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>

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>

Cynara scolymus L. Inhibits the LPS-induced Inflammatory Reaction via Suppression of NF-κB Activity in RAW 264.7 Cells

Kyung-Jun Boo(Kyung-Jun Boo),Kiman Lee(Kiman Lee),Il-Ho Park(Il-Ho Park),Tae Jin Kang(Tae Jin Kang) 대한약학회 2023 약학회지 Vol.67 No.1

Cynara scolymus L. (artichoke) has been traditionally used in the treatment of digestive-related disease, severe hyperlipidemia and liver disease. Recently, anti-inflammatory effect of artichoke has been reported by several studies, but its mechanisms are still unclear. In this study, the anti-inflammatory mechanism of artichoke was studied using an in vitro acute inflammation model. The effect of artichoke on the expression of pro-inflammatory cytokines, such as interleukin- 1beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α) in murine macrophage cell line, RAW264.7, was examined by using ELISA and RT-PCR. As a result, artichoke inhibited the expression of IL-1β, IL-6 and TNF-α in macrophages activated by lipopolysaccharide (LPS) at a dose dependent manner. The expression of inflammatory mediators such as NO and PGE2 was next investigated in RAW264.7 cells stimulated with LPS. Artichoke also inhibited the production of NO and PGE2 in the cells at a dose dependent manner. Artichoke suppressed the mRNA expression of iNOS and COX-2 in macrophages by LPS. The effect of artichoke on the activation of NF-κB was examined and LPS-induced NF-κB activation was decreased by treatment of artichoke, suggesting that artichoke has anti-inflammatory effect by inhibiting NF- κB activation.

1995~96년도 전국 모성사망원인 조사

박정한,서경,박문일,박중신,한영자,도세록 한국모자보건학회 1999 한국모자보건학회지 Vol.3 No.2

DBA/1JCrj Mouse에 있어서 콜라젠유도관절염에 관한 면역학적 고찰

박승규,이지연,정일엽,최용경,최인성,김효준 大韓免疫學會 1996 大韓免疫學會誌 Vol.18 No.3

There is growing evidence that a variety of cytokines are secreted by cells at the inflammation sites of rheumatoid arthritis (RA) and that CDS+ B cell, a minor subtype of B cell population producing natural autoantibodies, is implicated in pathogenesis of RA. In this study, we evaluated the both cytokne levels and change of CDS+ B cell population in the peripheral blood from DBA/lJCrj mice(H-2`) which are collagen-induced arthritis(CIA) susceptible strain. Surprisingly, the healthy DBA/1JCrj and MRL/Ipr/Ipr(H-2'`) mice which were autoimmune susceptible strains tested in this experiment, showed lower IL-4, IL-6 and IL-10 levels in serum by 60% than heal-thy normal mouse strains such as Balb/c(H-2d), C57BL/6(H-2') and outbred ICR mice. MRL/lpr/ 1pr mice in which onset of spontaneous autoimmune disease is dependent upon age were similar to healthy DBA/1JCrj mice in levels of the cytokines in the serum when they are young. After the CIA(for DBA/1JCrj) or the spontaneous autoimmune disease(for MRL/lpr/Ipr) had been developed in the susceptible mouse strains, the levels of IL-6 and IL-4 in the serum were increased to 1.8- and 13-fold, respectively, as compaired with those from control groups while level of IL-10 remained relatively constant. The elevated levels of IL-4- and IL-6, however, in the serum from mice with disease status were still below those of the healthy normal mouse strains. On the other hand, CDS+ B cell population in the peripheral blood, which were reported to be increased with the development of RA for human, was rather significantly decreased for the CIA-induced DBA/lJCrj mice as evidenced by FACS analysis. It could be due to the differences in the pathogenic mechanism between CIA and RA. Taken together, our results. suggest that the levels of both these cytokines and CDS+ B cells may be utilized as important diagnostic markers for arthritides.

Sequential evolution of IL-17 responses in the early period of allograft rejection

Sang Il Min,하종원,박정규,Jae Kyung Won,Yang Jin Park,민승기,김상준 생화학분자생물학회 2009 Experimental and molecular medicine Vol.41 No.10

In addition to CD4+CD25+Foxp3+ regulatory T (Treg) cells which protect against autoimmune tissue injury, IL-17-producing CD4+ T (Th17) cells have been recently described and shown to play a crucial role in autoimmune injury. It appears that there is a reciprocal developmental pathway between Th17 and Treg cells. Although IL-17 is known to be associated with allograft rejection, the cellular source of IL-17 and the nature of Th17 in the context of allograft rejection remain unknown. In the current study, the dynamics of Treg and IL-17-producing cells after syngeneic and allogeneic transplantation were examined using a wild-type murine cardiac transplantation model. Ly6G+ cells were found to produce IL-17 during the early postoperative period and CD8+ as well as CD4+ T cells were also found to produce IL-17 during alloimmune response. Graft-infiltrating Ly6G+, CD4+, and even CD8+ cells were found to express IL-17 highly compared to those in spleen. Although the frequencies of Th17 and Treg were found to gradually increase in both syngeneic and allogeneic recipients, Th17/Treg ratios were significantly higher in recipients with allograft rejection than in syngeneic recipients. In conclusion, IL-17 is produced by neutrophils during the early postoperative period and subsequently by Th17 and CD8+ T cells during allograft rejection. Th17/Treg imbalance is associated with the development of allograft rejection. This study would provide basic information on Th17 biology for future investigation in the field of transplantation.

Association of DOCK8, IL17RA, and KLK12 Polymorphisms with Atopic Dermatitis in Koreans

( Won Il Heo ),( Kui Young Park ),( Mi-kyung Lee ),( Yu Jeong Bae ),( Nam Ju Moon ),( Seong Jun Seo ) 대한피부과학회 2020 Annals of Dermatology Vol.32 No.3

Background: Early-onset and severe atopic dermatitis (AD) in patients increase the probability of the development of allergic rhinitis or asthma. Treatment and prevention strategies in infants and young children with AD are targeted toward treating the symptoms, restoring skin barrier functions, and reducing the absorption of environmental allergens in an attempt to attenuate or block the onset of asthma and food allergy. Objective: Given that the initiating events in AD remain poorly understood, identifying those at risk and implementing strategies to prevent AD is necessary. Methods: Whole-exome sequencing (WES) was performed in a 43 control group and a disease group with 20 AD patients without atopic march (AM) and 20 with AM. Sanger sequencing was carried out to validate found variants in cohorts. Results: DOCK8, IL17RA, and KLK12 single-nucleotide polymorphisms were identified by WES as missense mutations: c.1289C>A, p.P97T (rs529208); c.1685C>A, p.P562G (rs12484684); and c.457+27>C, rs3745540, respectively. A case-control study show that total immunoglobulin E (IgE) level was significantly increased in the AA genotype of DOCK8 compared to the CA genotype in allergic patients. The rs12484684 of IL17RA increased risk of adult-onset AD (odds ratio: 1.63) compared to the control for (A) allele frequency. AD and AM Patients with the IL17RA CA genotype also had elevated IgE levels. rs3745540 of KLK12 was associated with AD in dominant model (odds ratio: 2.86). Conclusion: DOCK8 (rs529208), IL17RA (rs12484684), and KLK12 (rs3745540), were identified using a new WES filtering method. the result suggests that polymorphism of DOCK8 and IL17RA might be related to increase the total IgE level. (Ann Dermatol 32(3) 197∼205, 2020)

P179 : Activin suppresses LPS-induced Toll-like receptors, cytokines, and nitric oxide expression by inhibiting activation of NF-κB and MAPK pathways in normal human melanocytes

( Young Il Kim ),( Seung Won Park ),( Jeong Hwee Choi ),( Myong Il Bae ),( Min Kyung Shin ),( Mu Hyoung Lee ) 대한피부과학회 2013 대한피부과학회 학술발표대회집 Vol.65 No.2

Background: Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-β (TGF-β) superfamily. Objectives: To know the mechanism how activin regulates transcription of lipopolysaccharide (LPS)-induced Toll-like receptors (TLRs), cytokines, and inducible nitric oxide synthase (iNOS) in human melanocytes, and the involvement of nuclear transcription factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Methods: Normal human melanocytes were pretreated with activin A before exposure to LPS. Total RNAs were purified and real-time PCR was performed. Also we conducted immunoblot analysis to know the expression levels of proteins. Results: LPS increased mRNA expressions of TLRs (1-10) and cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α), and enhanced mRNA and protein expression of iNOS. Activin inhibited LPS-induced mRNA expressions of TLRs and cytokines, and decreased mRNA and protein expression of LPS-induced iNOS. Also activin suppressed NF-κB p65 activation and blocked IκBα degradation in LPS-stimulated melanocytes, and reduced LPS-induced p38 MAPK and MEK/ERK activations. Conclusion: Activin inhibited expression of genes of TLRs, cytokines, and iNOS in LPS-activated normal human melanocytes. Moreover, anti-inflammatory effect of activin was mediated through suppressing activation of NF-κB and MAPKs signaling pathways in LPS-activated normal human melanocytes, resulting in reduced expression of TLRs, cytokines, and nitric oxide.

Interleukin-4와 히스타민이 알레르기성 비염과 비 알레르기성 비염에서 비점막 섬유아세포에 미치는 영향

김성완,조중생,박재경,차창일,김광일 대한이비인후과학회 1999 대한이비인후과학회지 두경부외과학 Vol.42 No.3

당화된 레스베라트롤의 대식세포 RAW 264.7 세포의 생존능력과 레스베라트롤의 면역제어 활성을 증가

라메스프라시드판데이 ( Ramesh Prasad Pandey ),이지선 ( Jisun Lee ),박용일 ( Yong Il Park ),송재경 ( Jae Kyung Sohng ) 한국미생물생명공학회(구 한국산업미생물학회) 2017 한국미생물·생명공학회지 Vol.45 No.1

레스베라트롤의 면역제어 성질과 대식세포의 생존능력과 관련하여 당화된 레스베라트롤의 효과를 확인하기 위해 대식세포 RAW264.7에서 연구하였다. 인비토로에서 대식세포에서 총 4개의 레스베라트롤 및 당화된 유도체 (E)-resveratrol, (E)-resveratrol 3-O-β-D-glucoside (R-3-G), 및 (E)-resveratrol 4`-O-β-D-glucoside (R-4`-G)를 여러 가지 농도로 처리한 후 일산화질소 (NO)와 인터루킨 6 (IL-6) 발현을 연구하였다. 앞서 언급한 물질로 처리한 후 인비토로에서 RAW 264.7 세포의 생존능력도 연구하였다. 대식세포 생존능력 평가분석 결과를 보면, 두 개의 레스베라트롤 모노글루코사이드인 R-3-G와 R-4`-G은 (E)-resveratrol와 비교하여 A549 and HepG2 세포에서 50-80% 감소된 독성을 보여준다. 당이 없는 레스베라트롤과 비교하면, 당화된 레스베라트 유도체는 긍정적으로 전사적으로 IL-6 및 iNOS 발현이 높아지는 방향으로 NO 및 대식세포에서 IL-6의 생산이 조절된다. 레스베라트롤의 당의 역할은 RAW 264.7 세포의 생존능력과 레스베라트롤의 면역제어 활성을 증가시켜 주는 것으로 보여주고 있다. DEffects of resveratrol glucosylation on the immunomodulation properties of resveratrol and on the viabil-ity of macrophage cells have been studied by using murine macrophage RAW 264.7 cells. Nitric oxide (NO) and interleukin 6 (IL-6) expression in macrophages in vitro were studied after treatment with different concentrations of (E)-resveratrol, (E)-resveratrol 3-O-β-D-glucoside (R-3-G), or (E)-resveratrol 4`-O-β-D-gluco-side (R-4`-G). In vitro viability of RAW 264.7 cells after treatment with the aforementioned three compounds was also studied. As demonstrated by macrophage cell viability assays, two different resveratrol monoglu-cosides, R-3-G and R-4`-G, exhibited 50-80% reduced cytotoxicity in comparison to (E)-resveratrol in A549 and HepG2 cells. Compared to the resveratrol aglycon, both glucosylated resveratrol derivatives positively modulated NO and IL-6 production in macrophages positively via transcriptionally up-regulating IL-6 and iNOS expression. Conjugation of a glucose moiety on resveratrol was found to enhance the immunomod-ulating activity of resveratrol and the viability of RAW 264.7 cells.