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You, Sungyong,Yoo, Seung-Ah,Choi, Susanna,Kim, Ji-Young,Park, Su-Jung,Ji, Jong Dae,Kim, Tae-Hwan,Kim, Ki-Jo,Cho, Chul-Soo,Hwang, Daehee,Kim, Wan-Uk National Academy of Sciences 2014 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.111 No.1
<P>Rheumatoid synoviocytes, which consist of fibroblast-like synoviocytes (FLSs) and synovial macrophages (SMs), are crucial for the progression of rheumatoid arthritis (RA). Particularly, FLSs of RA patients (RA-FLSs) exhibit invasive characteristics reminiscent of cancer cells, destroying cartilage and bone. RA-FLSs and SMs originate differently from mesenchymal and myeloid cells, respectively, but share many pathologic functions. However, the molecular signatures and biological networks representing the distinct and shared features of the two cell types are unknown. We performed global transcriptome profiling of FLSs and SMs obtained from RA and osteoarthritis patients. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining invasiveness of RA-FLSs and proinflammatory properties of RA-SMs, respectively. Interestingly, under the interleukin-1β (IL-1β)–stimulated condition, the RA-FLSs newly acquired proinflammatory signature dominant in RA-SMs without losing invasive properties. We next reconstructed a network model that delineates the shared, RA-FLS–dominant (invasive), and RA-SM–dominant (inflammatory) processes. From the network model, we selected 13 genes, including periostin, osteoblast-specific factor (POSTN) and twist basic helix–loop–helix transcription factor 1 (TWIST1), as key regulator candidates responsible for FLS invasiveness. Of note, POSTN and TWIST1 expressions were elevated in independent RA-FLSs and further instigated by IL-1β. Functional assays demonstrated the requirement of POSTN and TWIST1 for migration and invasion of RA-FLSs stimulated with IL-1β. Together, our systems approach to rheumatoid synovitis provides a basis for identifying key regulators responsible for pathological features of RA-FLSs and -SMs, demonstrating how a certain type of cells acquires functional redundancy under chronic inflammatory conditions.</P>
Lee, Naeun,You, Sungyong,Shin, Min Sun,Lee, Won-Woo,Kang, Ki Soo,Kim, Sang Hyun,Kim, Wan-Uk,Homer, Robert J,Kang, Min-Jong,Montgomery, Ruth R,Dela Cruz, Charles S,Shaw, Albert C,Lee, Patty J,Chupp, Ge American Lung Association 2014 American journal of respiratory and critical care Vol.190 No.12
<P>Cytokine receptors can be markers defining different T-cell subsets and considered as therapeutic targets. The association of IL-6 and IL-6 receptor 관 (IL-6R관) with asthma was reported, suggesting their involvement in asthma.</P>
Transcription factor NFAT5 promotes macrophage survival in rheumatoid arthritis
Choi, Susanna,You, Sungyong,Kim, Donghyun,Choi, Soo Youn,Kwon, H. Moo,Kim, Hyun-Sook,Hwang, Daehee,Park, Yune-Jung,Cho, Chul-Soo,Kim, Wan-Uk American Society for Clinical Investigation 2017 The Journal of clinical investigation Vol.127 No.3
<P>Defective apoptotic death of activated macrophages has been implicated in the pathogenesis of rheumatoid arthritis (RA). However, the molecular signatures defining apoptotic resistance of RA macrophages are not fully understood. Here, global transcriptome profiling of RA macrophages revealed that the osmoprotective transcription factor nuclear factor of activated T cells 5 (NFAT5) critically regulates diverse pathologic processes in synovial macrophages including the cell cycle, apoptosis, and proliferation. Transcriptomic analysis of NFAT5-deficient macrophages revealed the molecular networks defining cell survival and proliferation. Proinflammatory M1-polarizing stimuli and hypoxic conditions were responsible for enhanced NFAT5 expression in RA macrophages. An in vitro functional study demonstrated that NFAT5-deficient macrophages were more susceptible to apoptotic death. Specifically, CCL2 secretion in an NFAT5-dependent fashion bestowed apoptotic resistance to RA macrophages in vitro. Injection of recombinant CCL2 into one of the affected joints of Nfat5+/-mice increased joint destruction and macrophage infiltration, demonstrating the essential role of the NFAT5/CCL2 axis in arthritis progression in vivo. Moreover, after intra-articular injection, NFAT5-deficient macrophages were more susceptible to apoptosis and less efficient at promoting joint destruction than were NFAT5-sufficient macrophages. Thus, NFAT5 regulates macrophage survival by inducing CCL2 secretion. Our results provide evidence that NFAT5 expression in macrophages enhances chronic arthritis by conferring apoptotic resistance to activated macrophages.</P>
Choi, Bo-Hwa,You, Sungyong,Park, Chang-Shin,Cho, Eun-Ho,Park, Taeeun D.,Kim, Sungsoo,Kim, Young-Ju,Lee, Tack,Kim, Jayoung Landes Bioscience 2017 Cell Cycle Vol.16 No.8
<P>Interstitial cystitis (IC) is a chronic bladder dysfunction characterized as urinary frequency, urgency, nocturia, and pelvic pain. The changes in urethra may wind up with the bladder changes in structure and functions, however, the functions of the urethra in IC remains elusive. The aim of this study was to understand the perturbed gene expression in urethra, compared with urinary bladder, associated with the defected urodynamics. Using female IC mimic rats, a comprehensive RNA-sequencing combined with a bioinformatics analysis was performed and revealed that IC-specific genes in bladder or urethra. Gene ontology analysis suggested that the cell adhesion or extracellular matrix regulation, intracellular signaling cascade, cardiac muscle tissue development, and second messenger-mediated signaling might be the most enriched cellular processes in IC context. Further study of the effects of these bladder- or urethra-specific genes may suggest underlying mechanism of lower urinary tract function and novel therapeutic strategies against IC.</P>
MicroRNA-143 and -145 modulate the phenotype of synovial fibroblasts in rheumatoid arthritis
Hong, Bong-Ki,You, Sungyong,Yoo, Seung-Ah,Park, Dohyun,Hwang, Daehee,Cho, Chul-Soo,Kim, Wan-Uk Nature Publishing Group 2017 Experimental and molecular medicine Vol.49 No.8
<P>Fibroblast-like synoviocytes (FLSs) constitute a major cell subset of rheumatoid arthritis (RA) synovia. Dysregulation of microRNAs (miRNAs) has been implicated in activation and proliferation of RA-FLSs. However, the functional association of various miRNAs with their targets that are characteristic of the RA-FLS phenotype has not been globally elucidated. In this study, we performed microarray analyses of miRNAs and mRNAs in RA-FLSs and osteoarthritis FLSs (OA-FLSs), simultaneously, to validate how dysregulated miRNAs may be associated with the RA-FLS phenotype. Global miRNA profiling revealed that miR-143 and miR-145 were differentially upregulated in RA-FLSs compared to OA-FLSs. miR-143 and miR-145 were highly expressed in independent RA-FLSs. The miRNA-target prediction and network model of the predicted targets identified insulin-like growth factor binding protein 5 (IGFBP5) and semaphorin 3A (SEMA3A) as potential target genes downregulated by miR-143 and miR-145, respectively. IGFBP5 level was inversely correlated with miR-143 expression, and its deficiency rendered RA-FLSs more sensitive to TNFα stimulation, promoting IL-6 production and NF-κB activity. Moreover, SEMA3A was a direct target of miR-145, as determined by a luciferase reporter assay, antagonizing VEGF<SUB>165</SUB>-induced increases in the survival, migration and invasion of RA-FLSs. Taken together, our data suggest that enhanced expression of miR-143 and miR-145 renders RA-FLSs susceptible to TNFα and VEGF<SUB>165</SUB> stimuli by downregulating IGFBP5 and SEMA3A, respectively, and that these miRNAs could be therapeutic targets.</P>
A novel pathogenic role of the ER chaperone GRP78/BiP in rheumatoid arthritis
Yoo, Seung-Ah,You, Sungyong,Yoon, Hyung-Ju,Kim, Dong-Ho,Kim, Hyun-Sook,Lee, Kyungho,Ahn, Jin Hee,Hwang, Daehee,Lee, Amy S.,Kim, Ki-Jo,Park, Yune-Jung,Cho, Chul-Soo,Kim, Wan-Uk The Rockefeller University Press 2012 The Journal of experimental medicine Vol.209 No.4
<▼1><P>The ER chaperone GRP78/BiP is crucial for the development of rheumatoid arthritis.</P></▼1><▼2><P>An accumulation of misfolded proteins can trigger a cellular survival response in the endoplasmic reticulum (ER). In this study, we found that ER stress–associated gene signatures were highly expressed in rheumatoid arthritis (RA) synoviums and synovial cells. Proinflammatory cytokines, such as TNF and IL-1β, increased the expression of GRP78/BiP, a representative ER chaperone, in RA synoviocytes. RA synoviocytes expressed higher levels of GRP78 than osteoarthritis (OA) synoviocytes when stimulated by thapsigargin or proinflammatory cytokines. Down-regulation of <I>Grp78</I> transcripts increased the apoptosis of RA synoviocytes while abolishing TNF- or TGF-β–induced synoviocyte proliferation and cyclin D1 up-regulation. Conversely, overexpression of the <I>Grp78</I> gene prevented synoviocyte apoptosis. Moreover, <I>Grp78</I> small interfering RNA inhibited VEGF<SUB>165</SUB>-induced angiogenesis in vitro and also significantly impeded synoviocyte proliferation and angiogenesis in Matrigel implants engrafted into immunodeficient mice. Additionally, repeated intraarticular injections of BiP-inducible factor X, a selective GRP78 inducer, increased synoviocyte proliferation and angiogenesis in the joints of mice with experimental OA. In contrast, mice with <I>Grp78</I> haploinsufficiency exhibited the suppression of experimentally induced arthritis and developed a limited degree of synovial proliferation and angiogenesis. In summary, this study shows that the ER chaperone GRP78 is crucial for synoviocyte proliferation and angiogenesis, the pathological hallmark of RA.</P></▼2>
Wen, He,Lee, Tack,You, Sungyong,Park, Soo-Hwan,Song, Hosook,Eilber, Karyn S.,Anger, Jennifer T.,Freeman, Michael R.,Park, Sunghyouk,Kim, Jayoung American Chemical Society 2015 JOURNAL OF PROTEOME RESEARCH Vol.14 No.1
<P/><P>Interstitial cystitis/painful bladder syndrome (IC) is a chronic syndrome of unknown etiology that presents with bladder pain, urinary frequency, and urgency. The lack of specific biomarkers and a poor understanding of underlying molecular mechanisms present challenges for disease diagnosis and therapy. The goals of this study were to identify noninvasive biomarker candidates for IC from urine specimens and to potentially gain new insight into disease mechanisms using a nuclear magnetic resonance (NMR)-based global metabolomics analysis of urine from female IC patients and controls. Principal component analysis (PCA) suggested that the urinary metabolome of IC and controls was clearly different, with 140 NMR peaks significantly altered in IC patients (FDR < 0.05) compared to that in controls. On the basis of strong correlation scores, fifteen metabolite peaks were nominated as the strongest signature of IC. Among those signals that were higher in the IC group, three peaks were annotated as tyramine, the pain-related neuromodulator. Two peaks were annotated as 2-oxoglutarate. Levels of tyramine and 2-oxoglutarate were significantly elevated in urine specimens of IC subjects. An independent analysis using mass spectrometry also showed significantly increased levels of tyramine and 2-oxoglutarate in IC patients compared to controls. Functional studies showed that 2-oxoglutarate, but not tyramine, retarded growth of normal bladder epithelial cells. These preliminary findings suggest that analysis of urine metabolites has promise in biomarker development in the context of IC.</P>