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>

PLZF+ Innate T Cells Support the TGF-beta-Dependent Generation of Activated/Memory-Like Regulatory T Cells

Kyeong-Cheon Jung,Byung Hyun Kang,Hyo Jin Park,Hi Jung Park,Jae-il Lee,Seong Hoe Park 한국분자세포생물학회 2016 Molecules and cells Vol.39 No.6

PLZF-expressing invariant natural killer T cells and CD4 T cells are unique subsets of innate T cells. Both are selected via thymocyte-thymocyte interaction, and they contribute to the generation of activated/memory-like CD4 and CD8 T cells in the thymus via the production of IL-4. Here, we investigated whether PLZF+ innate T cells also affect the development and function of Foxp3+ regulatory CD4 T cells. Flow cytometry analysis of the thymus and spleen from both CIITA transgenic C57BL/6 and wild-type BALB/c mice, which have abundant PLZF+ CD4 T cells and invariant natural killer T cells, respectively, revealed that Foxp3+ T cells in these mice exhibited a CD103+ activated/memory-like phenotype. The frequency of CD103+ regulatory T cells was considerably decreased in PLZF+ cell-deficient CII-TATgPlzflu/lu and BALB/c.CD1d−/− mice as well as in an IL-4-deficient background, such as in CIITATgIL-4−/− and BALB/ c.IL-4−/− mice, indicating that the acquisition of an activated/memory-like phenotype was dependent on PLZF+ innate T cells and IL-4. Using fetal thymic organ culture, we further demonstrated that IL-4 in concert with TGF- enhanced the acquisition of the activated/memory-like phenotype of regulatory T cells. In functional aspects, the activated/memory-like phenotype of Treg cells was directly related to their suppressive function; regulatory T cells of CIITATgPIV-/- mice more efficiently suppressed ovalbumin-induced allergic airway inflammation compared with their counterparts from wild-type mice. All of these findings suggest that PLZF+ innate T cells also augmented the generation of activated/memory-like regulation via IL-4 production.

PLZF⁺ Innate T Cells Support the TGF-β-Dependent Generation of Activated/Memory-Like Regulatory T Cells

Kang, Byung Hyun,Park, Hyo Jin,Park, Hi Jung,Lee, Jae-Il,Park, Seong Hoe,Jung, Kyeong Cheon Korean Society for Molecular and Cellular Biology 2016 Molecules and cells Vol.39 No.6

PLZF-expressing invariant natural killer T cells and CD4 T cells are unique subsets of innate T cells. Both are selected via thymocyte-thymocyte interaction, and they contribute to the generation of activated/memory-like CD4 and CD8 T cells in the thymus via the production of IL-4. Here, we investigated whether $PLZF^+$ innate T cells also affect the development and function of $Foxp3^+$ regulatory CD4 T cells. Flow cytometry analysis of the thymus and spleen from both CIITA transgenic C57BL/6 and wild-type BALB/c mice, which have abundant $PLZF^+$ CD4 T cells and invariant natural killer T cells, respectively, revealed that $Foxp3^+$ T cells in these mice exhibited a $CD103^+$ activated/memorylike phenotype. The frequency of $CD103^+$ regulatory T cells was considerably decreased in $PLZF^+$ cell-deficient $CIITA^{Tg}Plzf^{lu/lu}$ and $BALB/c.CD1d^{-/-}$ mice as well as in an IL-4-deficient background, such as in $CIITA^{Tg}IL-4^{-/-}$ and $BALB/c.IL-4^{-/-}$ mice, indicating that the acquisition of an activated/ memory-like phenotype was dependent on $PLZF^+$ innate T cells and IL-4. Using fetal thymic organ culture, we further demonstrated that IL-4 in concert with TGF-${\beta}$ enhanced the acquisition of the activated/memory-like phenotype of regulatory T cells. In functional aspects, the activated/ memory-like phenotype of Treg cells was directly related to their suppressive function; regulatory T cells of $CIITA^{Tg}PIV^{-/-}$ mice more efficiently suppressed ovalbumin-induced allergic airway inflammation compared with their counterparts from wild-type mice. All of these findings suggest that $PLZF^+$ innate T cells also augmented the generation of activated/memory-like regulation via IL-4 production.

Glucocorticoid-induced tumor necrosis factor receptor–related protein co-stimulation facilitates tumor regression by inducing IL-9–producing helper T cells

Kim, Il-Kyu,Kim, Byung-Seok,Koh, Choong-Hyun,Seok, Jae-Won,Park, Jun-Seok,Shin, Kwang-Soo,Bae, Eun-Ah,Lee, Ga-Eun,Jeon, Hyewon,Cho, Jaebeom,Jung, Yujin,Han, Daehee,Kwon, Byoung S,Lee, Ho-Young,Chung, Nature Publishing Group, a division of Macmillan P 2015 Nature medicine Vol.21 No.9

<P>T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) elicits antitumor activity in various tumor models; however, the underlying mechanism of action remains unclear. Here we demonstrate a crucial role for interleukin (IL)-9 in antitumor immunity generated by the GITR agonistic antibody DTA-1. IL-4 receptor knockout (Il4ra(-/-)) mice, which have reduced expression of IL-9, were resistant to tumor growth inhibition by DTA-1. Notably, neutralization of IL-9 considerably impaired tumor rejection induced by DTA-1. In particular, DTA-1-induced IL-9 promoted tumor-specific cytotoxic T lymphocyte (CTL) responses by enhancing the function of dendritic cells in vivo. Furthermore, GITR signaling enhanced the differentiation of IL-9-producing CD4(+) T-helper (T(H)9) cells in a TNFR-associated factor 6 (TRAF6)- and NF-kappa B-dependent manner and inhibited the generation of induced regulatory T cells in vitro. Our findings demonstrate that GITR co-stimulation mediates antitumor immunity by promoting T(H)9 cell differentiation and enhancing CTL responses and thus provide a mechanism of action for GITR agonist-mediated cancer immunotherapies.</P>

15-deoxy- <b>Δ_12,14</b> -prostaglandin J <b>₂</b> Down-Regulates Activin-Induced Activin Receptor, Smad, and Cytokines Expression via Suppression of NF- <b><i><i><i>κ</i></i></i></b> B and MAPK Signaling in HepG2 Cells

Park, Seung-Won,Cho, Chunghee,Cho, Byung-Nam,Kim, Youngchul,Goo, Tae Won,Kim, Young Il Hindawi Publishing Corporation 2013 PPAR research Vol.2013 No.-

<P>15-Deoxy-Δ<SUP>12,14</SUP>-prostaglandin J<SUB>2</SUB> (15d-PGJ<SUB>2</SUB>) and activin are implicated in the control of apoptosis, cell proliferation, and inflammation in cells. We examined both the mechanism by which 15d-PGJ<SUB>2</SUB> regulates the transcription of activin-induced activin receptors (ActR) and Smads in HepG2 cells and the involvement of the nuclear factor-<I><I>κ</I></I>B (NF-<I><I>κ</I></I>B) and mitogen-activated protein kinase (MAPK) pathways in this regulation. Activin A (25 ng/mL) inhibited HepG2 cell proliferation, whereas 15d-PGJ<SUB>2</SUB> (2 <I><I>μ</I></I>M and 5 <I><I>μ</I></I>M) had no effect. Activin A and 15d-PGJ<SUB>2</SUB> showed different regulatory effects on ActR and Smad expression, NF-<I><I>κ</I></I>B p65 activity and MEK/ERK phosphorylation, whereas they both decreased IL-6 production and increased IL-8 production. When co-stimulated with 15d-PGJ<SUB>2</SUB> and activin, 15d-PGJ<SUB>2</SUB> inhibited the activin-induced increases in ActR and Smad expression, and decreased activin-induced IL-6 production. However, it increased activin-induced IL-8 production. In addition, 15d-PGJ<SUB>2</SUB> inhibited activin-induced NF-<I><I>κ</I></I>B p65 activity and activin-induced MEK/ERK phosphorylation. These results suggest that 15d-PGJ<SUB>2</SUB> suppresses activin-induced ActR and Smad expression, down-regulates IL-6 production, and up-regulates IL-8 production via suppression of NF-<I><I>κ</I></I>B and MAPK signaling pathway in HepG2 cells. Regulation of ActR and Smad transcript expression and cytokine production involves NF-<I><I>κ</I></I>B and the MAPK pathway via interaction with 15d-PGJ<SUB>2</SUB>/activin/Smad signaling.</P>

방풍의 항염 효과 기전

노성일 ( Sung Il Noh ),김상돈 ( Sang Don Kim ),박성철 ( Sung Cheul Park ),서병윤 ( Byung Yun Seo ),염승룡 ( Seung Ryong Yeom ),권영달 ( Young Dal Kwon ),신병철 ( Byung Cheul Shin ),송용선 ( Yung Sun Song ) 한방재활의학과학회 2005 한방재활의학과학회지 Vol.15 No.2

목적 : 방풍은 임상적으로 관절염을 포함한 다양한 염증성 질환 치료제로 사용되어 왔다. 본 연구에서는 인간 비만세포를 이용하여 세포 독성에 영향을 주지 않는 농도에서 방풍의 항염 효과 및 그 기전을 검토했다. 방법 : 인간의 HMC-1세포를 IMDM에서 페니실린, 스트렙토마이신, 모노티오글리세린를 첨가하여 배양하고 방풍추출액을 투여하였다. 그 다음 MTT, ELISA, RT-PCR, 세포내 칼슘측정, 핵단백분석을 이용하여 TNF-α, IL-6, IL-8 각각의 형성과 mRNA발현, 세포내 칼슘 수준, NF-κB 발현에 대한 방풍추출액의 반응을 측정하고 통계처리 하였다. 결과 : 방풍은 PMA와 calcium ionophore A23187로 활성화된 비만세포에서 세포내 칼슘 수준과 NF-κB, TNF-α와 IL-6의 발현을 억제 시켰고 RT-PCR을 이용한 mRNA 발현에서 TNF-α와 IL-6의 발현을 억제하였다. 결론 : 방풍은 비만세포내 칼슘 수준 및 NF-κB의 활성을 억제하고 염증성 세포 활성 물질인 TNF-α와 IL-6의 분비도 억제하여 항염 효과를 나타냄을 암시하고 있다.

주조직적합항원이 불일치하는 마우스 동종 조혈모세포이식에서 IL-2로 유도된 CD4+CD25+ T세포를 이용한 이식편대숙주병의 억제

현재호,정대철,정낙균,박수정,민우성,김태규,최병옥,김원일,한치화,김학기,Hyun, Jae Ho,Jeong, Dae Chul,Chung, Nak Gyun,Park, Soo Jeong,Min, Woo Sung,Kim, Tai Gyu,Choi, Byung Ock,Kim, Won Il,Han, Chi Wha,Kim, Hack Ki 대한면역학회 2003 Immune Network Vol.3 No.4

Background: In kidney transplantation, donor specific transfusion may induce tolerance as a result of some immune regulatory cells against the graft. In organ transplantation, the immune state arises from a relationship between the immunocompromised graft and the immunocompetent host. However, a reverse immunological situation exists between the graft and the host in hematopoietic stem cell transplantation (HSCT). In addition, early IL-2 injections after an allogeneic murine HSCT have been shown to prevent lethal graft versus host disease (GVHD) due to CD4+ cells. We investigated the induction of the regulatory CD4+CD25+ cells after a transfusion of irradiated recipient cells with IL-2 into a donor. Methods: The splenocytes (SP) were obtained from 6 week-old BALB/c mice ($H-2^d$) and irradiated as a single cell suspension. The donor mice (C3H/He, $H-2^k$) received $5{\times}10^6$ irradiated SP, and 5,000 IU IL-2 injected intraperitoneally on the day prior to HSCT. The CD4+CD25+ cell populations in SP treated C3H/He were analyzed. In order to determine the in vivo effect of CD4+CD25+ cells, the lethally irradiated BALB/c were transplanted with $1{\times}10^7$ donor BM and $5{\times}10^6$ CD4+CD25+ cells. The other recipient mice received either $1{\times}10^7$ donor BM with $5{\times}10^6$ CD4+ CD25- cells or the untreated SP. The survival and GVHD was assessed daily by a clinical scoring system. Results: In the MLR assay, BALB/c SP was used as a stimulator with C3H/He SP, as a responder, with or without treatment. The inhibition of proliferation was $30.0{\pm}13%$ compared to the control. In addition, the MLR with either the CD4+CD25+ or CD4+CD25- cells, which were isolated by MidiMacs, from the C3H/He SP treated with the recipient SP and IL-2 was evaluated. The donor SP treated with the recipient cells and IL-2 contained more CD4+CD25+ cells ($5.4{\pm}1.5%$) than the untreated mice SP ($1.4{\pm}0.3%$)(P<0.01). There was a profound inhibition in the CD4+CD25+ cells ($61.1{\pm}6.1%$), but a marked proliferation in the CD4+CD25- cells ($129.8{\pm}65.2%$). Mice in the CD4+CD25+ group showed low GVHD scores and a slow progression from the post-HSCT day 4 to day 9, but those in the control and CD4+CD25- groups had a high score and rapid progression (P<0.001). The probability of survival was 83.3% in the CD4+CD25+ group until post-HSC day 35 and all mice in the control and CD4+CD25- groups died on post-HSCT day 8 or 9 (P=0.0105). Conclusion: Donor graft engineering with irradiated recipient SP and IL-2 (recipient specific transfusion) can induce abundant regulatory CD4+CD25+ cells to prevent GVHD.

Bis(p-substituted phenyl) 2-decyloxyterephthalate의 액정 특성에 대한 치환기 효과

박주훈,이종규,최옥병,소봉근,이수민,이준우,진정일,Park, Joo-Hoon,Lee, Jong-Kyu,Choi, Ok-Byung,So, Bong-Keun,Lee, Soo-Min,Lee, Jun-Woo,Jin, Jung-Il 대한화학회 2000 대한화학회지 Vol.44 No.2

Eleven new compounds that are composed of bis(p-substituted phenyl) terephthalate unitand the decyloxy pendant as lateral were synthesized and their thermal and liquid crystalline properties were studied by the differential scanning calorimetry (DSC) and on a hot-stage of a polarizing microscope. The ter-minal substituent groups of the compound were varied; X= -H(II-H), -F(lI-F), -CII(II-CI), -Br(ll-Br), -I(II-I), -$NO_2(lI-NO_2$), $-CF_3(II-CF_3$), -$OC_2H_5(II-OC_2H_5$), -$OC_4H_9(II-OC_4H_9$), -$C_6H_5(Il-C_6H_5$). The compounds of $II-OC_2H_5,\;II-OC_4H_9$ and $II-C_6H_5$ were monotropically nematic. In contrast, the compounds of Il-H, II-F, II-Cl, II-Br, II-I, $lI-NO_2$, $II-CF_3$, and II-CN did not show liquid crystalline properties. 비스(파라-치환페닐)테레프탈산 에스테르의 중앙 테레프탈산 벤젠고리 측면에 데실옥시기가 결합하고 있는 열한개의 새로운 화합물을 합성하였고, 이들의 열적 및 액정 성질을 DSC와 가열판이 부착된 편광현미경을 사용하여 조사하였다. 메소겐의 말단 치환기 X= -H(II-H), -F(II-F), -Cl(Il-Cl), -Br(Il-Br), -I(II-I), -$NO_2(lI-NO_2$), $-CF_3(II-CF_3$), -$OC_2H_5(II-OC_2H_5$), -$OC_4H_9(II-OC_4H_9$), -CN(II-CN) 및 -$C_6H_5(Il-C_6H_5$)로 바꾸었다. $II-OC_2H_5,\;II-OC_4H_9$, 및 $II-C_6H_5$는 단방성 네마틱 액정이었으며, II-H, lI-F, II-Cl, Il-Br, II-I, $II-NO_2$, $II-CF_3$, 및 Il-CN은 액정이 아니었다.

Interleukin-2와 결핵균 30 kDa 항원이 구개편도 및 말초혈액 T 세포 증식에 미치는 상승효과

박정규,박찬권,조은경,김화중,백태현,고필준,김병국,남부현,나기상,박찬일 충남대학교 의과대학 지역사회의학연구소 1995 충남의대잡지 Vol.22 No.1

Widespread use of BCG has not controlled tuberculosis, and more effective vaccines are clearly needed. Although chemotherapy will remain the mainstay of antituberculosis treatment, the use of adjunctive immunotherapeutic modalitites is attractive, particularly in persons with drug-resistant tuberculosis. Administration of IL-2 or IFN-γto tuberculosis patients enhance bacillary elimination. Cell-mediated immunity is the critical protective immune response in tuberculosis. Mycobacterial antigens are recognized by T cells and that elicit production of protective cytokines are potentially important vaccine antigens. The 30 kDa antigen is secreted in large quantities by growing mycobacteria. That antigen elicits greater proliferation in lymphocytes from healthy tuberculin reactors than healthy tuberculin nonreactors. In this study, the T lymphocyte proliferative responses to 30 kDa antigen from Mycobactrium tuberculosis H37Rv were examined by using tonsilar and peripheral blood lymphocytes from PPD(+) and PPD(-) tonsilectomized persons. When cultured with 30 kD antigen, tonsilar mononuclear leukocytes and T cells of PPD(+) demonstrated more ^3H-thymidine incorporation than PPD(-) persons (stimulation index was 2.5 and 1.9, 0.8 and 1.0, repectively). Peripheral blood mononuclear cells (PBMC) and peripheral blood T lymphocytes were shown the similar responses to this antigen. The combination of IL-2 and 30 kDa antigen elicited a significant proliferative responsiveness in tonsilar mononuclear leukocytes and T cells of PPD(+) persons (SI was 20 and 14.1). PBMC and peripheral blood T cells of PPD(+) persons were also shown a significant responsiveness, but PPD(-) persons did not show. These results demonstrate that the 30 kDa antigen and IL-2 have a synergistic stimulatory property in mycobacteria sensitizing lymphocytes.

捻轉法이 竝行된 鍼刺戟 및 電鍼刺戟이 鎭痛效果에 미치는 影響

Park, Dong-Seok,Kim, Ji-Hoon,Min, Byung-Il,Oh, Soo-Myung 경희대학교 동서의학연구소 1999 INTERNATIONAL SYMPOSIUM ON EAST-WEST MEDICINE Vol.1999 No.1

Dong-Seok Park¹, Ji-Hoon Kim¹ and Byung-Il Min, Soo-Myung Oh,³¹Department of Acupuncture and Moxibustion, College of Medicine, ²Department of Physiology, College of Medicine, And ³East-West Medical Research Institute, Kyung Hee University,Seoul, Korea. Analgesic Effect of Manual Acupuncture and Electroacupuncture combined with Twirling Method. Proceeding of International Symposium on East-West Medicine Seoul. 187-200, 1999.-Twirling the needle (TN) is one of several needing methods frequently used for acupuncture in the oriental medicine. The present study was conducted to see if TN enhanced the antinociceptive effect produced by plain-or electroacupuncture in the rat tail flick test. Rats (Sprague-Dawley, 200-300g)lightly anesthetized with thiopental sodium(40mg/kg, i.p.) were used in the tail-flick test. The basal reaction time for tail-flick was 2 sec. For "plain" acupuncture(PA), a needle was inserted for 20 min into a Chock-samni (ST36) acupuncture point which (is located at the anterior tibial muscle and about 10mm below the knee joint). For electroacupuncture(EA), train-pulses(3 Hz,0.3-ms pulse width, 0.2-0.3mA) were applied to the inserted needle for the period of insertion. For combining TN with either PA or EA, TN was performed during the each acupuncture period. Two methods for TN were used; twirling 3 times for 1 second persisted for 1 min in every 5 mins(long-duration and long-interval;LDLI) and twirling 3 times for 1 second persisted for 10 sec in every 1 min(short-duration and short-interval;SDSI). PA and EA produced an increase in tail flick latency (TFL); peak increases were 21.3±5.1% and 42.1±17.3% of the pre-acupunture control, respectively, and occurred immediately after cessation of 20min-acupuncture. Performing TN combined with PA increased TFL more than PA itself by showing a greater peak increase in TFL when performed with a SDSI-TN than with a LDLI-TN(60.6±12.5% and 42.7±22.7% of the pre-acupuncture control, respectively). Performing TN combined with EA also increased TFL more than EA itself and a greater peak increase in TFL was observed with a SDSI-TN as compared to a LDLI-TN(77.5±13.8% and 67.3±14.0% of the pre-acupuncture control, respectively). These results indicate that TN enhances both PA-and EA-produced antinociception where an greater enhanced antinociception than a LDLI-TN. It is suggested that performing a SDSI-TN combined with EA seems to be one of the most effective ways to produce analgesia.