Interleukin-1B(1L-1B) polymorphisms and gastric mucosal levels of IL-Iβ cytokine in Korean patients with gastric cancer

Chang, Young-Woon,Jang, Jae-Young,Kim, Nam-Hoon,Lee, Jae Won,Lee, Hyo Jung,Jung, Woon Won,Dong, Seok-Ho,Kim, Hyo-Jong,Kim, Byung-Ho,Lee, Joung-Il,Rin Chang KYUNG HEE UNIVERSITY MEDICAL CENTER 2006 고황의학상 수상논문집 Vol.21-22 No.-

Interleukin-1B and IL-1 receptor antagonist gene polymorphisms are associated with an increased risk of gastric cancer (GC) in Caucasian populations. However, recent studies could not find any association between IL-1B-511T polymorphism and the risk of GC in Asians. We tested for an association between IL-1 loci polymorphisms with increased gastric mucosal levels of IL-1β and an increased risk of developing GC in a Korean population. Polymorphisms of IL-1A-889, IL-1B-31, IL-1B-511 and IL-1RN were genotyped in 434 controls and 234 patients with GC. Mucosal IL-1β cytokine was measured using an ELISA. The frequencies of IL-1A, IL-1B-511, IL-1B-31 and IL-1RN were not statistically different between controls and all patients with GC. After subclassification of GC, only patients with intestinal-type GC showed a higher frequency of IL-1B-31T homozygotes (OR = 2.2; 95% CI = 1.1-4.3) compared with controls. Risk was also significantly increased in these patients for IL-1B-31T homozygotes compared with patients with diffuse-type GC (OR = 3.4; 95% CI = 1.5-7.7). As in Caucasian populations, linkage disequilibrium between IL-1B-31 and IL-1B-511 was nearly complete, but the pattern of haplotype related to the risk of GC (IL-1B-31T/IL-1B-511C) was opposite (IL-1B-511T/IL-1B-31C). Mucosal IL-1β levels in H. pylori-infected GC patients were higher in patients homozygous for IL-1B-31T compared with IL-1B-31C/T and IL-1B-31C/C. Thus, the combined effects of H. pylori infection and IL-1B-31T/IL-1B-511C polymorphisms with enhanced mucosal IL-1β production contributed to the development of intestinal-type GC in this Korean population.

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>

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>

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.

麻醉前處置劑 Flunt (Ro 5-4200)과 Meperidine HCI의 比較的 硏究

金庸樂,咸秉文,崔重立,郭一龍 한국의 현대의학사 1974 한국의 현대의학 Vol.7 No.1

Different shapes of Al₂O₃ particles induce differential cytotoxicity via a mechanism involving lysosomal destabilization and reactive oxygen species generation

Kim, Byung Il,Joo, Yong Hoon,Pak, Pyo June,Kim, Joong-Su,Chung, Namhyun 한국응용생명화학회 2015 Applied Biological Chemistry (Appl Biol Chem) Vol.58 No.3

The biological effects of nano- and micro-sized $Al_2O_3$ particles are hypothesized to differ according to the shapes as well as the sizes of the particles. Thus, the mechanisms of interleukin (IL)-$1{\beta}$ production and the association between the shape of the $Al_2O_3$ particle and its cytotoxicity in macrophage-like THP-1 cells were investigated using particles with three different shapes [$N-Al_2O_3$ (<30 nm), $S-Al_2O_3$ ($2-4nm{\times}100-800nm$), $L-Al_2O_3$ ($2-4nm{\times}2800nm$)]. Levels of IL-$1{\beta}$ production and cytotoxicity were concentration-dependent and were in the following order: $S-Al_2O_3$ > $N-Al_2O_3$ > $L-Al_2O_3$. Stimulus of THP-1 cells by $Al_2O_3$ particles led to lysosomal destabilization, generation of intracellular reactive oxygen species (ROS), and subsequent release of cathepsin B. The magnitude of the stimulus was dependent on the shapes and aspect ratios of the particles. Additional results suggested that caspase-1 (NALP3 inflammasome) activation and IL-$1{\beta}$ production followed cathepsin B release. In addition, the cell death induced by $Al_2O_3$ particles was closely related with cathepsin B leakage. The mode of cell death was necrotic as much as apoptotic. We conclude that $Al_2O_3$ particles induce different levels of IL-$1{\beta}$ production and cytotoxicity depending on their particle shapes or aspect ratios. The current finding may support the development of safe forms of $Al_2O_3$ particles.

<i>In vivo</i> genotoxicity evaluation of lung cells from Fischer 344 rats following 28 days of inhalation exposure to MWCNTs, plus 28 days and 90 days post-exposure

Kim, Jin Sik,Sung, Jae Hyuck,Choi, Byung Gil,Ryu, Hyeon Yeol,Song, Kyung Seuk,Shin, Jae Hoon,Lee, Jong Seong,Hwang, Joo Hwan,Lee, Ji Hyun,Lee, Gun Ho,Jeon, Kisoo,Ahn, Kang Ho,Yu, Il Je Informa Healthcare 2014 INHALATION TOXICOLOGY Vol. No.

<P>Despite their useful physico-chemical properties, carbon nanotubes (CNTs) continue to cause concern over occupational and human health due to their structural similarity to asbestos. Thus, to evaluate the toxic and genotoxic effect of multi-wall carbon nanotubes (MWCNTs) on lung cells <I>in vivo</I>, eight-week-old rats were divided into four groups (each group = 25 animals), a fresh air control (0 mg/m<SUP>3</SUP>), low (0.17 mg/m<SUP>3</SUP>), middle (0.49 mg/m<SUP>3</SUP>), and high (0.96 mg/m<SUP>3</SUP>) dose group, and exposed to MWCNTs <I>via</I> nose-only inhalation 6 h per day, 5 days per week for 28 days. The count median length and geometric standard deviation for the MWCNTs determined by TEM were 330.18 and 1.72 nm, respectively, and the MWCNT diameters ranged from 10 to 15 nm. Lung cells were isolated from five male and five female rats in each group on day 0, day 28 (only from males) and day 90 following the 28-day exposure. The total number of animals used was 15 male and 10 female rats for each concentration group. To determine the genotoxicity of the MWCNTs, a single cell gel electrophoresis assay (Comet assay) was conducted on the rat lung cells. As a result of the exposure, the olive tail moments were found to be significantly higher (<I>p</I> < 0.05) in the male and female rats from all the exposed groups when compared with the fresh air control. In addition, the high-dose exposed male and middle and high-dose exposed female rats retained DNA damage, even 90 days post-exposure (<I>p</I> < 0.05). To investigate the mode of genotoxicity, the intracellular reactive oxygen species (ROS) levels and inflammatory cytokine levels (TNF-α, TGF- β, IL-1, IL-2, IL-4, IL-5, IL-10, IL-12 and IFN-γ) were also measured. For the male rats, the H<SUB>2</SUB>O<SUB>2</SUB> levels were significantly higher in the middle (0 days post-exposure) and high- (0 days and 28 days post-exposure) dose groups (<I>p</I> < 0.05). Conversely, the female rats showed no changes in the H<SUB>2</SUB>O<SUB>2</SUB> levels. The inflammatory cytokine levels in the bronchoalveolar lavage (BAL) fluid did not show any statistically significant difference. Interestingly, the short-length MWCNTs deposited in the lung cells were persistent at 90 days post-exposure. Thus, exposing lung cells to MWCNTs with a short tube length may induce genotoxicity.</P>

Comparison of Cytokine and Nitric Oxide Induction in Murine Macrophages between Whole Cell and Enzymatically Digested Bifidobacterium sp. Obtained from Monogastric Animals

Kim, Dong-Woon,Cho, Sung-Back,Lee, Hyun-Jeong,Chung, Wan-Tae,Kim, Kyoung-Hoon,HwangBo, Jong,Nam, In-Sik,Cho, Yong-Il,Yang, Mhan-Pyo,Chung, Il-Byung The Microbiological Society of Korea 2007 The journal of microbiology Vol.45 No.4

The principal objective of this study was to compare the effects of whole and hydrolyzed cells (bifidobacteria) treated with gastrointestinal digestive enzymes on the activation of cloned macrophages. Seven different strains of Bifidobacterium obtained from swine, chickens, and rats, were digested with pepsin followed by pancreatin and the precipitate (insoluble fraction) and supernatant (soluble fraction) obtained via centrifugation. The RAW 264.7 murine macrophages were incubated with either whole cells, the precipitate, or supernatant at various concentrations. Pronounced increases in the levels of nitric oxide (NO), interleukin $(IL)-1{\beta}$, IL-6, IL-12, and tumor necrosis factor $(TNF)-{\alpha}$ were observed in the whole cells and precipitates, but these effects were less profound in the supernatants. The precipitates also evidenced a slight, but significant, inductive activity for NO and all tested cytokines, with the exception of $(TNF)-{\alpha}$ in the macrophage model as compared with the whole cells. By way of contrast, $(TNF)-{\alpha}$ production when cultured with whole cells (100 ng/ml) resulted in marked increases as compared with what was observed with the precipitates. The results of this study indicated, for the first time, that digested Bifidobacterium sp. can induce the production of NO and several cytokines in RAW 264.7 murine macrophage cells. In the current study, it was demonstrated that Bifidobacterium strains treated with digestive enzymes, as compared with whole cells, are capable of stimulating the induction of macrophage mediators, which reflects that they may be able to modulate the gastrointestinal immune functions of the host.

GM-CSF Promotes Antitumor Immunity by Inducing Th9 Cell Responses

Kim, Il-Kyu,Koh, Choong-Hyun,Jeon, Insu,Shin, Kwang-Soo,Kang, Tae-Seung,Bae, Eun-Ah,Seo, Hyungseok,Ko, Hyun-Ja,Kim, Byung-Seok,Chung, Yeonseok,Kang, Chang-Yuil American Association for Cancer Research 2019 Cancer immunology research Vol.7 No.3

<P>Granulocyte-macrophage colony-stimulating factor (GM-CSF) functions as an adjuvant for antitumor immunity through an unclear mechanism. By activating monocyte-derived dendritic cells, GM-CSF induces Th9 development and IL9 production, which facilitates antitumor cytotoxic T lymphocyte responses.</P><P>GM-CSF as an adjuvant has been shown to promote antitumor immunity in mice and humans; however, the underlying mechanism of GM-CSF–induced antitumor immunity remains incompletely understood. In this study, we demonstrate that GM-CSF potentiates the efficacy of cancer vaccines through IL9-producing Th (Th9) cells. GM-CSF selectively enhanced Th9 cell differentiation by regulating the COX2–PGE<SUB>2</SUB> pathway while inhibiting the differentiation of induced regulatory T (iTreg) cells <I>in vitro</I> and <I>in vivo</I>. GM-CSF–activated monocyte-derived dendritic cells converted tumor-specific nai¨ve Th cells into Th9 cells, and delayed tumor growth by inducing antitumor CTLs in an IL9-dependent manner. Our findings reveal a mechanism for the adjuvanticity of GM-CSF and provide a rationale for the use of GM-CSF in cancer vaccines.</P>

세신약침(細辛藥鍼)의 천식억제 및 면역조절효과에 대한 실험적 연구

김일구 ( Il Gu Kim ),김영일 ( Young Il Kim ),홍권의 ( Kwon Eui Hong ),임윤경 ( Yun Kyoung Yim ),이현,이병렬 ( Byung Ryul Lee ) 대한경락경혈학회 2004 Korean Journal of Acupuncture Vol.21 No.1

Objectives and methods: The aim of this study was to investigate the effect of AHCR(ASARI HERBA CUM RADICE) herbal acupuncture at St36 on ovalbumin-induced asthma in mice. C57BL/6 mice were sensitized and challenged with OVA(ovalbumin) for 12 weeks(once a week). Two experimental groups were treated with different concentrations(1%, 0.1%) of AHCR-HAS at Chok-samni (St36) for the later 8 weeks (3times/week). Results: 1. Lung weight of the mice group treated with AHCR-HA decreased significantly compared with that of control group. 2. Total Leukocytes in BALF of the mice group treated wtih AHCR-HA decreased significantly compared with those of control group. 3. The number of Eosinophils in BALF of the mice group treated wtih AHCR-HA decreased significantly compared with that of control group. 4. The number of Gr-1+ /CD11b+, CCR3+, CD4+, CD3e+/CD69+, IgE+/B220+ cells in the lungs of the mice group treated with AHCR-HA decreased significantly compared with that of control group. 5. The number of CD8+ cells in the lungs of the mice group treated with AHCR-HA didn`t show significant difference compared with that of control group. 6. The concentration of IgE, IL-13, IL-4 in serum of the mice group treated with AHCR-HA decreased significantly compared with that of control group. Conclusion: We conclude that AHCR-HA is effective on OVA-induced asthma in C57BL/6 mouse.