Genetic effect of <i>CCR3</i> and <i>IL5RA</i> gene polymorphisms on eosinophilia in asthmatic patients

Lee, June-Hyuk,Chang, Hun Soo,Kim, Ji Hyun,Park, Se-Min,Lee, Yong Mok,Uh, Soo Taek,Rhim, Taiyoun,Chung, Il Yup,Kim, Yong-Hoon,Park, Byung Lae,Park, Choon-Sik,Shin, Hyoung Doo Elsevier 2007 The journal of allergy and clinical immunology Vol.120 No.5

<P><B>Background</B></P><P>Eosinophilic infiltration and peripheral blood eosinophilia in asthma require the cooperation of eosinophil-specific cytokines and chemokines and their receptors.</P><P><B>Objective</B></P><P>We investigated the association of polymorphisms in <I>CCR3</I> and <I>IL5RA</I> with asthma susceptibility or peripheral blood eosinophilia and the effects of the polymorphisms on receptor expression.</P><P><B>Methods</B></P><P>Polymorphisms in <I>CCR3</I> and <I>IL5RA</I> were identified and genotyped in 576 asthmatic patients and 180 healthy control subjects. CCR3 and IL-5 receptor α (IL-5Rα) protein expression on eosinophils was measured by means of flow cytometry.</P><P><B>Results</B></P><P>Although polymorphisms in <I>CCR3</I> were not associated with asthma susceptibility, the <I>CCR3</I> haplotype <I>ht2</I> showed a negative gene dose effect on the eosinophil count (<I>P</I> = .003–.009). <I>IL5RA c.−5091G>A</I> was weakly associated with eosinophil count. The effects of <I>ht2</I> were greater when paired with <I>IL5RA c.−5091A</I> (<I>P</I> = .001–.002). CCR3 protein expression was higher on eosinophils of asthmatic patients without <I>ht2</I> than in those with <I>ht2</I>. Asthmatic patients with the <I>IL5RA c.−5091A</I> allele showed higher IL-5Rα expression than those who were homozygous for the G allele.</P><P><B>Conclusion</B></P><P>The genetic association between <I>CCR3</I> polymorphisms and the number of circulating eosinophils was revealed as a novel finding. These associations were more pronounced when the <I>CCR3</I> polymorphisms were paired with polymorphisms in <I>IL5RA</I>. The protein expression levels of CCR3 and IL-5Rα on peripheral blood eosinophils are associated with the polymorphisms on their own genes.</P><P><B>Clinical implications</B></P><P>The identification of single nucleotide polymorphisms and haplotypes of <I>CCR3</I> and <I>IL5RA</I> might be useful in developing markers for intermediate phenotypes of eosinophil number and in designing strategies to control diseases related to hypereosinophilia.</P>

Association between chronic hepatitis B virus infection and interleukin-10, tumor necrosis factor-α gene promoter polymorphisms

Cheong, Jae Youn,Cho, Sung Won,Hwang, Il Lan,Yoon, Seung Kew,Lee, June Hyuk,Park, Choon Sik,Lee, Jong Eun,Hahm, Ki Baik,Kim, Jin Hong Blackwell Publishing Asia 2006 Journal of gastroenterology and hepatology Vol.21 No.7

<P>Abstract</P><P>Background: </P><P>The reasons for the viral persistence of hepatitis B virus infection (HBV) are unknown, but are probably related to host immune factors. Cytokines play a significant role in immune defense. The present study was undertaken to investigate the association between HBV infection and polymorphisms of tumor necrosis factor (TNF)-α and interleukin(IL)-10 gene promoter.</P><P>Methods: </P><P>A total of 412 Korean patients with HBV infection (72 inactive carriers, 261 witih chronic hepatitis, 79 with liver cirrhosis) and 204 healthy individuals who recovered from HBV infection, were studied. The polymorphisms in IL-10 gene promoter (−1082, −819, −592), and TNF-α gene promoter (−308, −238) were assessed by single base primer extension assay.</P><P>Results: </P><P>The frequency of C/C genotype at position −592 of IL-10 gene promoter was higher in the HBV clearance group than that in the persistence group in univariate analysis (12.7% vs 7.5%, <I>P</I> = 0.036). The IL-10 gene promoter −592 C/C genotype was related to clearance of HBV infection in logistic regression analysis after adjusting for age and sex (<I>P</I> = 0.003). Genotype frequencies of TNF-α gene promoter at position −308 and −238 were not different between the clearance and the persistence group in univariate analysis, but in multivariate analysis after adjusting for age and sex, −308G/−238G homozygotes were associated with HBV persistence (<I>P</I> = 0.005). Genotype distributions of both gene promoters in inactive carriers were similar to those in patients with chronic progressive liver disease.</P><P>Conclusions: </P><P>The carriers of the −592A allele in the IL-10 promoter and −308G/−238G haplotype homozygotes in the TNF-α promoter region have higher risk of persistent HBV infection.</P>

Recovery of ionic liquid and sugars from hydrolyzed biomass using ion exclusion simulated moving bed chromatography

Mai, Ngoc Lan,Nguyen, Nam Trung,Kim, Jin-Il,Park, Hyuk-Min,Lee, Sung-Kyun,Koo, Yoon-Mo Elsevier 2012 Journal of Chromatography A Vol.1227 No.-

<P><B>Highlights</B></P><P>► Ionic liquid was successfully separated from aqueous sugar mixtures by ion exclusion SMB. ► Ionic liquid and sugar recovery yield depend on the SMB zone flow rates. ► Complete recovery of ionic liquid could be obtained by optimization of SMB zone configuration.</P> <P><B>Abstract</B></P><P>Efficient recovery of ionic liquid (IL) from aqueous mixture of ILs and sugars (which derived from enzymatic or chemical catalyzed hydrolysis of ILs-pretreated biomass) is a major drawback for commercialization of biofuel and platform chemicals production from biomass utilized ILs as pretreatment solvent. In this study, simulated moving bed (SMB) chromatography equipped with ion exclusion column (containing [Emim]<SUP>+</SUP> cation) was investigated to separate sugars (glucose and xylose) which are the main products from biomass hydrolysate and 1-Ethyl-3-methylimidazolium acetate (EmimAc) which is the ILs used for biomass pretreatment. A four-zone SMB system with a configuration of 2-2-2-2 (2 ion exclusion columns in each zone) was used to recover glucose, xylose and EmimAc from their aqueous mixture with yield of 71.38, 99.37 and 98.92%, respectively. Moreover, the optimization of SMB zone configuration by simulation results in a complete recovery of ILs. This result indicates that for the first time, ion exclusion SMB chromatography could be used for complete recovery of ILs from aqueous sugar mixture.</P>

코디세핀이 마우스 복강 대식세포에서 전염증성 사이토카인의 생성에 미치는 영향

서민정(Min-Jeong Seo),강병원(Byoung-Won Kang),김민정(Min-Jeong Kim),이혜현(Hye-Hyeon Lee),서권일(Kwon-il Seo),김광혁(Kwang-Hyuk Kim),정영기(Yong-Kee Jeong) 한국식품과학회 2014 한국식품과학회지 Vol.46 No.1

본 연구는 동충하초(Cordyces militaris) 유래의 기능성 물질인 코디세핀의 면역활성을 검증하기 위하여 C57BL6 마우스 복강 대식세포를 이용하여 코디세핀이 대식세포의 활성화에 미치는 영향에 대하여 시험하였다. 그 결과 LPS에 의해 유도된 마우스 복강세포는 코디세핀의 작용에 의해 IL-1β, IL-12, TNF-α의 염증성 사이토카인의 생성이 증대되어 초기 염증매개 반응을 유도하여 선천면역반응의 활성화와 그리고 면역작용에 있어 후기 적응면역의 전환으로의 T 림프구의 활성화가 예상된다. 또한 IL-6의 생성증대로 활성화된 T 림프구에 의해 B 림프구의 항체생성반응을 매개하는 면역반응도 상승할 것으로 사료된다. 그리고 대식세포에 의한 염증반응에서 염증매개인자인 NO와 H₂O₂의 생성을 증대시킴에 따라 대식세포의 독성작용을 활성화시켜 염증반응을 효과적으로 유도할 것으로 보이며, 또한 H₂O₂의 후기 생성을 저해하였는데 이는 염증반응에 유도될 수 있는 세포의 손상으로부터 세포를 보호할 수 있을 것으로 사료된다. 따라서 코디세핀은 외부인자로부터 염증매개성 면역반응의 증강작용을 나타내는 것으로 사료된다. The effect of cordycepin purified from Cordyceps militaris on macrophage activation was investigated in peritoneal macrophages isolated from C57BL6 mice. Lipopolysaccharide-induced mouse peritoneal cells showed that cordycepin treatment increased the expression of the inflammatory cytokines interleukin (IL)-1β, IL-12, and tumor necrosis factor-α (TNF-α), leading to early inflammation-mediated reactions, the activation of immunological responses, and T lymphocyte activation. T lymphocytes, activated by a greater production of IL-6, resulted in antibody-generating immune reactions, suggesting that cordycepin was effective at inducing immunological responses. Consistent with the increase in the inflammation-mediating factors including nitric oxide (NO) and hydrogen peroxide (H₂O₂), the toxic response of macrophages was activated and effectively induced inflammation. These findings demonstrate that cordycepin is involved in reducing cell injury provoked by inflammatory reactions. Therefore, these results suggest that cordycepin treatment of mouse peritoneal cells induces inflammation-mediated immunological responses and immunostimulation.

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.

HCV, Acute, LT : Hepatic Stellate Cells Modulate Functions of Tregs in IFNγ-mediated Hepatitis of Mice

( Qin Ning ),( Young Sun Lee ),( Hyon Seung Yi ),( Hyuk Soo Eun ),( Won Il Jeong ) 대한간학회 2013 춘·추계 학술대회 (KASL) Vol.2013 No.1

Background: Hepatic stellate cells (HSCs) perform important roles not only in liver fibrosis but also in inflammation by regulating activation or induction of immune cells and producing various chemokines and cytokines. Moreover, it has been reported that HSCs are also involved in the induction of regulatory T cells (Tregs). Therefore, we investigated the immune regulatory role of HSCs to Tregs in interferon γ (IFNγ)- mediated hepatitis of mice. Methods: To induce IFNγ-mediated hepatitis in mice, we injected concanavalin A (ConA) to mice through tail vein at dose of 12 μg/g. Mice were sacrificed at 0, 3, 12 and 24 hours after ConA treatment. In vitro experiment, isolated natural Tregs from lymph nodes and spleen were co-cultured with HSCs and then analyzed the FoxP3 expression and gene expressions. Results: After ConA treatment, liver injuries sharply increased a n d p e a k e d a t 2 4 h o u r s a n d t h e p o p u l a t i o n o CD4+CD25+FoxP3+ Tregs was also significantly increased. In addition, isolated HSCs after ConA treatment showed enhanced expressions of TGF-β and IL-10. In vitro co-culturing Tregs with HSCs, HSCs significantly up-regulated Foxp3 expression in Tregs compared to that of non-co-cultured Tregs. Moreover, levels of IL-10 and TGF-β at supernatant remarkably increased in the co-cultured group compared with those of Tregs or HSCs only cultured group. Conclusions: In ConA-induced hepatitis, HSCs might regulate the expression of FoxP3 in Tregs by producing cytokines such as IL-10 and TGF-β. Therefore, the regulation of function in HSCs could be a new therapeutic target for immune-mediated hepatitis.

반복적 관절내 출혈이 관절 활막과 연골 세포의 변화에 미치는 영향

유명철(Myung Chul Yoo),조윤제(Yoon Jae Cho),김강일(Kang Il Kim),전성욱(Sung Wook Chun),소동혁(Dong Hyuk So),조형준(Hyung Jun Cho),양형인(Hyung-In Yang),이상훈(Sang-Hoon Lee),이연아(Yeon-Ahn Lee) 대한정형외과학회 2008 대한정형외과학회지 Vol.43 No.3

목적: 혈액의 관절강내 반복주사 동물 모델을 이용하여, 혈우병성 관절염에서 활막의 변화와 연골 파괴에 대한 병리 기전과 경과 과정을 연구하였다. 대상 및 방법: 뉴질랜드 백색 토끼 수컷 20마리에 18주간 1주 3회씩 귀에서 자가 혈액을 채취하여 우측 슬관절에 1 ㎖를 주사하고, 좌측 슬관절에 생리식염수 1㎖를(대조군) 주사하였다. 11주 후와 18주 후에 양측 슬관절의 X선 촬영을 시행하였고, 활액막과 연골을 채취하여 조직검사를 시행하였다. 활막 세포 배양에서 RT PCR를 이용한 cytokine의 변화를 관찰 하였고, 연골 세포를 추출 배양하여 GAG 및 PGE₂, MMP-1,3 생성을 측정하였다. 결과: 11주째 육안적 변화는 없었으나, 우측 슬관절의 활액막은 조직학적으로 경한 증식반응과 형질세포 및 단핵세포의 활액막내 침착을 보이며 약간의 염증 소견을 나타냈다. 단순 방사선 소견상 특이 소견은 발견되지 않았다. 18주 후에는 육안적으로 우측 슬관절이 좌측에 비하여 부어 있었고, 단순 방사선학적 소견에서는 관절의 퇴행성 변화가 관찰 되었다. 병리학적 소견은 활막의 심한 증식과 염증세포의 침윤이 관찰되었다. 활막의 real-time RT PCR 시행결과 TNF-alpha, IL-1, MMP-1 mRNA 발현이 증가되었다. 연골세포 배양에서 대조군과 비교시 GAG 생성은 감소하고 PGE₂는 증가하였으며 MMP-1과 MMP-3는 변화가 없었다. 결론: 반복적인 관절 내 출혈은 활막세포를 자극하여 활막의 심한 증식과, proinflammatory cytokines의 생성을 증가시키며, 이는 연골 세포의 재생을 억제하고 연골세포의 염증을 증가시켜 연골의 대사기능이 억제되면서 퇴행성 변화를 촉진하여 점차적으로 관절염으로 이행되는 것으로 사료된다. Purpose: We designed this study to demonstrate the pathophysiology of hemophilic arthropathy (HA) by creating an animal model for determining the effect of repeated intraarticular bleeding in the synovium and articular cartilage. Materials and Methods: 20 normal male New Zealand white rabbits were used for this study. We injected 1 ㎖ of autologous blood from the ear vein of the rabbits into the right knee joint three timeds a week for 18 weeks, and we injected 1 ㎖ of normal saline into the left knee joint three times a week for 18 weeks as a control group. We examined the pathologic changes by microscopy and plain X-ray, and we determined the mRNA expression of proinflammatory cytokines in the synovium of the HA by performing real time RT-PCR at the 11<SUP>th</SUP> week and 18<SUP>th</SUP> week after starting blood-injection. We also examined the GAG and the PGE2 production in cultured chondrocytes that were extracted from the HA knees. Results: At the 11<SUP>th</SUP> week, after blood injection there were no remarkable gross changes in the HA knees and the control knee joints. At the 18<SUP>th</SUP> weeks, the experimental knee joints (HA knees) showed grossly swelling and degenerative changes by X-ray. The infiltration of inflammatory cells and the synovial proliferation in the HA knee joints were compared with that in the control knee joints by microscopic examination. The expressions of the mRNA of TNF-alpha, IL-1, MMP-1 and MMP-3 in the HA synovium were increased, as determined by real time RT-PCR, as compared with that in the control knee. In the cultured chondrocytes, the GAG production was decreased and the PGE2 was increased, but the MMP-1 and MMP-3 were not changed, as determined by ELISA. Conclusion: Our results showed that the GAG production of chondrocytes of the HA knees was decreased and there was increased PGE2, so that the cartilage degeneration by intra-articular bleeding was caused by the decreased metabolism of chondrocytes rather than by increased catabolism of the chondrocytes. We suggest that HA was associated with synovitis and cartilage degeneration, but decreased cartilage metabolism was the major mechanism of HA.

Blockade of Retinol Metabolism Protects T Cell-Induced Hepatitis by Increasing Migration of Regulatory T Cells

Lee, Young-Sun,Yi, Hyon-Seung,Suh, Yang-Gun,Byun, Jin-Seok,Eun, Hyuk Soo,Kim, So Yeon,Seo, Wonhyo,Jeong, Jong-Min,Choi, Won-Mook,Kim, Myung-Ho,Kim, Ji Hoon,Park, Keun-Gyu,Jeong, Won-Il Korean Society for Molecular and Cellular Biology 2015 Molecules and cells Vol.38 No.11

Retinols are metabolized into retinoic acids by alcohol dehydrogenase (ADH) and retinaldehyde dehydrogenase (Raldh). However, their roles have yet to be clarified in hepatitis despite enriched retinols in hepatic stellate cells (HSCs). Therefore, we investigated the effects of retinols on Concanavalin A (Con A)-mediated hepatitis. Con A was injected into wild type (WT), Raldh1 knockout ($Raldh1^{-/-}$), $CCL2^{-/-}$ and $CCR2^{-/-}$ mice. For migration study of regulatory T cells (Tregs), we used in vivo and ex vivo adoptive transfer systems. Blockade of retinol metabolism in mice given 4-methylpyrazole, an inhibitor of ADH, and ablated Raldh1 gene manifested increased migration of Tregs, eventually protected against Con A-mediated hepatitis by decreasing interferon-${\gamma}$ in T cells. Moreover, interferon-${\gamma}$ treatment increased the expression of ADH3 and Raldh1, but it suppressed that of CCL2 and IL-6 in HSCs. However, the expression of CCL2 and IL-6 was inversely increased upon the pharmacologic or genetic ablation of ADH3 and Raldh1 in HSCs. Indeed, IL-6 treatment increased CCR2 expression of Tregs. In migration assay, ablated CCR2 in Tregs showed reduced migration to HSCs. In adoptive transfer of Tregs in vivo and ex vivo, Raldh1-deficient mice showed more increased migration of Tregs than WT mice. Furthermore, inhibited retinol metabolism increased survival rate (75%) compared with that of the controls (25%) in Con A-induced hepatitis. These results suggest that blockade of retinol metabolism protects against acute liver injury by increased Treg migration, and it may represent a novel therapeutic strategy to control T cell-mediated acute hepatitis.

내측회장동맥에 의해 형성된 척수경막동정맥루로 인한 척수병증 1예

이일형,배재천,이상무,김진혁,권기한,이병철 대한신경과학회 1999 대한신경과학회지 Vol.17 No.3

만성 C형 간염 환자에서 페그인터페론 알파2a와 리바비린 병합 치료중 발생한 벨마비 1예

김일환,장제혁,유충헌,최규남,고정해,김윤정,서광원,김지현,박성재,박은택,이연재,이상혁,설상영 인제대학교 2008 仁濟醫學 Vol.29 No.-

페그인터페론과 리바비린 병합요법은 만성 C형 간염의 일차 치료법이다. 저자들은 만성 C형 간염 환자에서 페그인터페론 과 리바비린 병합 요법 중에 발생한 벨마비 1예를 경험하였기에 문헌고찰과 함께 보고하는 바이다. 환자는 5년 전부터 만성 C형 간염을 앓아온 48세 남자이며, PEG-IFN α-2a 135μgm 피하주사 주1회와 하루 1200㎎의 리바비린을 투여하였다. 치료시작 후 9개월째 환자는 오른쪽 안면의 근력약화를 호소하였으며 벨마비로 진단되었다. 페그인터페론과 리바비린 병합요법을 지속하면서 관찰하였다. 환자의 벨마비는 페그인터페론 치료를 중단하지 않았음에도 3개월후 증상이 회복되고 이후 벨마비 재발 없이 현재 경과관찰 중이다. 만성 C형 간염에서 페그인터페론과 리바비린 병합 요법시 벨마비의 발생 가능성을 염두에 두어야 하겠다. A Case of Bell's Palsy Associated with Combination Therapy of Pegylated Interferon Alfa-2a (PEG-IFN) and Ribavirin for Chronic Hepatitis C Virus Infection Pegylated interferon alfa(PEG-IFN α) and ribavirin therapy is the first line treatment for chronic hepatitis C. Mild complications of the therapy are common, but more serious complications are rare. We report here a case of Bell's palsy that occurred in a patient with chronic hepatitis C virus infection during combination therapy of PEG-IFN α-2a and ribavirin. The patient was 49-year-old man with chronic hepatitis C (genotype 1b) for 8 years. He had compensated liver cirrhosis with splenomegaly. Therapy with PEG-IFN α- 2a 135mcg/week and ribavirin 1200mg/day was initiated. After 9 months of the therapy, the patient showed a loss of muscular tone on the right side of his face. A diagnosis of Bell's palsy was made. The Bell's palsy resolved over 3 months despite continuation of the combination therapy.