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REVIEW : Modifiers of TGF-b1 effector function as novel therapeutic targets of pulmonary fibrosis
( Chang Min Lee ),( Jin Wook Park ),( Won Kyung Cho ),( Yang Zhou ),( Bo Ram Han ),( Pyoung Oh Yoon ),( Jei Wook Chae ),( Jack A Elias ),( And Chun Geun Lee ) 대한내과학회 2014 The Korean Journal of Internal Medicine Vol.29 No.3
Pulmonary fibrosis is a fatal progressive disease with no effective therapy. Transforminggrowth factor (TGF)-b1 has long been regarded as a central mediator oftissue fibrosis that involves multiple organs including skin, liver, kidney, and lung. Thus, TGF-b1 and its signaling pathways have been attractive therapeutic targetsfor the development of antifibrotic drugs. However, the essential biological functionsof TGF-b1 in maintaining normal immune and cellular homeostasis significantlylimit the effectiveness of TGF-b1-directed therapeutic approaches. Thus,targeting downstream mediators or signaling molecules of TGF-b1 could be an alternativeapproach that selectively inhibits TGF-b1-stimulated fibrotic tissue responsewhile preserving major physiological function of TGF-b1. Recent studiesfrom our laboratory revealed that TGF-b1 crosstalk with epidermal growth factorreceptor (EGFR) signaling by induction of amphiregulin, a ligand of EGFR, plays acritical role in the development or progression of pulmonary fibrosis. In addition,chitotriosidase, a true chitinase in humans, has been identified to have modulatingcapacity of TGF-b1 signaling as a new biomarker and therapeutic target of scleroderma-associated pulmonary fibrosis. These newly identified modifiers of TGF-b1effector function significantly enhance the effectiveness and flexibility in targetingpulmonary fibrosis in which TGF-b1 plays a significant role.
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>
Role of breast regression protein-39/YKL-40 in asthma and allergic responses
이춘근,Jack A Elias 대한천식알레르기학회 2010 Allergy, Asthma & Immunology Research Vol.2 No.1
BRP-39 and its human homolog YKL-40 have been regarded as a prototype of chitinase-like proteins (CLP) in mammals. Exaggerated levels of YKL-40 protein and/or mRNA have been noted in a number of diseases characterized by inflammation, tissue remodeling, and aberrant cell growth. Asthma is an inflammatory disease characterized by airway hyperresponsiveness and airway remodeling. Recently, the novel regulatory role of BRP-39/YKL-40 in the pathogenesis of asthma has been demonstrated both in human studies and allergic animal models. The levels of YKL-40 are increased in the circulation and lungs from asthmatics where they correlate with disease severity, and CHI3L1 polymorphisms correlate with serum YKL-40levels, asthma and abnormal lung function. Animal studies using BRP-39 null mutant mice demonstrated that BRP-39 was required for optimal allergen sensitization and Th2 inflammation. These studies suggest the potential use of BRP-39 as a biomarker as well as a therapeutic target for asthma and other allergic diseases. Here, we present an overview of chitin/chitinase biology and summarize recent findings on the role of BRP-39 in the pathogenesis of asthma and allergic responses
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.
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.
Chitinase 3-Like 1 Contributes to Food Allergy via M2 Macrophage Polarization
Eun Gyul Kim,김미나,홍정연,Jae Woo Lee,Soo Yeon Kim,김경원,이춘근,Jack A Elias,송태원,손명현 대한천식알레르기학회 2020 Allergy, Asthma & Immunology Research Vol.12 No.6
Purpose: Food allergy is a hypersensitive immune response to specific food proteins. Chitinase 3-like 1 (CHI3L1, also known as YKL-40 in humans or BRP-39 in mice) is associated with various chronic diseases, such as cancer, rheumatoid arthritis, and allergic disease. CHI3L1 is involved in allergen sensitization and type 2 helper T (Th2) inflammation, but the role of CHI3L1 in food allergy remains unclear. In this study, we sought to investigate the role of CHI3L1 in the development of food allergy. Methods: We measured serum levels of CHI3L1 in food allergic patients. Food allergy was induced in wild-type (WT) and CHI3L1 null mutant (CHI3L1−/−) BALB/c mice with ovalbumin (OVA). We investigated Th2 immune responses, M2 macrophage polarization, and mitogen-activated protein kinase (MAPK)/phosphoinositide 3-kinase (PI3K) signaling pathways, and also performed transcriptome analysis. Results: Serum levels of CHI3L1 were significantly higher in children with food allergy compared with those in healthy controls. Furthermore, CHI3L1 expression levels were elevated in WT mice after OVA treatment. Food allergy symptoms, immunoglobulin E levels, Th2 cytokine production, and histological injury were attenuated in food allergy-induced CHI3L1−/− mice compared with those in food allergy-induced WT mice. CHI3L1 expression was increased in OVA-treated WT intestinal macrophages and caused M2 macrophage polarization. Furthermore, CHI3L1 was involved in the extracellular signal-regulated kinases (ERK) and AKT signaling pathways and was associated with immune response and lipid metabolism as determined through transcriptome analysis. Conclusions: CHI3L1 plays a pivotal role in Th2 inflammation and M2 macrophage polarization through MAPK/ERK and PI3K/AKT phosphorylation in food allergy.