IL-12-STAT4-IFN-${\gamma}$ axis is a key downstream pathway in the development of IL-13-mediated asthma phenotypes in a Th2 type asthma model

Kim, You-Sun,Choi, Seng-Jin,Choi, Jun-Pyo,Jeon, Seong-Gyu,Oh, Sun-Young,Lee, Byung-Jae,Gho, Yong-Song,Lee, Chun-Geun,Zhu, Zhou,Elias, Jack A.,Kim, Yoon-Keun Korean Society for Biochemistry and Molecular Bion 2010 Experimental and molecular medicine Vol.42 No.8

IL-4 and IL-13 are closely related cytokines that are produced by Th2 cells. However, IL-4 and IL-13 have different effects on the development of asthma phenotypes. Here, we evaluated downstream molecular mechanisms involved in the development of Th2 type asthma phenotypes. A murine model of Th2 asthma was used that involved intraperitoneal sensitization with an allergen (ovalbumin) plus alum and then challenge with ovalbumin alone. Asthma phenotypes, including airway- hyperresponsiveness (AHR), lung inflammation, and immunologic parameters were evaluated after allergen challenge in mice deficient in candidate genes. The present study showed that methacholine AHR and lung inflammation developed in allergen-challenged IL-4-deficient mice but not in allergen-challenged IL-13-deficient mice. In addition, the production of OVA-specific IgG2a and IFN-${\gamma}$-inducible protein (IP)-10 was also impaired in the absence of IL-13, but not of IL-4. Lung-targeted IFN-${\gamma}$ over-expression in the airways enhanced methacholine AHR and non-eosinophilic inflammation; in addition, these asthma phenotypes were impaired in allergen-challenged IFN-${\gamma}$-deficient mice. Moreover, AHR, non-eosinophilic inflammation, and IFN-${\gamma}$ expression were impaired in allergen- challenged IL-$12R{\beta}2$- and STAT4-deficient mice; however, AHR and non-eosinophilic inflammation were not impaired in allergen-challenged IL-$4R{\alpha}$-deficient mice, and these phenomena were accompanied by the enhanced expression of IL-12 and IFN-${\gamma}$. The present data suggest that IL-13-mediated asthma phenotypes, such as AHR and non-eosinophilic inflammation, in the Th2 type asthma are dependent on the IL-12-STAT4-IFN-${\gamma}$ axis, and that these asthma phenotypes are independent of IL-4Ralpha-mediated signaling.

IL-12-STAT4-IFN-γ axis is a key downstream pathway in the development of IL-13-mediated asthma phenotypes in a Th2 type asthma model

You-Sun Kim,Seng-Jin Choi,Jun-Pyo Choi,전성규,이병재,고용송,이춘근,Jack A. Elias,Yoon-Keun Kim,Sun-Young Oh,Zhou Zhu 생화학분자생물학회 2010 Experimental and molecular medicine Vol.42 No.8

IL-4 and IL-13 are closely related cytokines that are produced by Th2 cells. However, IL-4 and IL-13 have different effects on the development of asthma phenotypes. Here, we evaluated downstream molecular mechanisms involved in the development of Th2 type asthma phenotypes. A murine model of Th2 asthma was used that involved intraperitoneal sensitization with an allergen (ovalbumin) plus alum and then challenge with ovalbumin alone. Asthma phenotypes, including airway-hyperresponsiveness (AHR), lung inflammation,and immunologic parameters were evaluated after allergen challenge in mice deficient in candidate genes. The present study showed that methacholine AHR and lung inflammation developed in allergen-challenged IL-4-deficient mice but not in allergen-challenged IL-13-deficient mice. In addition, the production of OVA-specific IgG2a and IFN-γ-inducible protein (IP)-10was also impaired in the absence of IL-13, but not of IL-4. Lung-targeted IFN-γ over-expression in the airways enhanced methacholine AHR and non-eosinophilic inflammation; in addition, these asthma phenotypes were impaired in allergen-challenged IFN-γ-deficient mice. Moreover, AHR, non-eosinophilic inflammation,and IFN-γ expression were impaired in allergen-challenged IL-12Rβ2- and STAT4-deficient mice; however, AHR and non-eosinophilic inflammation were not impaired in allergen-challenged IL-4Rα-deficient mice, and these phenomena were accompanied by the enhanced expression of IL-12 and IFN-γ. The present data suggest that IL-13-mediated asthma phenotypes, such as AHR and non-eosinophilic inflammation, in the Th2 type asthma are dependent on the IL-12-STAT4-IFN-γ axis, and that these asthma phenotypes are independent of IL-4Ralpha-mediated signaling.

Nitrosation Products of N-Acyl-$N^{\prime}$-Substituted Phenylhydrazines

Jack C. Kim,Sun-Hong Han Korean Chemical Society 1994 Bulletin of the Korean Chemical Society Vol.15 No.2

Symposium 7 : Immunology & Virology ; Human Monoclonal Antibodies Derived from Phage Display Neutralize Hepatitis A Virus

( Sang Jick Kim ),( Myung Hee Jang ),( Jack T. Stapleton ),( Sun Ok Yoon ),( Eun Seok Jeon ),( Hyo Jeong Hong ) 한국생화학분자생물학회 (구 한국생화학회) 2002 생화학분자생물학회 춘계학술발표논문집 Vol.2002 No.-

Cytotoxic Phenylpropanoids from the Rhizomes of Alpinia galanga

Nam, Joo-Won,Kim, Sun-Jack,Han, Ah-Reum,Lee, Sang-Kook,Seo, Eun-Kyoung 이화여자대학교 약학연구소 2005 藥學硏究論文集 Vol.- No.15

A bioassay-guided fractionation of the n-hexane and chloroform extracts of the rhizomes of Alpinia galanga led to the isolation of two active compounds, l'S-l-acetoxychavicol acetate (1) and p-coumaryl alcohol τ-O-methyl ehter (2). 1'S'-1-acetoxychavicol acetate (1) exhibited significant cytotoxicity against all human cancer cell lines tested (A549; 8.14, SNU638; 1.27, HCT16; 1.77, HT1080; 1.2, HL60; IC50 2.39 μg/ml), whereas p-coumaryl alcohol τ-O0methyl ether (2) showed selective cytotoxicity against the SNU638 cell (IC_(50) value of 1.62μg/ml).

Cytotoxic Phenylpropanoids from the Rhizomes of Alpinia galanga

( Joo Won Nam ),( Sun Jack Kim ),( Ah Reum Han ),( Sang Kook Lee ),( Eun Kyoung Seo ) 한국응용약물학회 2005 Biomolecules & Therapeutics(구 응용약물학회지) Vol.13 No.4

형태가 고정된 ${\beta}$-아미노케톤의 탈케탈화 (반응) 의 연구

김정균,이용태,윤웅찬,조인섭,문성환,한선홍,Jack C. Kim,Yong Tae Lee,Ung Chan Yoon,In-Seop Cho,Sung Hwan Moon,Sun Hong Han 대한화학회 1988 대한화학회지 Vol.32 No.6

구조 형태가 고정된 ${\beta}$-아미노 케탈의 탈케탈화 실패요인으로서, 반응 중간체의 정전기적 반발, 구조상 특징에 의한 전이상태의 각스트레인의 증가, 그리고 고정된 구조형태에서 오는 물분자의 $SN_2$ 형태공격의 입체적 차단에 의한 것으로 추정하고 그들 요인의 중요성을 분리 평가하였다. 2-에틸렌디옥시-1-아세나프테닐아민, N-(2-에틸렌디옥시-1-아세나프테닐)아세트 아미드, 그리고 트리메틸-2-에틸렌디옥시-1-아세나프테닐암모니움 요오드를 합성하여 그들의 탈케탈화 반응을 검토함으로서 이중 양이온의 정전기적 반발요인에 의한 실패요인 정도를 평가하였다. ${\beta}$-아미노기에 전자흡인기인 아세틸기를 넣어 아미노기의 양성자화 정도를 감소시킴으로서 탈케탈화를 용이하게 일으킬 수 있었다. 이 결과는 정전기적 반발요인이 ${\beta}$-아미노 케탈화의 탈케탈화 방해요인으로 매우 중요하게 작용하고 있음을 보여준다. 그리고 구조상 특징에 의한 방해요인을 검토하기 위해 구조형태가 고정되지 않은 ${\beta}$-아미노케탈, 2-아미노-1-에틸렌디옥시아세토페논과 아미노아세탈, 디메틸 아미노 포름알데히드 디메틸아세탈과 2-아미노아세트알데히드 디메틸아세탈의 탈케탈화 및 탈아세탈화 용이도를 검토한 결과 용이하게 탈아세탈화되었다. 이 결과는 구조상 특징에 의한 요인도 매우 중요함을 보여준다. The causes of failure in the deketalization of rigid ${\beta}$-aminoketals were separately investigated by examining the deketalization of 3 ketals, 2-ethylenedioxy-l-acenaphthenylamine (2), N-(2-ethylenedioxy-l-acenaphthenyl)acetamide(13) and trimethyl-2-ethylenedioxy-1-acenaphthenylammonium iodide(14), and by examining the deketalization of non-rigid ${\beta}$-aminoketal, 2-amino-l-ethylenedioxyacetophenone(19) and non-rigid aliphatic acetals, dimethylaminoformaldehyde dimethylacetal (20) and 2-aminoactaldehyde dimethyl acetal(21). While compounds 2 and 14 were not able to be hydrolyzed in the various acidic conditions 13 was easily deketalized. The result indicated the importance of electrostatic repulsion in the possible dicationic intermediates as a factor of failure in the deketalization. The observations of easy deketalization of compounds 19, 20 and 21 indicated that the structural characters of rigid $\beta-aminoketals$ are also important factors in the hydrolysis of ${\beta}$-aminoketals.

5-Fluorouracil-1-yl-3-butanone의 항암제 내성 극복에 관한 연구

서보정,허경,강치덕,김선희,정병선,김정균 부산대학교 유전공학연구소 1994 분자생물학 연구보 Vol.10 No.-

암화학요법에 대한 암세포의 약제내성을 극복하기 위한 하나의 방법으로 항암제와 그 유사체의 병용에 의한 항종양 활성의 향상이 시도되고 있다. 5-FU는 유암, 자궁암,위암 등에 사용되고 있는 fluorinated pyrimidine계 항암제이나, 암세포의 5-FU에 대한 내성이 치료에 장애가 되고 있다. 5-FU의 항종양 활성의 향상과 내성극복을 위하여 5종의 5-FU 유도체에 대하여 MTT방법으로 5-FU와의 병용에 의하여 5-FU의 활성증강을 시키는 물질을 조사한 바, 신합성물질인 5-Fouirouracil-1-yl-3-butanone(5-FUBO)에 의한 5-FU의 세포독성 증강효과가 5-FU에 감수성인 암세포에서 보다 내성인 암세포에서 병용효과가 높았으며, 5-FU뿐만아니라 임상적으로 사용되고 있는 항암제인 VCR, VBL과의 병용효과를 나타내는 흥미있는 현상을 발견하였다. 이 합성물질에 의한 VCR 내성극복은 항암제 다제내성세포를 사용하여 조사한 바, VCR과 상기의 합성물질인 5-FUBO(o.1㎍/㎖)의 병용에 의한 VCR 내성극복 정도는 다제내성도가 낮은 암세포에서는 2.4배를 나타내었으며 다제내성도가 높은 세포에서는 11배로서 그 효과가 현저히 높은 것으로 확인하였다. 이와 같이 5-FUBO는 5-FU뿐만 아니라 vinca alkaloid계 항암제인 VCR, VBL과의 병용효과를 나타내는 매우 흥미있는 합성물질로서, 이 물질이 항암제 다제내성 변이주에서 발현하는 MDR1 유전자의 발현을 농도의존적으로 억제하였다. The potentiation effect of anticancer agents by their analogues is one of the possible strstergies for overcoming cellular resistance to chemotherapy. 5-Fouirouracil(5-FU)is a fluorinated pyrimidine which has been used in the treatment of gastrointestinal, breast and ovarian cancers. In attempts to improve the efficasy of 5-FU and overcome 5-FU resistance, We enaluated the sensitizing effect om 5-FU-induced cytotoxicity of various newly synthesized 5-FU derivatives by means of a colormetric MTT assay. 5-Fouirouracil-1-yl-3-butanone(5-FUBO), a newly synthesized 5-FU derivative, potentiates the cytotoxicity of 5-FU in 5-FU resistant mutant to a greater extent than drug-sensitive parental cells. Also, it potentiates the cytotoxic activity of clinically useful antitumor agents such as vincristine(VCR) and vinblastine(VBL). Overcoming by VCR resistance by 5-FUBO was investigated by using multidrug resistant (MDR) cells, VCR cytotoxicity was potentiated 2.4 fold in low-grade MDR cells compared with parental cells by 5-FUBO at o.1㎍/㎖ . In MDR P388(P388/M) cells, 5-FUBO gene inhibited the epression of MDR1 gene in dose-dependent manner. It may be noteworthy the cytotoxicity of structurally different anticancer agents were more potentiated drug resistant mutant to a greater extent than the parental cells.

Growth inhibition and cell cycle arrest of schizandrin in T47D human breast cancer cells

LEE Sang Kook,KANG Sam Sik,BAE KiHwan,KIM Yeong Shik,YOUN Ui Jung,HUNG Tran Manh,KIM Sun-Jack 大韓藥學會 2006 大韓藥學會 總會 및 學術大會 Vol.2006 No.2

Association between genetic variations of vascular endothelial growth factor receptor 2 and atopy in the Korean population

Park, Heung-Woo,Lee, Jong-Eun,Shin, Eun-Soon,Lee, Jae-Young,Bahn, Joon-Woo,Oh, Heung-Bum,Oh, Sun-Young,Cho, Sang-Heon,Moon, Hee-Bum,Min, Kyung-Up,Elias, Jack A.,Kim, You-Young,Kim, Yoon-Keun Elsevier 2006 The journal of allergy and clinical immunology Vol.117 No.4

<P><B>Background</B></P><P>Vascular endothelial growth factor (VEGF) has been suggested to be a key mediator in the development of atopy and T<SUB>H</SUB>2 inflammation.</P><P><B>Objective</B></P><P>We sought to evaluate the effects of variations in the gene coding VEGF receptor (VEGFR) 2 on intermediate phenotypes of asthma in the Korean population.</P><P><B>Methods</B></P><P>A cohort of 2055 children and adolescents responded to a questionnaire concerning asthma symptoms and risk factors and underwent methacholine bronchial challenge and skin tests. The <I>VEGFR2</I> gene, including the promoter area, was sequenced on 24 healthy subjects to discover informative single nucleotide polymorphisms (SNPs; minor allele frequency >2%). After haplotype reconstruction, 4 tagging SNPs (IVS6+54A>G, +889G>A, +1416T>A, and IVS25-92G>A) were scored. These SNPs were also scored in 480 adult asthmatic patients to verify the above genetic association study.</P><P><B>Results</B></P><P>The prevalence of atopy was associated with a single SNP (+889G>A) of VEGFR2 with borderline significance (<I>P</I> = .048; relative risk, 1.13; 95% CI, 1.00-1.28). However, haplotype analysis showed that the atopy prevalence was strongly associated with a haplotype (AGAG) of VEGFR2 (<I>P</I> = .002; relative risk, 1.25; 95% CI, 1.09-1.42). As for airway hyperresponsiveness, neither individual SNPs nor haplotypes were found to be associated. Interestingly, the significant association was also found between atopy and the AGAG haplotype among adult asthmatic patients (<I>P</I> = .008; odds ratio, 1.66; 95% CI, 1.14-2.44).</P><P><B>Conclusions</B></P><P>The present study demonstrated that genetic variations of VEGFR2 are significantly associated with atopy in the Korean population.</P>