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>

Oleoylethanolamide induces eosinophilic airway inflammation in bronchial asthma

Kwon Eun-Kyung,최영우,Yoon Il-Hee,Won Ha-Kyeong,심소윤,Lee Hee-Ra,Kim Hyoung Su,예영민,신유섭,박해심,Ban Ga-Young 생화학분자생물학회 2021 Experimental and molecular medicine Vol.53 No.-

Asthma is a chronic eosinophilic inflammatory disease with an increasing prevalence worldwide. Endocannabinoids are known to have immunomodulatory biological effects. However, the contribution of oleoylethanolamide (OEA) to airway inflammation remains to be elucidated. To investigate the effect of OEA, the expression of proinflammatory cytokines was measured by RT-qPCR and ELISA in airway epithelial (A549) cells. The numbers of airway inflammatory cells and cytokine levels in bronchoalveolar lavage fluid, airway hyperresponsiveness, and type 2 innate lymphoid cells (ILC2s) were examined in BALB/c mice after 4 days of OEA treatment. Furthermore, eosinophil activation after OEA treatment was evaluated by measuring cellular CD69 levels in eosinophils from human peripheral eosinophils using flow cytometry. OEA induced type 2 inflammatory responses in vitro and in vivo. OEA increased the levels of proinflammatory cytokines, such as IL-6, IL-8, and IL-33, in A549 cells. In addition, it also induced eosinophilic inflammation, the production of IL-4, IL-5, IL-13, and IL-33 in bronchoalveolar lavage fluid, and airway hyperresponsiveness. OEA increased the numbers of IL-5- or IL-13-producing ILC2s in a mouse model. Finally, we confirmed that OEA increased CD69 expression (an eosinophil activation marker) on purified eosinophils from patients with asthma compared to those from healthy controls. OEA may play a role in the pathogenesis of asthma by activating ILC2s and eosinophils.

Antiviral and anti-inflammatory activity of budesonide against human rhinovirus infection mediated via autophagy activation

Kim, Seong-Ryeol,Song, Jae-Hyoung,Ahn, Jae-Hee,Lee, Geun-Shik,Ahn, Huijeong,Yoon, Sung-il,Kang, Seung Goo,Kim, Pyeung-Hyeun,Jeon, Sang-Min,Choi, Eun-Ji,Shin, Sooyoung,Cha, Younggil,Cho, Sungchan,Kim, Elsevier 2018 Antiviral research Vol.151 No.-

<P>Human rhinovirus (HRV) infection causes more than 80% of all common colds and is associated with severe complications in patients with asthma and chronic obstructive pulmonary disease. To identify antiviral drug against HRV infection, we screened 800 FDA-approved drugs and found budesonide as one of the possible drug candidates. Budesonide is a corticosteroid, which is commonly used to prevent exacerbation of asthma and symptoms of common cold. Budesonide specifically protects host cells from cytotoxicity following HRV infection, which depend on the expression of glucocorticoid receptor. Intranasal administration of budesonide lowered the pulmonary HRV load and the levels of IL-1 beta cytokine leading to decreased lung inflammation. Budesonide regulates IL-1 beta production following HRV infection independent of inflammasome activation. Instead, budesonide induces mitochondrial reactive oxygen species followed by activation of autophagy. Further, the inhibition of autophagy following chloroquine or bafilomycin Al treatment reduced the anti-viral effect of budesonide against HRV, suggesting that the antiviral activity of budesonide was mediated via autophagy. The results suggest that budesonide represents a promising antiviral and anti-inflammatory drug candidate for the treatment of human rhinovirus infection.</P>

15-deoxy-Δ12, 14-prostaglandin j2 inhibits the expression of toll-like receptor and pro-inflammatory mediator genes induced by lps in normal human melanocytes

( Young Il Kim ),( Eun Jae Shin ),( Min Jae Gwak ),( Ki Heon Jeong ),( Min Kyung Shin ),( Mu Hyoung Lee ) 대한피부과학회 2015 대한피부과학회 학술발표대회집 Vol.67 No.2

Background: Prostaglandin J2 (PGJ2) and its metabolites ツ12-PGJ2 and 15-deoxy-ツ12,14-PGJ2 (15d-PGJ2) are naturally occurring derivatives of prostaglandin D2 that have been suggested to exert anti-inflammatory effects in vivo. 15d-PGJ2 is a high-affinity ligand for the peroxisome proliferator-activated receptor ャ (PPARャ) and has been demonstrated to inhibit the induction of inflammatory response genes, including inducible NO synthase and tumor necrosis factor メ, in a PPARャ -dependent manner. Objectives: To analyze the effectiveness of 15d-PGJ2 on the expression of TLR 1-10, IL-1モ, 6, 8, TNF-メ, and iNOS mRNA in human melanocytes stimulated with LPS. Methods: Melanocytes were treated with LPS and 15d-PGJ2 in a dose-dependent manner and cell proliferation was determined using the MTT assay. Todetermine the effect of 15d-PGJ2 on the expression of TLR 1-10, IL-1モ, 6, 8, TNF-メ, and iNOS mRNA in human melanocytes in the presence or absence of LPS, melanocytes were treated with LPS and 15d-PGJ2 for 24 h. We performed RT-PCR for mRNA expression. Results: In this study, TLR 1-10, IL-1モ, 6, 8, TNF-メ, and iNOS mRNA expression was examined, and the expression increased after LPS stimulation. The increased expression was inhibited with 15d-PGJ2. These results revealed a similar pattern to normal human keratinocyte. Conclusion: 15d-PGJ2 may play a role in the pigmentary disorder via anti-inflammatory action.

P179 : Activin suppresses LPS-induced Toll-like receptors, cytokines, and nitric oxide expression by inhibiting activation of NF-κB and MAPK pathways in normal human melanocytes

( Young Il Kim ),( Seung Won Park ),( Jeong Hwee Choi ),( Myong Il Bae ),( Min Kyung Shin ),( Mu Hyoung Lee ) 대한피부과학회 2013 대한피부과학회 학술발표대회집 Vol.65 No.2

Background: Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-β (TGF-β) superfamily. Objectives: To know the mechanism how activin regulates transcription of lipopolysaccharide (LPS)-induced Toll-like receptors (TLRs), cytokines, and inducible nitric oxide synthase (iNOS) in human melanocytes, and the involvement of nuclear transcription factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Methods: Normal human melanocytes were pretreated with activin A before exposure to LPS. Total RNAs were purified and real-time PCR was performed. Also we conducted immunoblot analysis to know the expression levels of proteins. Results: LPS increased mRNA expressions of TLRs (1-10) and cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α), and enhanced mRNA and protein expression of iNOS. Activin inhibited LPS-induced mRNA expressions of TLRs and cytokines, and decreased mRNA and protein expression of LPS-induced iNOS. Also activin suppressed NF-κB p65 activation and blocked IκBα degradation in LPS-stimulated melanocytes, and reduced LPS-induced p38 MAPK and MEK/ERK activations. Conclusion: Activin inhibited expression of genes of TLRs, cytokines, and iNOS in LPS-activated normal human melanocytes. Moreover, anti-inflammatory effect of activin was mediated through suppressing activation of NF-κB and MAPKs signaling pathways in LPS-activated normal human melanocytes, resulting in reduced expression of TLRs, cytokines, and nitric oxide.

The Free Radical Scavenger NecroX-7 Attenuates Acute Graft-versus-Host Disease via Reciprocal Regulation of Th1/Regulatory T Cells and Inhibition of HMGB1 Release

Im, Keon-Il,Kim, Nayoun,Lim, Jung-Yeon,Nam, Young-Sun,Lee, Eun-Sol,Kim, Eun-Jung,Kim, Hyoung Jin,Kim, Soon Ha,Cho, Seok-Goo The American Association of Immunologists, Inc. 2015 JOURNAL OF IMMUNOLOGY Vol.194 No.11

<P>Graft-versus-host disease (GVHD) is a major complication associated with allogeneic hematopoietic stem cell transplantation. Despite the prominent role of the adaptive immune system, the importance of controlling the innate immune system in the pathogenesis of GVHD has recently been rediscovered. High-mobility group box 1 (HMGB1) is a crucial damage-associated molecular pattern signal that functions as a potent innate immune mediator in GVHD. In the present study, we investigated treatment of experimental GVHD through HMGB1 blockade using the compound cyclopentylamino carboxymethylthiazolylindole (NecroX)-7. Treated animals significantly attenuated GVHD-related mortality and inhibited severe tissue damage. These protective effects correlated with the decrease in HMGB1 expression and lower levels of reactive oxidative stress. Additionally, NecroX-7 inhibited the HMGB1-induced release of TNF and IL-6, as well as the expression of TLR-4 and receptor for advanced glycation end products. We also observed increased regulatory T cell numbers, which may be associated with regulation of differentiation signals independent of HMGB1. Taken together, these data indicate that NecroX-7 protects mice against lethal GVHD by reciprocal regulation of regulatory T/Th1 cells, attenuating systemic HMGB1 accumulation and inhibiting HMGB1-mediated inflammatory response. Our results indicate the possibility of a new use for a clinical drug that is effective for the treatment of GVHD.</P>

疎風活血湯이 Monosodium Iodoacetate로 유발한 흰쥐의 골관절염 억제에 미치는 영향

김대형 ( Dae Hyoung Kim ),정수현 ( Su Hyeon Jeong ),서일복 ( Il Bok Seo ),김순중 ( Soon Joong Kim ) 한방재활의학과학회 2011 한방재활의학과학회지 Vol.21 No.1

Objectives: This study was to investigate the suppression effects of Sopunghwalhyeol-tang(Shufenghuoxie-tang) on the monosodium iodoacetate-induced osteoarthritis in rats. Methods: Arthritis was induced by injection of monosodium iodoacetate(0.5 mg) into the both knee joints of rats. Arthritic rats were divided into control(n=8) and treated(n=8) group. Control group was taken distilled water for 20 days. Treated group was taken extracts of Sopunghwalhyeol-tang(Shufenghuoxie-tang) by oraly for same duration. Normal group(n=8) was injected with normal saline and was taken distilled water for 20 days. Macroscopic examination and histopathological study on articular cartilage of knee joint were operated at 20 days after injection. Proteoglycan(PG) content of articular cartilages of knee joint was represented by safranine O staining, was measured at 20 days after injection. Tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), in synovial fluid were measured with enzyme-linked immuno sorbent assay(ELISA) kit at 20 days after injection. Immunohistochemical staining of cyclo-oxygenase-2(COX-2), inducible nitric oxide synthase(iNOS) in knee joints were observed at 20 days after injection. Results: 1. Lymphocytes in peripheral blood the treated group was significantly decreased compared with the control group. 2. PG content in articular cartilage of the treated group was significantly increased compared with the control group. 3. Histopathologically, osteoarthritic scores of the treated group was significantly decreased compared with the control group. 4. TNF-α content in synovial fluid of the treated group was significantly decreased compared with the control group. 5. COX-2 revelation index in chondrocytes and synovial membrane of the treated group was significantly decreased compared with the control group. 6. Matrix metalloproteinase-3(MMP-3) revelation index in chondrocytes and synovial membrane of the treated group was significantly decreased compared with the control group. Conclusions :On the basis of these results, we concluded that Sopunghwalhyeol-tang(Shufenghuoxie-tang) has inhibiting effects on the TNF-α, COX-2 and MMP-3 secretion of chondrocytes and synovial membrane in Monosodium Iodoacetate-induced osteoarthritis model of rats.

Antiviral activity of gemcitabine against human rhinovirus in vitro and in vivo

Song, Jae-Hyoung,Kim, Seong-Ryeol,Heo, Eun-Young,Lee, Jae-Young,Kim, Dong-eun,Cho, Sungchan,Chang, Sun-Young,Yoon, Byung-Il,Seong, Jeongmin,Ko, Hyun-Jeong ELSEVIER 2017 ANTIVIRAL RESEARCH Vol.145 No.-

<P>Rhinovirus, a major causative agent of the common cold, is associated with exacerbation of asthma and chronic obstructive pulmonary disease. Currently, there is no antiviral treatment or vaccine for human rhinovirus (HRV). Gemcitabine (2',2'-difluorodeoxycytidine, dFdC) is a deoxycytidine analog with antiviral activity against rhinovirus, as well as enterovirus 71, in vitro. However, the antiviral effects of gemcitabine in vivo have not been investigated. In the current study, we assessed whether gemcitabine mediated antiviral effects in the murine HRV infection model. Intranasal administration of gemcitabine significantly lowered pulmonary viral load and inflammation by decreasing proinflammatory cytokines, including TNE-alpha and IL-1 beta, and reduction in the number of lung-infiltrating lymphocytes. Interestingly, we found that the addition of UTP and CTP significantly attenuated the antiviral activity of gemcitabine. Thus the limitation of UTP and CTP by the addition of gemcitabine may inhibit the viral RNA synthesis. These results suggest that gemcitabine, an antineoplastic drug, can be repositioned as an antiviral drug to inhibit HRV infection. (C) 2017 Elsevier B.V. All rights reserved.</P>

Fermented Herbal Formulas KIOM-MA128 Ameliorate IL-6-Induced Intestinal Barrier Dysfunction in Colon Cancer Cell Line

Park, Kwang Il,Kim, Dong Gun,Lee, Bo Hyoung,Ma, Jin Yeul Hindawi Publishing Corporation 2016 MEDIATORS OF INFLAMMATION Vol.2016 No.-

<P>Inflammatory bowel disease (IBD) comprises Crohn's disease (CD) and ulcerative colitis (UC). IBD increases the risk of colorectal cancer (CRC), depending on the extent and duration of intestinal inflammation. Increased IL-6 expression has been reported in IBD patients, which may be associated with intestinal barrier function through discontinuous tight junction (TJ). KIOM-MA is a specific agent for allergic diseases and cancer, and it is composed of several plants; these herbs have been used in traditional oriental medicine. We fermented KIOM-MA, the product of KIOM-MA128, using probiotics to improve the therapeutic efficacy via the absorption and bioavailability of the active ingredients. In this study, we demonstrated that KIOM-MA/MA128 exhibited anticolitis effects via the modulation of TJ protein. Interleukin-6 resulted in a dose-dependent decrease in the TER and an increase in the FITC-dextran permeability; however, pretreatment with 400 <I>µ</I>g/ml KIOM-MA/MA128 resulted in a significant increase in the TER and a decrease in the FITC-dextran permeability via IL-6 induction. Furthermore, protein and mRNA TJ levels remained stable after pretreatment with 400 <I>µ</I>g/ml KIOM-MA/MA128. Moreover, KIOM-MA/MA128 suppressed the expression of PLC<I>γ</I>1 and PKC. Taken together, these findings suggest novel information and clue of the anticolitis effects of KIOM-MA128 via regulation of tight junction.</P>

세치제 평가에 있어서 변형실험치은염모형의 안전성

황수정 ( Soo Jeong Hwang ),백대일 ( Dai Il Paik ),김현덕 ( Hyun Duck Kim ),진보형 ( Bo Hyoung Jin ),배광학 ( Kwang Hak Bae ),김남희 ( Nam Hee Kim ) 대한예방치과·구강보건학회 2010 大韓口腔保健學會誌 Vol.34 No.2

연구목적. 일부 연구자들은 치은염 예방 또는 치료 성분이 포함되어 있는 특수세치제의 치은염 억제 효과를 입증하기 위하여 Loe의 실험치은염모형을 변형한 변형실험치은염 모형을 사용하고 있으나, 변형실험치은염모형에 대한 안전성 검토는 미비한 상태이다. 따라서, 본 연구는 3주간 구강분할동시현상비교연구법(split mouth method)을 사용하여 변형실험치은염모형의 안전성을 검토하고 치은염의 일부 기구를 알아보고자 하였다. 연구방법. 성인남자 59명을 대상으로 3주 동안 잇솔질시 잇솔질방지판과 세치제를 편측 소구치부위에 착용하여 기계적 잇솔질을 금지한 실험치은염을 발생시켜 잇솔질방지하악소구치부와 잇솔질허용하악소구치부의 치은염지수, 치면세균막지수, 치은열 구액내의 MMP-9의 농도, IL-1β의 농도를 비교 검토하였다. 연구결과. 잇솔질방지하악소구치부는 3주간의 실험기간동안 실험시작 후 2주차 때 치은염지수와 치면세균막지수가 가장 높았으며 시간에 따라 차이변화가 유의하였으며(p<0.02) 실험 종료 후 초기상태로 회복되었다. 3주간의 실험기간동안 잇솔질방지하악 소구치부와 잇솔질허용하악소구치부 사이에서는 치은열구액내 염증지표인 MMP-9의 농도변화는 유의하지 않았고 염증전단계지표인 IL-1β의 농도변화는 유의하였으나(p=0.03) 잇솔질방지하악소구치부의 MMP-9의 농도와 IL-1β의 농도는 유의한 상관 관계를 보였다. 결론. 잇솔질방지하악소구치부내 MMP-9의 농도는 유의하게 변화하지 않았으므로 치은의 직접적인 파괴는 나타나지 않은 것으로 사료되어 변형실험치은염모형은 세치제의 효과를 평가함에 있어 안전한 모형으로 사료되었다.