan and Bomunsan. Pinus densiflora dominate Wolpyeong park and Quercus acutissima dominate Namsun park. On the basis of our result of analysis of soil chemical properties, all investigated areas have low pHs, available phosphates and exchangeable cations. They indicate that the soil of those areas have been acidifying progressively. Soil hardness measurements were conducted to know the conditions of trampled soils and the results of them show that soil hardness in Namsun park was higher than the others. This indicates that human interference affect the health of the urban forest.

Interleukin-6가 사람 골수기질세포의 Alkaline Phosphatase, Osteontin, Decorin 및 a1(1)-Collagen mRNA 발현에 미치는 영향

김동관,김철희,김기수,손광현,박승일 대한내분비학회 1996 Endocrinology and metabolism Vol.11 No.2

Background: Inter1eukin-6(IL-6) is known to be produced by osteoblastic cells and to have impartant role in regulation of bone remodelling, Most previous studies indicated that IL-6 bas a major role in stimulating osteoclastic resorption by increasing recruitment and proliferation of preosteoclasts. But its autocrine effect on osteoblastic cells has not been well established yet. Therefore, we studied the effects of IL-6 on messenger RNA (mRNA) expression of proteins that are characteristic of osteoblastic cells in human bone marrow stromal (osteoprogenitor) cells (hRMSC). Methods: The expression of mRNAs for alkaline phosphatase, al(1)-collagen, osteopontin and decorin were studied by northern blot analysis after 3 7 days' treatrnent with IL-6 in the concenttation range of 101,000 U/ml. Results: The mRNA levels for any of the osteoblastic proteins studied did not change significantly by IL-6 treatment up to the concentration of 1,000 U/ml. Conclusion: These results suggest that IL-6 does not have a significant role in differentiatian or activities of human bone rnarrow stromal (osteoprogenitor) cells (J Kor Soc Endocrinol ll:156 162, 1996).

몇 가지 항균제가 시험관내에서 내독소와 TNF-α, IL-6 분비에 미치는 영향

최정현,문건웅,김명훈,이동건,박윤희,김상일,김태연,유진홍,김양리,신완식,강문원 대한화학요법학회 1997 대한화학요법학회지 Vol.15 No.2

To evaluate antibiotic-induced endotoxin release(AIER) and its correlation with some cytokines, we measured endotoxin level and tumor necrosis factor alpha(TNF-α) and interleukin6(IL-6) production in mononuclear cells in vitro after exposure of Pseudomonas aeruginosa to antibiotics belonging to different class with two extreme concentrations. The tested concetration of antibiotics were set up according to peak serum level. The low concetration of ceftazidirne and low concentration of imiperiem increased AIER, but high concentration of ceftazideme, high concentration of ciprofloxacin, high concentration of cefoperazone/sulbactam, high concentration of amikacin, and high concentration of meropenem reduced AIER.Interestingly, combined treatment of these antibiotics markedly reduced AIER, But the major cyotkines, TNF-α and IL-6 were not affect by type and concettration of antibiotics, combined treatment of antibiotics, and level of endotoxin released by antiboitics. In this study, we observed AIER was different according to type of antibiotics, concentration of antibiotics, and combination of antibiotics, But AIER had poor correlation with TNF-α and IL-6 in Pseudomonas aeruginosa. It suggests that cytokine release is not solely dependent to endotoxin, but more complex cascade is needed. More invesfigations, such as endotoxin induced cytokine mRNA expression, relationship with penicillin-binding proteins and endotoxin-neutralizing effect of antibiotic itself, must be performed.

류마티스 활막염에 있어 염증매개물질에 의한 Transforming Growth Factor-β-inducible Gene-h3 (βig-h3) 생산 조절 기전

강영모 ( Young Mo Kang ),김성일 ( Sung Il Kim ),김정섭 ( Jeong Seup Kim ),유동완 ( Dong Wan You ),사금희 ( Kheum Hee Sa ),박은주 ( Eun Ju Park ),김성욱 ( Sung Uk Kim ),서재석 ( Jae Seok Seo ),한승우 ( Seung Woo Han ),남언정 ( Eon 대한류마티스학회 2005 대한류마티스학회지 Vol.12 No.2

Objective: To investigate the expression pattern of transforming growth factor-β-inducible gene-h3 (βig-h3) within rheumatoid synovial tissue and the regulation of βig-h3 synthesis in fibroblast-like synoviocyte (FLS). Methods: Synovial tissues obtained from patients with rheumatoid arthritis and osteoarthritis were obtained during joint replacement surgery. βig-h3 expression was evaluated with immunohistochemical stain. FLS was isolated from synovial tissues and stimulated with cytokines including TGF-β, TNF-α, IL-1β, IFN-γ, IL-6, IL-4, and IL-10. βig-h3 synthesis was measured using semiquantitative RT-PCR, ELISA, immunofluorescence stain, and flow cytometry. Results: Expression of βig-h3 was diffuse and abundant in both lining and sublining layers of rheumatoid synovium, which was more prominent than those of osteoarthritis. Production of βig-h3 in FLS was regulated by TGF-β1 in a dose-dependent manner and was highest at 5 ng/mL of TGF-β1. TNF-α and IL-1β upregulated the production of βig-h3 from FLS synergistically with TGF-β1 but other cytokines such as IL-4, IL-6, IL-10 did not affect. βig-h3 synthesis was efficiently inhibited by dexamethasone at higher dose (100 nM) but not by cyclosporine-A. Conclusion: Production of βig-h3, which is highly upregulated in rheumatoid synovitis, is differentially regulated by inflammatory cytokines.

Triptolide suppresses interleukin-1beta-induced human beta-defensin-2 mRNA expression through inhibition of transcriptional activation of NF-kappaB in A549 cells.

Jang, Byeong-Churl,Lim, Ki-Jo,Choi, In-Hak,Suh, Min-Ho,Park, Jong-Gu,Mun, Kyo-Chul,Bae, Jae-Hoon,Shin, Dong-Hoon,Suh, Seong-Il D.A. Spandidos 2007 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE Vol.19 No.5

<P>The immunosuppressive effect of triptolide has been associated with suppression of T-cell activation. However, the immunosuppressive effects of triptolide on innate immunity in the epithelial barrier remain to be elucidated. Human beta-defensin (HBD)-2 is an inducible antimicrobial peptide and plays an important role in the innate immunity. We have previously demonstrated that IL-1beta induced HBD-2 mRNA expression in A549 cells through activation of nuclear factor-kappaB (NF-kappaB) transcriptional factor as well as p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), or phosphatidylinositol-3-kinase (PI3K). In this study, we investigated effects of triptolide on IL-1beta-induced HBD-2 mRNA expression in A549 cells. Triptolide inhibited IL-1beta-induced HBD-2 mRNA expression in a dose-dependent manner. Addition of triptolide did not suppress activation of p38 MAPK, JNK, or PI3K in response to IL-1beta. Triptolide inhibited IL-1beta-induced MAPK phosphatase-1 expression at the transcriptional level and resulted in sustained phosphorylation of JNK or p38 MAPK, explaining the little effect of triptolide on IL-1beta-induced phosphorylation of these kinases. Although triptolide partially suppressed IL-1beta-mediated degradation of IkappaB-alpha and nuclear translocation of p65 NF-kappaB, triptolide potently inhibited NF-kappaB promoter-driven luciferase activity in A549 cells. These results collectively suggest that the inhibitory effect of triptolide on IL-1beta-induced HBD-2 mRNA expression in A549 cells seems to be at least in part mediated through nuclear inhibition of NF-kappaB transcriptional activity, but not inhibition of p38 MAPK, JNK, or PI3K. This inhibition may explain the ability of triptolide to diminish innate immune response.</P>