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)

Blockade of indoleamine 2,3-dioxygenase protects mice against lipopolysaccharide-induced endotoxin shock.

Jung, In Duk,Lee, Min-Goo,Chang, Jeong Hyun,Lee, Jun Sik,Jeong, Young-Il,Lee, Chang-Min,Park, Won Sun,Han, Jin,Seo, Su-Kil,Lee, Sang Yong,Park, Yeong-Min Williams Wilkins 2009 JOURNAL OF IMMUNOLOGY Vol.182 No.5

<P>Suppression of an excessive systemic inflammatory response is a promising and potent strategy for treating endotoxic sepsis. Indoleamine 2,3-dioxygenase (IDO), which is the rate-limiting enzyme for tryptophan catabolism, may play a critical role in various inflammatory disorders. In this study, we report a critical role for IDO in the dysregulated immune response associated with endotoxin shock. We found that IDO knockout (IDO(-/-)) mice and 1-methyl-D-tryptophan-treated, endotoxin-shocked mice had decreased levels of the cytokines, TNF-alpha, IL-6, and IL-12, and enhanced levels of IL-10. Blockade of IDO is thought to promote host survival in LPS-induced endotoxin shock, yet little is known about the molecular mechanisms that regulate IDO expression during endotoxin shock. In vitro and in vivo, IDO expression was increased by exogenous IL-12, but decreased by exogenous IL-10 in dendritic cells and splenic dendritic cells. Interestingly, whereas LPS-induced IL-12 levels in serum were higher than those of IL-10, the balance between serum IL-12 and IL-10 following challenge became reversed in IDO(-/-)- or 1-methyl-D-tryptophan-treated mice. Our findings demonstrate that the detrimental immune response to endotoxin shock may occur via IDO modulation. Restoring the IL-12 and IL-10 balance by blocking IDO represents a potential strategy for sepsis treatment.</P>

A hot-water extract of <i>Sanguisorba officinalis</i> ameliorates endotoxin-induced septic shock by inhibiting inflammasome activation : HSO attenuates inflammasome activation

Seo, Dong-Won,Cho, Yong-Il,Gu, Suna,Kim, Da-Hee,Yi, Young-Joo,Lee, Sang-Myeong Center for Academic Publications Japan 2018 Microbiology and immunology Vol.62 No.1

<P>The inflammasome is a multiprotein signaling complex that mediates inflammatory innate immune responses through caspase 1 activation and subsequent IL-1 secretion. However, because its aberrant activation often leads to inflammatory diseases, targeting the inflammasome holds promise for the treatment of inflammation-related diseases. In this study, it was found that a hot-water extract of Sanguisorba officinalis (HSO) suppresses inflammasome activation triggered by adenosine 5-triphosphate, nigericin, microbial pathogens, and double stranded DNA in bone marrow-derived macrophages. HSO was found to significantly suppress IL-1 production in a dose-dependent manner; this effect correlated well with small amounts of caspase 1 and little ASC pyroptosome formation in HSO-treated cells. The anti-inflammatory activity of HSO was further confirmed in a mouse model of endotoxin-induced septic shock. Oral administration of HSO reduced IL-1 titers in the serum and peritoneal cavity, increasing the survival rate. Taken together, our results suggest that HSO is an inhibits inflammasome activation through nucleotide-binding domain and leucine-rich repeat pyrin domain 3, nucleotide-binding domain and leucine-rich repeat caspase recruitment domain 4 and absent in melanoma 2 pathways, and may be useful for treatment of inflammasome-mediated diseases.</P>

CP-690550 Treatment Ameliorates Established Disease and Provides Long-Term Therapeutic Effects in an SKG Arthritis Model

오근희,Myung Won Seo,In Gyu Kim,Young-il Hwang,Hee-Yoon Lee,이동섭 대한면역학회 2013 Immune Network Vol.13 No.6

Although pathogenesis of human rheumatoid arthritis (RA) remains unclear, arthritogenic T cells and downstream signaling mediators have been shown to play critical roles. An increasing numbers of therapeutic options have been added for the effective control of RA. Nevertheless, there is still a category of patients that fails treatment and suffers from progressive disease. The recently developed immunosuppressant CP-690550, a small molecule JAK kinase inhibitor, has been implicated as an important candidate treatment modality for autoimmune arthritis. In this study, we evaluated the therapeutic effect of CP-690550 on established arthritis using an SKG arthritis model, a pathophysiologically relevant animal model for human RA. CP-690550 treatment revealed remarkable long-term suppressive effects on SKG arthritis when administered to the well-advanced disease (clinical score 3.5∼4.0). The treatment effect lasted at least 3 more weeks after cessation of drug infusion, and suppression of disease was correlated with the reduced pro-inflammatory cytokines, including IL-17, IFN-γ, and IL-6 and increased level of immunoregulatory IL-10.

큰느타리버섯 균사체로 제조한 발효두부 추출물의 면역 활성

이상원(Sang-Won Lee),강종우(Jong-Woo Kang),김재용(Jae-Yong Kim),박경욱(Kyung-Wuk Park),박석규(Seok-Kyu Park),주옥수(Ok-Soo Joo),이성태(Sung-Tae Yee),서권일(Kwon-Il Seo) 한국식품영양과학회 2010 한국식품영양과학회지 Vol.39 No.1

두부의 기능성 및 저장성을 향상시킬 목적으로 큰느타리버섯 균사체를 이용한 발효두부를 제조하여 물과 메탄올로 추출하여 면역세포 활성에 미치는 효과를 조사하였다. 큰느타리버섯 균사체를 배양하기 위한 최적 배지는 PD broth 배지인 것을 확인하였으며, 큰타리버섯 균사체를 이용한 두부의 최적 발효기간은 7일 정도가 적당하였다. 큰느타리버섯 균사체를 이용하여 발효한 두부의 물 및 메탄올추출물은 0.01 ㎍/mL 농도 이상에서 비장세포의 증식을 유도하였으며, 이들 추출물은 IL-6, IFN-γ 분비를 유도하는 것으로 나타났다. 발효두부 물 추출물은 대조군에 비해 대식세포의 일산화질소 생산을 1 ㎍/mL 농도 이상에서 유의적으로 증가시키는 것을 알 수 있었으며, 메탄올 추출물은 10 ㎍/mL 농도 이상에서 그 생산을 증가시켰다. 발효두부 추출물들은 대식세포가 분비하는 IL-6, TNF-α, IL-1β 및 GM-CSF 분비량을 유의하게 증가시켰다. 따라서 큰느타리버섯 균사체로 발효한 두부는 기능성 두부로 개발이 가능하리라 생각된다. In order to improve the functional benefits and storage properties of soybean tofu, fermented tofu was developed using Pleurotus eryngii mycelia. The immune activities of water and methanol extracts of the tofu were investigated. The optimal medium for the growth of Pleurotus eryngii mycelia was PD broth medium and the optimal fermentation period for the tofu was 7 days. The water and methanol extracts of the fermented tofu induced the proliferation of spleen cells at above 0.01 ㎍/mL. The water extract increased IL-2, IFN-γ production, while the methanol extract increased IFN-γ synthesis. The water and methanol extracts of the fermented tofu induced the NO production in RAW264.7 macrophage cells at above 1 ㎍/mL and above 10 ㎍/mL concentration, respectively. The extracts also significantly increased the production of IL-6, TNF-α, IL-1β and GM-CSF in the cells. These results suggest that the tofu fermented with Pleurotus eryngii mycelia could be developed as a functional tofu.

CP-690550 Treatment Ameliorates Established Disease and Provides Long-Term Therapeutic Effects in an SKG Arthritis Model

Oh, Keunhee,Seo, Myung Won,Kim, In Gyu,Hwang, Young-Il,Lee, Hee-Yoon,Lee, Dong-Sup The Korean Association of Immunobiologists 2013 Immune Network Vol.13 No.6

Although pathogenesis of human rheumatoid arthritis (RA) remains unclear, arthritogenic T cells and downstream signaling mediators have been shown to play critical roles. An increasing numbers of therapeutic options have been added for the effective control of RA. Nevertheless, there is still a category of patients that fails treatment and suffers from progressive disease. The recently developed immunosuppressant CP-690550, a small molecule JAK kinase inhibitor, has been implicated as an important candidate treatment modality for autoimmune arthritis. In this study, we evaluated the therapeutic effect of CP-690550 on established arthritis using an SKG arthritis model, a pathophysiologically relevant animal model for human RA. CP-690550 treatment revealed remarkable long-term suppressive effects on SKG arthritis when administered to the well-advanced disease (clinical score 3.5~4.0). The treatment effect lasted at least 3 more weeks after cessation of drug infusion, and suppression of disease was correlated with the reduced pro-inflammatory cytokines, including IL-17, IFN-${\gamma}$, and IL-6 and increased level of immunoregulatory IL-10.

The whole-exome sequencing in three families with atopic dermatitis

( Joon Hyuk Seo ),( Moo Yeol Hyun ),( Won Il Heo ),( Kapsok Li ),( Seong Joon Seo ),( Chang Kwun Hong ) 대한피부과학회 2015 대한피부과학회 학술발표대회집 Vol.67 No.2

Background: The prevalence of atopic dermatitis (AD) has increased over a recent 10-year. AD tends to run in families that passed down from generation to generation and commonly starts in childhood. It is as high as 20% in children less than 5 years old. Thus, early discovery and therapy of AD are important. It has emerged the necessity of biomarker for early detection of AD. Objectives: The goal of this study is to find novel gene markers for diagnosis of early-onset atopic dermatitis in Koreans. Methods: Peripheral blood was obtained from three families (6 early-onset AD patients and 6 controls) with autosomal dominant condition. Whole Exome Sequencing (WES) was performed using SureSelect Human All Exon V4+UTR 71 Mb. Variants of atopic dermatitis were filtered step by step to gain the important candidate genes. Results: We have confirmed overlapping genes in common variants of filter 5 in three family. 15 genes were overlapped in filter 5 and two of them reached to filter 7 can be called “rare variant”. Uniquely, COL6A6 gene appeared in all of three family. We also found variants of filaggrin, filaggrin2 and IL4R that is well-known makers of atopic dermatitis. Conclusion: We were able to detect COL6A6 gene by finding overlapping genes in rare and common variants of three family. It may become a novel gene as early-onset AD marker.

Enzyme Hydrolysates of Ginseng Marc Polysaccharides Promote the Phagocytic Activity of Macrophages Via Activation of TLR2 and Mer Tyrosine Kinase

( Jeong Yeon Seo ),( Ji Won Choi ),( Jae Yeon Lee ),( Young Shik Park ),( Yong Il Park ) 한국미생물생명공학회(구 한국산업미생물학회) 2018 Journal of microbiology and biotechnology Vol.28 No.6

Although ginseng marc is a by-product obtained during manufacturing of various commercial ginseng products and has been routinely discarded as a waste, it still contains considerable amounts of potential bioactive compounds, including saponins and polysaccharides. Previously, we reported that ginseng oligosaccharides derived from ginseng marc polysaccharides by enzymatic hydrolysis exert immunostimulatory activities in macrophages and these activated macrophages are in turn able to inhibit the growth of skin melanoma cells by inducing apoptosis. In the present study, a more detailed investigation of the immunostimulatory activity and underlying action mechanisms of an enzymatic hydrolysate (GEH) containing these oligosaccharides derived from ginseng marc polysaccharides was performed. The levels of proinflammatory cytokines and anti-inflammatory cytokines were measured in GEH-stimulated RAW264.7 macrophages using RT-PCR analysis and ELISA. The expression levels of Toll-like receptor 2 (TLR2) and TLR4, Dectin-1, and MerTK were measured by RT-PCR analysis or western blot analysis, and the phagocytic activities of GEH-challenged bone marrow-derived macrophages toward apoptotic Jurkat cells were assayed using fluorescence microscopy. GEH induced the production of both proinflammatory cytokines TNF-α and IL-6, and anti-inflammatory cytokine IL-10 in RAW 264.7 cells. The expression of the TLR2 and MerTK mRNAs was increased upon GEH treatment. Phagocytosis of apoptotic Jurkat cells was enhanced in GEH-treated macrophages. Based on the results, this enzymatic hydrolysate (GEH) containing oligosaccharides exerts immunostimulatory effects by maintaining the balance between M1 and M2 cytokines, facilitating macrophage activation and contributing to the efficient phagocytosis of apoptotic cells. Therefore, the GEH could be developed as value-added, health-beneficial food materials with immunostimulatory effects.

사람의 자궁 내막 조직내에서 Phosphodiesterase IV Inhibitor에 의한 IL-12의 조절 및 이에 따른 Th-1, Th-2 cytokine 분비 양상의 변화

박원일 ( Park Won Il ),김은경 ( Kim Eun Gyeong ),고덕성 ( Go Deog Seong ),홍서유 ( Hong Seo Yu ),나중열 ( Na Jung Yeol ),김대운 ( Kim Dae Un ),신정환 ( Sin Jeong Hwan ) 대한산부인과학회 2003 Obstetrics & Gynecology Science Vol.46 No.8

목적 : 사람의 초기 임신 과정에서 phosphodiesterase type IV inhibitor인 rolipram이 탈락막내 IL-12를 억제하고 이에 따라 Th-1 계열의 cytokine이 감소하고 Th-2 cytokine이 증가하는지를 규명하는 것이 목적이다. 연구 방법 : 임신 12주 이전에 계류 유산으로 진단받은 10명과 정상임신에서 임신 중절 수술을 시행받은 10명에서 자궁 소파술을 통하여 탈락막 조직을 획득한 후 조직을 rolipram으로 Objective : To assess the capability of phosphodiesterase type IV inhibitor (rolipram) to suppress IL-12 in human decidua and the subsequent changes of Th-2 cytokine (IL-10) and Th-1 cytokine (TNF-α). Methods : Decidual tissues of 10 first-trimester pregn

YCG063 inhibits Pseudomonas aeruginosa LPS-induced inflammation in human retinal pigment epithelial cells through the TLR2-mediated AKT/NF-κB pathway and ROS-independent pathways

PAENG, SUNG HWA,PARK, WON SUN,JUNG, WON-KYO,LEE, DAE-SUNG,KIM, GI-YOUNG,CHOI, YUNG HYUN,SEO, SU-KIL,JANG, WON HEE,CHOI, JUNG SIK,LEE, YOUNG-MIN,PARK, SAEGWANG,CHOI, IL-WHAN UNKNOWN 2015 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE Vol.36 No.3

<P>YCG063 is known as an inhibitor of reactive oxygen species?(ROS); however, its intracellular mechanisms of action remain poorly understood. In the present study, we investigated the effects of YCG063 on the inflammatory response of Pseudomonas aeruginosa lipopolysaccharide?(PA-LPS)?stimulated human retinal pigment epithelial cells?(RPE cells). Human adult RPE cells?(ARPE?19) were stimulated with PA-LPS. We then investigated the LPS-induced expression of several inflammatory mediators, such as interleukin?(IL)-6, IL-8, monocyte chemoattractant protein-1?(MCP-1) and intracellular adhesion molecule-1?(ICAM-1) in the ARPE-19 cells. We performed an enzyme-linked immunosorbent assay?(ELISA), western blot analysis, electrophoretic mobility shift assay?(EMSA) and fluorescence-activated cell sorting?(FACS) to elucidate the mechanisms involved in the anti-inflammatory effects of YCG063 in the PA-LPS-stimulated cells. The results revealed that treatment with YCG063 significantly inhibited the levels of IL-6, IL-8, MCP-1 and ICAM-1 in the PA-LPS-stimulated ARPE-19 cells. YCG063 also markedly inhibited the phosphorylation of AKT in the PA?LPS-stimulated cells. In addition, the activation of nuclear factor-κB?(NF-κB) was also attenuated folllowing treatment with YCG063. ROS were not generated in the PA-LPS-stimulated cells. In conclusion, our data indicate that YCG063 may prove to be a potential protective agent against inflammation, possibly through the downregulation of Toll?like receptor?2?(TLR2) and the AKT-dependent NF-κB activation pathway in PA-LPS-stimulated ARPE-19 cells. Furthermore, this anti-inflammatory activity occurred through ROS-independent signaling pathways.</P>