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>

IL-15에 의한 류마티스관절염 환자 활막 섬유모세포에서의 SDF-1 유도

박영은 ( Young Eun Park ),김성일 ( Sung Il Kim ),박성후 ( Seong Hu Park ),백승훈 ( Seung Hoon Baek ),오혜좌 ( Hye Jwa Oh ),허양미 ( Yang Mi Heo ),조미라 ( Mi La Cho ) 대한류마티스학회 2010 대한류마티스학회지 Vol.17 No.3

Objective: Interleukin-15 (IL-15) recruits and activates synovial T cells, and IL-15 plays an important role in amplifying and perpetuating inflammation in the pathogenesis of rheumatoid arthritis (RA). Stromal cell-derived factor-1 (SDF-1) is a potent chemoattractant for memory T cells in the inflamed RA synovium. This study investigated the effect of IL-15 on SDF-1 production in RA fibroblast-like synoviocytes (FLS). Methods: The expressions of IL-15 and SDF-1 were determined from the synovium of patients with RA and osteoarthritis (OA) by performing immunohistochemistry. The expressions of SDF-1 was measured from the RA FLS that were cultured with IL-15 and IL-17 by real-time RT-PCR and ELISA. The SDF-1 expression was also measured, via ELISA, from the RA FLS stimulated by IL-15 together with the inhibitors of such intracellular signal molecules as phosphatidylinositol 3-kinase (PI 3-kinase, LY294002), STAT3 (AG490), MAP Kinase (PD98059), NF-κB (parthenolide) and activator protein 1 (AP-1, curcumin). Results: IL-15 and SDF-1 were mainly expressed in the RA synovium compared to that of the OA synovium. IL-15 increased the SDF-1 expressions and it, and had an additive effect with IL-17 on the SDF-1 expressions in the cultured RA FLS. The IL-15 induced increase of the SDF-1 expression in the cultured RA FLS was blocked by the inhibitors of PI 3-kinase, NF-κB and AP-1. Conclusion: The SDF-1 expression was increased in the RA synovium and it was up-regulated by IL-15 in the RA FLS through the PI 3-kinase, NF-κB, and AP-1 pathways. These results imply that the IL-15 induced increase of the SDF-1 expressions may be involved in the immunopathogenesis of RA.

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>

Effect of high-mobility group box 1 on keratinocytes and fibroblasts

( Chan-yang Lee ),( In-hye Kang ),( Seung-min Oh ),( Jin-woo Lee ),( Young Il Kim ),( Ki-heon Jeong ) 대한피부과학회 2020 대한피부과학회 학술발표대회집 Vol.72 No.1

Background: High-mobility group protein B1 (HMGB1) is a physiological activator of immune responses. In patients with chronic inflammatory skin disorders including lupus, atopic dermatitis, and psoriasis, HMGB1 is increased in the cutaneous lesions. Objectives: This study was designed to investigate the effect of HMGB1 on keratinocytes and fibroblasts. Methods: In this study, keratinocytes and fibroblasts were exposed to narrow band ultraviolet B (NBUVB). Thereafter, release of HMGB1 were measured. Then keratinocytes and fibroblasts were treated with recombinant HMGB1 (rHMGB1) and production of inflammatory factors such as interleukin (IL)-1β, IL-6, IL-8, IL-18, chemokine (C-X-C motif) ligand (CXCL)1, CXCL2 and tumor necrosis factor (TNF)-α were examined. Results: 24h after NBUVB irradiation, the level of HMGB1 mRNA was increased in the fibroblasts but it was decreased in the keratinocytes. Extracellular level of HMGB1 was significantly increased in both keratinocytes and fibroblasts, 72h after NBUVB irradiation. After rHMGB1 treatment, proinflammatory molecule such as CXCL-1, IL-6, IL-8 and IL-18 were significantly increased in the keratinocytes and CXCL-1, IL-6 and IL-8 were significantly increased in the fibroblasts. Conclusion: HMGB1 can be released from keratinocytes and fibroblasts by external stress such as NBUVB irradiation and leads to activation of inflammatory signaling pathways in the keratinocytes and fibroblasts.

Scoparone from Artemisia capillaris Inhibits the Release of Inflammatory Mediators in RAW 264.7 Cells upon Stimulation Cells by Interferon-γ Plus LPS

Seon Il Jang,Young-Jun Kim,Woo-Yiel Lee,Kyung Chell Kwak,Seung Hwa Baek,Gyu Beum Kwak,Young-Gab Yun,Tae-Oh Kwon,Hun Taeg Chung,Kyu-Yun Chai 대한약학회 2005 Archives of Pharmacal Research Vol.28 No.2

Scoparone is a major component of the shoot of Artemisia capillaris (Compositae), which has been used for the treatment of hepatitis and biliary tract infection in oriental countries. In the present study we observed that, scorparone exhibited no cytotoxic effect in unstimulated macrophages, but reduced the release of nitric oxide (NO) and prostaglandin E2 (PGE2) upon stimulation by IFN-γ/LPS or LPS. The inhibitory effects were found to be in conjuction with the suppression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in IFN-γ/LPS stimulated RAW 264.7 cells. Moreover, scoparone also attenuated the production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in LPS-stimulated RAW264.7 cells. These results suggest that scoparone decreases the production of the inflammatory mediators such as NO and PGE2 in macrophages by inhibiting iNOS and COX-2 expression.

Scoparone from Artemisia capillaris Inhibits the Release of Inflammatory Mediators in RAW 264.7 Cells upon Stimulation Cells by Interferon-${\gamma}$ Plus LPS

Jang Seon Il,Kim Young-Jun,Lee Woo-Yiel,Kwak Kyung Chell,Baek Seung Hwa,Kwak Gyu Beum,Yun Young-Gab,Kwon Tae-Oh,Chung Hun Taeg,Chai Kyu-Yun The Pharmaceutical Society of Korea 2005 Archives of Pharmacal Research Vol.28 No.2

Scoparone is a major component of the shoot of Artemisia capillaris (Compositae), which has been used for the treatment of hepatitis and biliary tract infection in oriental countries. In the present study we observed that, scorparone exhibited no cytotoxic effect in unstimulated macrophages, but reduced the release of nitric oxide (NO) and prostaglandin $E_2\;(PGE_2)$ upon stimulation by IFN-${\gamma}$/LPS or LPS. The inhibitory effects were found to be in conjuction with the suppression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in IFN-${\gamma}$/LPS stimulated RAW 264.7 cells. Moreover, scoparone also attenuated the production of tumor necrosis factor (TNF)-${\alpha}$, interleukin (IL)-$1{\beta}$ and IL-6 in LPS-stimulated RAW264.7 cells. These results suggest that scoparone decreases the production of the inflammatory mediators such as NO and $PGE_2$ in macrophages by inhibiting iNOS and COX-2 expression.

A Novel Function of Interleukin-10 Promoting Self-Renewal of Hematopoietic Stem Cells

Kang, Young-Ju,Yang, Seung-Jip,Park, Gyeongsin,Cho, Bin,Min, Chang-Ki,Kim, Tae-Yoon,Lee, Joon-Sung,Oh, Il-Hoan Wiley (John WileySons) 2007 Stem Cells Vol.25 No.7

<P>Self-renewal of hematopoietic stem cells (HSCs) is key to their reconstituting ability, but the factors regulating the process remain poorly understood. Here, we show that Interleukin-10 (IL-10), a pleiotropic immune modulating cytokine, can also play a role in regulating HSC self-renewal. First, a quantitative decrease of primitive hematopoietic cell populations, but not more matured cells, was observed in the bone marrows of IL-10 disrupted mice as determined by long-term in vitro cultures or in vivo competitive repopulation assays. In contrast, normal HSCs from 5-fluorouracil treated marrows cultured on the IL-10 secreting stroma displayed an enhanced repopulating activity compared with cells grown on control stroma, with ninefold higher numbers of donor-derived HSCs in the reconstituted recipient marrows. Moreover, limiting dilution transplantation assay demonstrated that exogenous addition of IL-10 in the stroma-free cultures of purified Lin- Sca-1+ c-kit+ cells caused three- to fourfold higher frequencies of HSCs in the 5-day short-term culture without indirect inhibitory effect of IL-10 on tumor necrosis factor-alpha or interferon-gamma secretion. Interestingly, primitive hematopoietic cells, including Lin- Sca-1+ c-kit+ or side population cells, expressed the surface receptor for IL-10, and microenvironmental production of IL-10 was sharply increased in the osteoblasts lining the trabecular regions of the radiation-stressed marrow but not in the steady-state marrows. These results show that IL-10 may be a ligand that can stimulate self-renewal of HSCs to promote their regeneration in addition to being a ligand for immune regulation. Disclosure of potential conflicts of interest is found at the end of this article.</P>

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>

관절1호방이 Collagen Ⅱ로 유발된 관절염 억제에 관한 연구

한규진 ( Kyu Jin Han ),진광선 ( Kwang Seon Jin ),신혜란 ( Hye Ran Shin ),윤일지 ( Il Ji Yoon ),최승훈 ( Seung Hoon Choi ),오민석 ( Min Seok Oh ) 한방재활의학과학회 2005 한방재활의학과학회지 Vol.15 No.4

Objectives : The aim of this study was to know the immunity responses of Gwanjulbang-1(Quanjiefang-1)(hereinafter referred to GJB-1) to on Rheumatoid Arthritis in Collagen-induced Arthritis(CIA) Mice Methods : For this purpose, experiments were performed to measure the cytotoxicity against mLFC, hFLSs and the production of proinflammatory cytokines IL-1β, IL-6, TNF-α, IFN-γ in hFLSs and the production of pro-inflammatory cytokines IL-4, IL-10 and the value of CD3+(T), CD19+(B), CD3+/CD69+, CD4, γδ T cells, CD4+/CD25+ Results : 1. The cytotoxicity against mLFC, hFLSs were not measured. 2. The production of pro-inflammatory cytokines IFN-γ were reduced in hFLSs. 3. The production of pro-inflammatory cytokines IL-4, IL-10 were increased. 4. Statistically significant value of CD3+(T), CD19+(B), CD3+/CD69+, CD4, γδ T cells, CD4+/CD25+ compared with control group, wild type, MTX. Conclusions : Comparison of the results for this study showed that GJB-1 had immunomodulatory effects of suppressing or enhancing. So we expect that GJB-1 should be used as a effective drugs for not only rheumatoid arthritis but also another auto-immune disease. Therefore we have to survey continuously in looking for the effective substance and mechanism in the future.

심한 낙타혹(Hump)의 형성을 동반한 제 2 형 막증식성 사구체신염(Dense Deposit Disease) 1예

오희정,유민아,이영숙,김미연,김승정,강덕희,윤견일,최규복,성순희 이화여자대학교 의과대학 2004 EMJ (Ewha medical journal) Vol.27 No.1

Dense deposit disease (DDD), known as type Ⅱ MPGN, is an uncommon form of glomerulonephritis. It is an acquired primary glomerular disease, characterised by electron microscopic evidence of a continous, dense membrane deposition replacing the lamina densa. There is associated alternative pathway complement activation and a C3 nephritic factor maybe present. Patients with dense deposit disease tend to be young at clincal onset and more commonly have persistent nephrotic syndrome, gross hematuria, and acute nephritis episode and persistent depression of the serum complement level. The prognosis of dense deposit disease is worse than that of typeⅠMPGN. We experienced a patient with dense deposit disease that presenting persistent nephrotic syndrome, gross hematuria and having subepithelial hump. It is a first report of dense deposit disease having subepithelial hump in Korea, therefore we report this case with the review of relevant literatures.