Glucocorticoid-induced tumor necrosis factor receptor–related protein co-stimulation facilitates tumor regression by inducing IL-9–producing helper T cells

Kim, Il-Kyu,Kim, Byung-Seok,Koh, Choong-Hyun,Seok, Jae-Won,Park, Jun-Seok,Shin, Kwang-Soo,Bae, Eun-Ah,Lee, Ga-Eun,Jeon, Hyewon,Cho, Jaebeom,Jung, Yujin,Han, Daehee,Kwon, Byoung S,Lee, Ho-Young,Chung, Nature Publishing Group, a division of Macmillan P 2015 Nature medicine Vol.21 No.9

<P>T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) elicits antitumor activity in various tumor models; however, the underlying mechanism of action remains unclear. Here we demonstrate a crucial role for interleukin (IL)-9 in antitumor immunity generated by the GITR agonistic antibody DTA-1. IL-4 receptor knockout (Il4ra(-/-)) mice, which have reduced expression of IL-9, were resistant to tumor growth inhibition by DTA-1. Notably, neutralization of IL-9 considerably impaired tumor rejection induced by DTA-1. In particular, DTA-1-induced IL-9 promoted tumor-specific cytotoxic T lymphocyte (CTL) responses by enhancing the function of dendritic cells in vivo. Furthermore, GITR signaling enhanced the differentiation of IL-9-producing CD4(+) T-helper (T(H)9) cells in a TNFR-associated factor 6 (TRAF6)- and NF-kappa B-dependent manner and inhibited the generation of induced regulatory T cells in vitro. Our findings demonstrate that GITR co-stimulation mediates antitumor immunity by promoting T(H)9 cell differentiation and enhancing CTL responses and thus provide a mechanism of action for GITR agonist-mediated cancer immunotherapies.</P>

Chronological changes in inflammatory cytokines immunoreactivities in the mouse hippocampus after systemic administration of high dosage of tetanus toxin.

Yan, Bing Chun,Park, Joon Ha,Kim, In Hye,Shin, Bich Na,Ahn, Ji Hyeon,Yoo, Ki-Yeon,Lee, Deuk-Sik,Kim, Myong Jo,Kang, Il-Jun,Won, Moo-Ho Springer-Verlag 2012 Experimental brain research Vol.223 No.2

<P>Tetanus toxin (TeT) is an exotoxin and has a capacity for neuronal binding and internalization. In the present study, we compared changes in the immunoreactivities and protein levels of interleukin (IL-) 2 as a pro-inflammatory cytokine and IL-4 as an anti-inflammatory cytokine in the hippocampus proper (HP) and dentate gyrus (DG) after systemic treatment of 10 or 100?ng/kg TeT into mice. In this study, we could not find any neuronal damage or loss in any subregions of the hippocampus after TeT treatment. In the control groups, strong IL-2 immunoreactivity was shown in the stratum pyramidal (SP) of the HP and in the granule cell layer (GCL) of the DG. At 6?h post-treatment, IL-2 immunoreactivity was hardly detected in the SP and GCL; however, strong IL-2 immunoreactivity was shown in the stratum oriens of the HP in both the groups. Thereafter, intermediate IL-2 immunoreactivity was shown in the SP and GCL. On the other hand, intermediate IL-4 immunoreactivity was detected in the SP and GCL of the control groups. At 6?h post-treatment, IL-4 immunoreactivity in the SP and GCL was apparently increased. Thereafter, IL-4 immunoreactivity was lower than that at 6?h post-treatment. In brief, IL-2 and 4 immunoreactivities were easily detected in SP and GCL in the controls and dramatically decreased and increased at 6?h post-treatment, respectively.</P>

Protective effect of Silibinin on Silica Dioxide-induced inflammation through suppressing TXNIP/MAPKs/AP-1 signaling

Woong-Il Kim,Je-Oh Lim,Se-jin Lee,So-Won Pak,In-Sik Shin,Jong-choon Kim 한국실험동물학회 2021 한국실험동물학회 학술발표대회 논문집 Vol.2021 No.7

Silica dioxide nanoparticles (siONPs) have been applied to several fields, such as drug delivery and gene therapy. However, SiONPs are a constituent of fine dust and can induce excessive inflammatory responses in the lungs via the airways. Silibinin a major component of silymarin, has been known for its anti-oxidant and anti-inflammatory effects. In the present study, we explored the protective effects of silibinin against SiONPs-induced airway inflammation and explored its underlying mechanism of action, focusing on thioredoxin-interacting protein (TXNIP)/mitogen-activated protein kinase (MAPKs) in vitro and in vivo. In SiONPs-stimulated NCI-H292 airway epithelial cells, silibinin treatment effectively suppressed the elevation of the mRNA expression of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β, which was accompanied by the reduction in the expression of TXNIP, MAPKs, and activator protein-1 (AP-1). In SiONPs-treated mice, silibinin administration inhibited the increase in inflammatory cell counts and proinflammatory mediators, and it alleviated airway inflammation by SiONPs exposure. In addition, silibinin administration effectively suppressed the elevation of TXNIP / MAPKs / AP-1 signaling by SiONPs exposure. Taken together, silibinin effectively inhibited SiONPs-induced inflammatory responses, an this effect was closely related to the inhibition of TXNIP / MAPK/ AP-1 signaling. These results suggested that silibinin might be useful for reducing pulmonary inflammation induced by SiONPs.

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.

Whole-Blood Gene-Expression Profiles of Cows Infected with Mycobacterium avium subsp. paratuberculosis Reveal Changes in Immune Response and Lipid Metabolism

( Min Kyoung Shin ),( Hong Tae Park ),( Seung Won Shin ),( Myung Hwan Jung ),( Young Bin Im ),( Hyun Eui Park ),( Yong Il Cho ),( Han Sang Yoo ) 한국미생물 · 생명공학회 2015 Journal of microbiology and biotechnology Vol.25 No.2

Mycobacterium avium subsp. paratuberculosis (MAP) is the causative agent of Johne’s disease, a chronic debilitating disease affecting ruminants worldwide. In the present study, we aimed to determine the major gene networks and pathways underlying the immune response to MAP infection using whole-blood cells, as well as provide the potential transcriptional markers for identifying the status of MAP infection. We analyzed the transcriptional profiles of wholeblood cells of cattle identified and grouped according to the presence of MAP-specific antibodies and the MAP shed by them. The grouping was based on the results obtained by ELISA and PCR analyses as follows: i) Test1 group: MAP-negative results obtained by ELISA and positive results obtained by PCR; ii) Test2 group: MAP-positive results obtained by ELISA and negative results obtained by PCR; iii) Test3 group: MAP-positive results obtained by ELISA and positive results obtained by PCR; iv) uninfected control: MAP-negative results obtained both by ELISA and PCR analysis. The results showed down-regulated production and metabolism of reactive oxygen species in the Test1 group, activation of pathways related to the host-defense response against MAP (LXR/RXR activation and complement system) in the Test2 and Test3 groups, and anti-inflammatory response (activation of IL-10 signaling pathway) only in the Test3 group. Our data indicate a balanced response that serves the immune-limiting mechanism while the host-defense responses are progressing.

Regulation of Proinflammatory Mediators via NF- <i><i>κ</i></i> B and p38 MAPK-Dependent Mechanisms in RAW 264.7 Macrophages by Polyphenol Components Isolated from Korea <i>Lonicera japonica THUNB</i>

Park, Kwang-Il,Kang, Sang-Rim,Park, Hyeon-Soo,Lee, Do Hoon,Nagappan, Arulkumar,Kim, Jin A,Shin, Sung Chul,Kim, Eun Hee,Lee, Won Sup,Chung, Hyon-Jong,An, Su Jin,Kim, Gon Sup Hindawi Publishing Corporation 2012 Evidence-based Complementary and Alternative Medic Vol.2012 No.-

<P><I>Lonicera japonica THUNB.</I>, which abundantly contains polyphenols, has been used as a traditional medicine for thousands of years in East Asian countries because of the anti-inflammation properties. This study aimed to investigate the anti-inflammatory mechanism of polyphenol components isolated from Korea <I>L. japonica T.</I> by nuclear factor-kappaB (NF-<I><I>κ</I></I>B) and mitogen-activated protein kinases (MAPKs) pathway. Polyphenols significantly decreased lipopolysaccharide- (LPS-) induced mRNA and protein expression of inducible nitric oxide synthase and cyclooxygenase-2, as well as mRNA expression of tumor necrosis factor-alpha, interleukin- (IL-) 1<I><I>β</I></I>, and IL-6. Moreover, polyphenols inhibited nuclear translocation of NF-<I><I>κ</I></I>B p65, phosphorylation/degradation of the inhibitor of <I><I>κ</I></I>B, and phosphorylation of p38 MAPK, whereas the extracellular signal-regulated kinase and Janus N-terminal kinase were not affected. These results indicate that polyphenol components isolated from Korea <I>L. japonica T.</I> should have anti-inflammatory effect on LPS-stimulated RAW 264.7 cells through the decrease of proinflammatory mediators expression by suppressing NF-<I><I>κ</I></I>B and p38 MAPK activity.</P>

Pulmonary inflammation caused by silica dioxide nanoparticles in mice via TXNIP/NLRP3 signaling pathway

Je‑Oh Lim,Je‑Won Ko,Tae‑Yang Jung,Woong‑Il Kim,So‑Won Pak,In‑Sik Shin,Won‑Kee Yun,Hyoung‑Chin Kim,Jeong‑Doo Heo,Jong‑Choon Kim 대한독성 유전단백체 학회 2020 Molecular & cellular toxicology Vol.16 No.3

Background Silica dioxide nanoparticles (SiONPs) have been used for various medical applications, including therapeutics and imaging, and the use of SiONPs has increased gradually over the years. However, despite an increase in the use of SiONPs, not much is known about mechanism of action of SiONPs and their pulmonary toxicity. Objective The present study investigated the pulmonary toxicity of SiONPs and explored the underlying mechanism of action, primarily focusing on thioredoxin-interacting protein (TXNIP)/NOD-like receptor pyrin domain-containing 3 (NLRP3) in SiONPs-treated mice. We investigated the toxic effects of SiONPs in the lung of BALB/c mice administered 5, 10, and 20 mg/kg SiONPs for 3 days. Results Exposure to SiONPs markedly increased inflammatory cell counts, including those of neutrophils and macrophages, and levels of inflammatory mediators, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in a dose-dependent manner in the bronchoalveolar lavage fluid. Moreover, the inflammation was verified upon histopathological analysis. In addition, exposure to SiONPs increased the expression of TXNIP in a dose-dependent manner and, in turn, upregulated NLRP3 inflammasome proteins, which subsequently induced IL-1β production. Conclusion Collectively, exposure to SiONPs induced inflammation in the lungs of mice, which resulted in the activation of IL-1β production via the TXNIP-NLRP3 axis. Our results provide useful information on the pulmonary toxicity induced by SiONPs and provide insights into the underlying mechanism of action.

한국인의 연, 망간, 알루미늄 및 실리콘의 혈중 농도

김정만,안정모,김원술,김정일,신해림,정갑열,김준연 동아대학교 산업의학연구소 2000 산업의학연구소 논총 Vol.- No.5

Blood Lead, Manganese, Aluminium and Silicon Concentrations in Korean Adults Jung Man Kim, Jung Mo Ahn, Won Sul Kim1), Jung Il Kim2), Hai Rim Shin, Kap Yeol Jung2), Joon Youn Kim Department of Preventive Medicine, College of Medicine and Industrial Medicine Research Institute. Dong-A University Department of Health Care, Handong University Sunlin Presbyterian Hotpital1) Department of Occupational Medicine, College of Medicine, Dong-A University2) 0bjectives : This study was performed to determine the reference values of blood lead, manganese, aluminium, and silicon in healthy adults. Methods : The subjects were 132 (67 male and 65 female), and classified to three age groups (≤39,40∼49, and 50≤). Hood lead, manganese and aluminium were analyzed by atomic absorption spectrophotometer, and blood silicon was analyzed by direct current plasma optical omission spectrometer. Results : Blood lead levels(geometric mean, S.D) were (3.49, 1.70) ㎍/dL in male auld (3.04, 1.65) ㎍/dL in female, but the difference is not significant, and there was no significant difference between age groups. Mean blood manganese level was 0.99±0.41㎍/dL, and there was no significant difference between sex or age groups. Mean blood aluminium level was 0.59±0.35㎍/dL and there was no significant difference between sex or age groups. Mean blood silicon level was 54.41±27.64㎍/dL in male and 43.34±23.51㎍/dL in female, and the level in male was significantly higher than that in female (p〈0.05). There was significant difference between age groups, and the oldest showed the highest level in male (p〈0.05), but no significant difference between age groups in female. Conclusions : Authors hope that this study would provide basic data for determininig reference values and evaluating health effects.

The Effect of Human Placental Extract on Rheumatoid Arthritis in an Animal Model

Jeong Dong Park,신희석,Sang-Il Lee,A Ram Kim,Jong Moon Park,Sang-Yeop Shin,Jun Hwa Shin,Seung Won Moon,Hyun Park,오민균 대한재활의학회 2012 Annals of Rehabilitation Medicine Vol.36 No.2

Objective To assess the effi cacy of human placental extract (HPE) in an animal model of rheumatoid arthritis (RA). Method We used (i) KRN C57BL/6 TCR transgenic x NOD mice (KBx/N) serum transfer arthritis and (ii) collageninduced arthritis (CIA) mice to evaluate the effi cacy of HPE (1 ul or 100 ul, intra-peritoneal, three times per week)on RA. Incidence, severity of arthritis, and hind-paw thickness were quantifi ed. Joint destruction was analyzed using modifi ed mammographic imaging. Histopathological analysis for infl ammation, cartilage, and osteoclasts was performed using Hematoxylin-eosin (H-E), safranin-O, and tartrate-resistant acidic phosphatase (TRAP). ELISAs were used for detection of various cytokines in serum and joint tissue. Results Th ere were no signifi cant diff erences in incidence of arthritis, clinical scores of arthritis, and hind-paw thickness between HPE-treated and vehicle-treated groups for up to 2 weeks in the KBx/N serum transfer arthritis model. Histopathological analysis also showed no diff erences 2 weeks after treatment. Levels of TNF-α, IL-1β, IL-6, IL-10, and RANKL in serum and joint tissues were similar in all groups. Furthermore, there were no diff erences in clinical, radiological, and histological parameters between HPE-treated and vehicle-treated group for 3 weeks in the CIA model. Conclusion Systemic treatment with HPE has no benefi cial eff ects on arthritis in animal models of RA. Th erefore,indiscreet use of HPE in RA should be forbidden.

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.