A Novel Small-Molecule Inhibitor Targeting the IL-6 Receptor β Subunit, Glycoprotein 130

Hong, Soon-Sun,Choi, Jung Ho,Lee, Sung Yoon,Park, Yeon-Hwa,Park, Kyung-Yeon,Lee, Joo Young,Kim, Juyoung,Gajulapati, Veeraswamy,Goo, Ja-Il,Singh, Sarbjit,Lee, Kyeong,Kim, Young-Kook,Im, So Hee,Ahn, Sun The American Association of Immunologists, Inc. 2015 JOURNAL OF IMMUNOLOGY Vol.195 No.1

<P>IL-6 is a major causative factor of inflammatory disease. Although IL-6 and its signaling pathways are promising targets, orally available small-molecule drugs specific for IL-6 have not been developed. To discover IL-6 antagonists, we screened our in-house chemical library and identified-LMT-28, a novel synthetic compound, as a candidate IL-6 blocker. The activity, mechanism of action, and direct molecular target of LMT-28 were investigated. A reporter gene assay showed that LMT-28 suppressed activation of STAT3 induced by IL-6, but not activation induced by leukemia inhibitory factor. In addition, LMT-28 downregulated IL-6-stimulated phosphorylation of STAT3, gp130, and JAK2 protein and substantially inhibited IL-6-dependent TF-1 cell proliferation. LMT-28 antagonized IL-6-induced TNF-alpha production in vivo. In pathologic models, oral administration of LMT-28 alleviated collagen-induced arthritis and acute pancreatitis in mice. Based on the observation of upstream IL-6 signal inhibition by LMT-28, we hypothesized IL-6, IL-6R alpha, or gp130 to be putative molecular targets. We subsequently demonstrated direct interaction of LMT-28 with gp130 and specific reduction of IL-6/IL-6R alpha complex binding to gp130 in the presence of LMT-28, which was measured by surface plasmon resonance analysis. Taken together, our data suggest that LMT-28 is a novel synthetic IL-6 inhibitor that functions through direct binding to gp130.</P>

The effects of BRL-50481 on ovalbumin-induced asthmatic lung infl ammation exacerbated by co-exposure to Asian sand dust in the murine model

Hong Jo Kim,Jin Yong Song,Tae Il Park,Won Seok Choi,Jong Heon Kim,Oh Seong Kwon,Ji-Yun Lee 대한약학회 2022 Archives of Pharmacal Research Vol.45 No.1

Asian sand dust (ASD), which mainly originatesin China and Mongolia in the spring and blows into Korea,can exacerbate respiratory and immunological diseases. This study aims to observe eff ects of co-exposure to ASD onovalbumin (OVA)-induced asthmatic lung infl ammation andof treatment with a phosphodiesterase 7 (PDE7) inhibitor ina mouse model. The challenge with OVA increased airwayhyperresponsiveness (AHR) and infl ammatory cell infi ltrationinto the lung tissue. Interleukin (IL)-13, tumor necrosisfactor-alpha, monocyte-protein-1, mucin, and antigen-specific IgE and IgG1 production increased in mouse serum. The co-exposure of ASD signifi cantly exacerbated theseeff ects in this asthma model. Notably, the administration ofa PDE7 inhibitor, BRL-50481 (BRL), signifi cantly reducedAHR, infi ltration of infl ammatory cells into the lungs, andthe levels of type 2 T helper cell-related cytokines, antigenspecific immunoglobulins, and mucin. Thus, the administrationof BRL ameliorated OVA-induced allergic asthmaticresponses exacerbated by co-exposure to ASD. This studysuggests that PDE7 inhibition can be a therapeutic strategyfor infl ammatory lung diseases and asthma via the regulation of T lymphocytes and reduction of IL-13, and, consequently,mucin production.

몇 가지 항균제가 시험관내에서 내독소와 TNF-α, IL-6 분비에 미치는 영향

최정현,문건웅,김명훈,이동건,박윤희,김상일,김태연,유진홍,김양리,신완식,강문원 대한화학요법학회 1997 대한화학요법학회지 Vol.15 No.2

To evaluate antibiotic-induced endotoxin release(AIER) and its correlation with some cytokines, we measured endotoxin level and tumor necrosis factor alpha(TNF-α) and interleukin6(IL-6) production in mononuclear cells in vitro after exposure of Pseudomonas aeruginosa to antibiotics belonging to different class with two extreme concentrations. The tested concetration of antibiotics were set up according to peak serum level. The low concetration of ceftazidirne and low concentration of imiperiem increased AIER, but high concentration of ceftazideme, high concentration of ciprofloxacin, high concentration of cefoperazone/sulbactam, high concentration of amikacin, and high concentration of meropenem reduced AIER.Interestingly, combined treatment of these antibiotics markedly reduced AIER, But the major cyotkines, TNF-α and IL-6 were not affect by type and concettration of antibiotics, combined treatment of antibiotics, and level of endotoxin released by antiboitics. In this study, we observed AIER was different according to type of antibiotics, concentration of antibiotics, and combination of antibiotics, But AIER had poor correlation with TNF-α and IL-6 in Pseudomonas aeruginosa. It suggests that cytokine release is not solely dependent to endotoxin, but more complex cascade is needed. More invesfigations, such as endotoxin induced cytokine mRNA expression, relationship with penicillin-binding proteins and endotoxin-neutralizing effect of antibiotic itself, must be performed.

Effects of the pro-inflammatory milieu on the dedifferentiation of cultured fibroblast-like synoviocytes

CHOI, HONG SEO,RYU, CHUN JEIH,CHOI, HYUN MI,PARK, JIN SUNG,LEE, JAE-HOON,KIM, KANG IL,YANG, HYUNG-IN,YOO, MYUNG CHUL,KIM, KYOUNG SOO D.A. Spandidos 2012 MOLECULAR MEDICINE REPORTS Vol.5 No.4

<P>The aim of this study was to determine whether the inflammatory milieu and/or hypoxia induces the dedifferentiation of synovial cells into mesenchymal stem-like cells, which may contribute to the tumor-like growth of synovial cells. Expression of mesenchymal stem cell markers (CD24, CD44, CD90, CD106, CD146 and Stro-1) was compared among cultured fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA) or osteoarthritis (OA), bone marrow mesenchymal stem cells (BM MSCs) and normal dermal fibroblasts. After the cells were stimulated with pro-inflammatory cytokines for 3 days under hypoxia or normoxia, the stem cell markers were analyzed by FACS. CD44 and CD90 were expressed constitutively in all four cell types. Only the BM MSCs strongly expressed CD146. The expression of stem cell markers was similar between FLSs from RA and those from OA patients. In addition, the expression levels in FLSs were similar to those in normal dermal fibroblasts. The stimulation of FLSs and dermal fibroblasts with IL-1β or a mixture of cytokines under hypoxia did not induce a marked change in the expression of stem cell markers. These results indirectly suggest that the pro-inflammatory milieu may be not sufficient to induce the dedifferentiation of FLSs in arthritic joints.</P>

Reversal of serologic, immunologic, and histologic dysfunction in mice with systemic lupus erythematosus by long‐term serial adipose tissue–derived mesenchymal stem cell transplantation

Choi, Eun Wha,Shin, Il Seob,Park, So Young,Park, Ji Hyun,Kim, Jong Sung,Yoon, Eun Ji,Kang, Sung Keun,Ra, Jeong Chan,Hong, Sung Hwa Wiley Subscription Services, Inc., A Wiley Company 2012 Vol.64 No.1

<P><B>Abstract</B></P><P><B>Objective</B></P><P>To investigate the efficacy of human adipose tissue–derived mesenchymal stem cell (AD‐MSC) transplantation in systemic lupus erythematosus (SLE) and to determine the optimal transplantation window for stem cells either before or after disease onset.</P><P><B>Methods</B></P><P>(NZB × NZW)F<SUB>1</SUB> mice with SLE were administered human AD‐MSCs (5 × 10<SUP>5</SUP>) intravenously every 2 weeks from age 6 weeks until age 60 weeks, while the control group received saline vehicle on the same schedule. Another experiment was carried out with a different initiation time point for serial transplantation (age 6 weeks or age 32 weeks).</P><P><B>Results</B></P><P>Long‐term serial administration (total of 28 times) of human AD‐MSCs ameliorated SLE without any adverse effects. Compared with the control group, the human AD‐MSC–treated group had a significantly higher survival rate with improvement of histologic and serologic abnormalities and immunologic function, and also had a decreased incidence of proteinuria. Anti–double‐stranded DNA antibodies and blood urea nitrogen levels decreased significantly with transplantation of human AD‐MSCs, and serum levels of granulocyte–macrophage colony‐stimulating factor, interleukin‐4 (IL‐4), and IL‐10 increased significantly. A significant increase in the proportion of CD4+FoxP3+ cells and a marked restoration of capacity for cytokine production were observed in spleens from the human AD‐MSC–treated group. In the second experiment, an early stage treatment group showed better results (higher survival rates and lower incidence of proteinuria) than an advanced stage treatment group.</P><P><B>Conclusion</B></P><P>Serial human AD‐MSC transplantation had beneficial effects in the treatment of SLE, without adverse effects. Transplantation of human AD‐MSCs before disease onset was preferable for amelioration of SLE and restoration of immune homeostasis.</P>

중증근무력증 환자의 말초 혈액내 T 림프구 분획의 변화

최철희,최인홍,김우경,선우일남,최철희 대한신경과학회 1998 대한신경과학회지 Vol.16 No.1

A novel, topical, nonsteroidal, TRPV1 antagonist, PAC-14028 cream improves skin barrier function and exerts anti-inflammatory action through modulating epidermal differentiation markers and suppressing Th2 cytokines in atopic dermatitis

Lee, Ji-Hae,Choi, Chang Soon,Bae, Il-Hong,Choi, Jin Kyu,Park, Young-Ho,Park, Miyoung Elsevier 2018 JOURNAL OF DERMATOLOGICAL SCIENCE Vol.91 No.2

<P><B>Abstract</B></P> <P><B>Background</B></P> <P>Although it is established that epidermal barrier disturbance and immune dysfunction resulting in IgE sensitization are critical factors in the development of cutaneous inflammation, the pathogenesis and targeted therapy of atopic dermatitis (AD)-specific pathways have still been unknown.</P> <P><B>Objective</B></P> <P>Taking into account the fact that Th2 cytokines in AD have both unique and overlapping functions including increased epidermal thickening, inflammation, and decreased expressing of the barrier proteins keratinocyte differentiation, we sought to clarify our hypothesis that TRPV1 antagonist plays a critical role in skin barrier function and can be a therapeutic target for AD.</P> <P><B>Methods</B></P> <P>AD-like dermatitis was induced in hairless mice by repeated oxazolone (Ox) challenges to hairless mice. The functional studies concerning skin barrier function, anti-inflammatory action, and molecular mechanism by TRPV1 antagonism were conducted by histopathological assays, ELISA, qPCR, western blotting, and skin blood flow measurement.</P> <P><B>Results</B></P> <P>Topically administered TRPV1 antagonist, PAC-14028 (Asivatrep: C<SUB>21</SUB>H<SUB>22</SUB>F<SUB>5</SUB>N<SUB>3</SUB>O<SUB>3</SUB>S), improved AD-like dermatitis and skin barrier functions, and restored the expression of epidermal differentiation markers. In addition, the PAC-14028 cream significantly inhibited cutaneous inflammation by decreasing the expression of serum IgE, and the epidermal expression of IL-4, and IL-13 in Ox-AD mice. These results may provide a novel insight into the molecular mechanism of PAC-14028 cream involved in anti-inflammatory effects and skin barrier functions by suppressing the multiple signaling pathways including IL-4/-13-mediated activation of JAK/STAT, TRPV1, and neuropeptides.</P> <P><B>Conclusion</B></P> <P>PAC-14028 cream can be a potential therapeutic tool for the treatment of chronic inflammation and disrupted barrier function in patients with AD.</P> <P><B>Highlights</B></P> <P> <UL> <LI> PAC-14028 1% topical cream is an anti-inflammatory, non-steroidal TRPV1 antagonist. </LI> <LI> PAC-14028 cream treatment reduced AD-like symptoms and improved skin barrier functions in Ox-induced <I>in vivo</I> murine model. </LI> <LI> PAC-14028 suppressed the signaling pathways including IL-4/-13 mediated activation of JAK/STAT, TRPV1, and neuropeptides. </LI> </UL> </P>

Ameliorating effect of dipotassium glycyrrhizinate on an IL-4- and IL-13-induced atopic dermatitis-like skin-equivalent model

Lee, Sung Hoon,Bae, Il-Hong,Choi, Hyangtae,Choi, Hyeong Won,Oh, Soojung,Marinho, Paulo A.,Min, Dae Jin,Kim, Dae-Yong,Lee, Tae Ryong,Lee, Chang Seok,Lee, Jongsung Springer-Verlag 2019 Archives of dermatological research Vol.311 No.2

Humic acid가 카드뮴 어독성에 미치는 영향

류지성,정규혁,최필선,이길철,최덕일,최성수,류홍일,박광식 한국환경독성학회 1998 환경독성보건학회지 Vol.13 No.1

Cadmium, a major aquatic pollutant in many parts of the world, is toxic and readily accumulated in aquatic organisms. It mainly exists in water as complexes with organic ligands such as dissolved organic carbon and this complexation is known to have effects on the aquatic toxicities. In this study, acute toxicity, histology, and bioaccumulation were studied to evaluate effects of humic acid on cadmium toxicity and bioavailability to fish using Oryzias latipcs and Cypriruts carpio. 96h~LC50 of cadmium was 6.38 mg/L using Oryzias latipes. However, the mortality showed the dose-dependent decrease when humic acid was added to the test solution. When fish were exposed to 5 mg/L of cadmium, histological changes in the exposed organs (caudal fins, gills, kidney, liver, and gut) of Cyprinifs carpio were decreased by humic acid, especially in kidney and liver. Bioaccumulation of cadmium also decreased by treatment of humic acid. It seems that the formation of complexes between cadmium and humic acid may decrease bioavailability of cadmium to fish, and thus reduce the toxic effects of cadmium.

Humic acid가 카드뮴 어독성에 미치는 영향

류지성,정규혁,최필선,이길철,최덕일,최성수,류홍일,박광식 성균관대학교 약학연구소 1998 成均藥硏論文集 Vol.10 No.1

Cadmium, a major aquatic pollutant in many parts of the world, is toxic and readily accumulated in aquatic organisms. It mainly exists in water as complexes with organic ligands such as dissolved organic carbon and this complexation is known to have effects on the aquatic toxicities. In this study, acute toxicity, histology, and bioaccumulation were studied to evaluate effects of humic acid on cadmium toxicity and bioavailability to fish using Oryzias latipes and Cyprinus carpio. 96h-LC50 of cadmium was 6.38 ㎎/L using Oryzias latipes. However, the mortality showed the dose-dependent decrease when humic acid was added to the test solution. When fish were exposed to 5㎎/L of cadmium, histological changes in the exposed organs(caudal fins, gills, kidney, liver, and gut) of Cyprinus carpio were decreased by humic acid, especially in kidney and liver. Bioaccumulation of cadmium also decreased by treatment of humic acid. It seems that the formation of complexes between cadmium and humic acid may decrease bioavailability of cadmium to fish, and thus reduce the toxic effects of cadmium.