Blockade of indoleamine 2,3-dioxygenase protects mice against lipopolysaccharide-induced endotoxin shock.

Jung, In Duk,Lee, Min-Goo,Chang, Jeong Hyun,Lee, Jun Sik,Jeong, Young-Il,Lee, Chang-Min,Park, Won Sun,Han, Jin,Seo, Su-Kil,Lee, Sang Yong,Park, Yeong-Min Williams Wilkins 2009 JOURNAL OF IMMUNOLOGY Vol.182 No.5

<P>Suppression of an excessive systemic inflammatory response is a promising and potent strategy for treating endotoxic sepsis. Indoleamine 2,3-dioxygenase (IDO), which is the rate-limiting enzyme for tryptophan catabolism, may play a critical role in various inflammatory disorders. In this study, we report a critical role for IDO in the dysregulated immune response associated with endotoxin shock. We found that IDO knockout (IDO(-/-)) mice and 1-methyl-D-tryptophan-treated, endotoxin-shocked mice had decreased levels of the cytokines, TNF-alpha, IL-6, and IL-12, and enhanced levels of IL-10. Blockade of IDO is thought to promote host survival in LPS-induced endotoxin shock, yet little is known about the molecular mechanisms that regulate IDO expression during endotoxin shock. In vitro and in vivo, IDO expression was increased by exogenous IL-12, but decreased by exogenous IL-10 in dendritic cells and splenic dendritic cells. Interestingly, whereas LPS-induced IL-12 levels in serum were higher than those of IL-10, the balance between serum IL-12 and IL-10 following challenge became reversed in IDO(-/-)- or 1-methyl-D-tryptophan-treated mice. Our findings demonstrate that the detrimental immune response to endotoxin shock may occur via IDO modulation. Restoring the IL-12 and IL-10 balance by blocking IDO represents a potential strategy for sepsis treatment.</P>

Nicotine Suppresses TNF-${\alpha}$ Expression in Human Fetal Astrocyte through the Modulation of Nuclear Factor-${\kappa}B$ Activation

Son, Il-Hong,Park, Yong-Hoon,Yang, Hyun-Duk,Lee, Sung-Ik,Han, Sun-Jung,Lee, Jai-Kyoo,Ha, Dae-Ho,Kang, Hyung-Won,Park, Joo-Young,Lee, Sung-Soo The Korean Society of Toxicogenomics and Toxicopro 2008 Molecular & cellular toxicology Vol.4 No.2

Parkinson's disease (PD) progresses severely by a gradual loss of dopaminergic neurons in the substantia nigra (SN). Epidemiological studies showed that the incidences of PD were reduced by smoking of which the major component, nicotine might be neuroprotective. But the function of nicotine, which might suppress the incidences of PD, is still unknown. Fortunately, recently it was reported that a glial reaction and inflammatory processes might participate in a selective loss of dopaminergic neurons in the SN. The levels of tumour necrosis factor (TNF)-${\alpha}$ synthesised by astrocytes and microglia are elevated in striatum and cerebrospinal fluid (CSF) in PD. TNF-${\alpha}$ kills the cultured dopaminergic neurons through the apoptosis mechanism. TNF-${\alpha}$ release from glial cells may mediate progression of nigral degeneration in PD. Nicotine pretreatment considerably decreases microglial activation with significant reduction of TNF-${\alpha}$ mRNA expression and TNF-${\alpha}$ release induced by lipopholysaccharide (LPS) stimulation. Thus, this study was intended to explore the role of nicotine pretreatment to inhibit the expressions of TNF-${\alpha}$ mRNA in human fetal astrocytes (HFA) stimulated with IL-$1{\beta}$. The results are as follows: HFA were pretreated with 0.1, 1, and $10{\mu}g/mL$ of nicotine and then stimulated with IL-$1{\beta}$ (100 pg/mL) for 2h. The inhibitory effect of nicotine on expressions of TNF-${\alpha}$ mRNA in HFA with pretreated $0.1{\mu}g/mL$ of nicotine was first noted at 8hr, and the inhibitory effect was maximal at 12 h. The inhibitory effect at $1{\mu}g/mL$ of nicotine was inhibited maximal at 24 h. Cytotoxic effects of nicotine were noted above $10{\mu}g/mL$ of nicotine. Moreover, Nicotine at 0.1, 1 and $10{\mu}g/mL$concentrations significantly inhibited IL-$1{\beta}$-induced TF-${\kappa}B$ activation. Collectively, these results indicate that in activated HFA, nicotine may inhibit the expression of TNF-${\alpha}$ mRNA through the pathway which suppresses the NF-${\kappa}B$ activation. This study suggests that nicotine might be neuroprotective to dopaminergic neurons in the SN and reduce the incidences of PD.

Adiponectin is a negative regulator of NK cell cytotoxicity.

Kim, Kun-Yong,Kim, Jae Kwang,Han, Seung Hyun,Lim, Jong-Seok,Kim, Keun Il,Cho, Dae Ho,Lee, Myeong-Sok,Lee, Jeong-Hyung,Yoon, Do-Young,Yoon, Suk Ran,Chung, Jin Woong,Choi, Inpyo,Kim, Eunjoon,Yang, Young American Association of Immunologists 2006 Journal of Immunology Vol.176 No.10

<P>NK cells are a key component of innate immune systems, and their activity is regulated by cytokines and hormones. Adiponectin, which is secreted from white adipose tissues, plays important roles in various diseases, including hypertension, cardiovascular diseases, inflammatory disorders, and cancer. In this study the effect of adiponectin on NK cell activity was investigated. Adiponectin was found to suppress the IL-2-enhanced cytotoxic activity of NK cells without affecting basal NK cell cytotoxicity and to inhibit IL-2-induced NF-kappaB activation via activation of the AMP-activated protein kinase, indicating that it suppresses IL-2-enhanced NK cell cytotoxicity through the AMP-activated protein kinase-mediated inhibition of NF-kappaB activation. IFN-gamma enhances NK cell cytotoxicity by causing an increase in the levels of expression of TRAIL and Fas ligand. The production of IFN-gamma, one of the NF-kappaB target genes in NK cells, was also found to be suppressed by adiponectin, accompanied by the subsequent down-regulation of IFN-gamma-inducible TRAIL and Fas ligand expression. These results clearly demonstrate that adiponectin is a potent negative regulator of IL-2-induced NK cell activation and thus may act as an in vivo regulator of anti-inflammatory functions.</P>

Adrenomedullin inhibits IL-1관-induced rheumatoid synovial fibroblast proliferation and MMPs, COX-2 and PGE2 production.

Lee, Eun-Gyeong,Lee, Sang-Il,Chae, Han-Jung,Park, Seoung Ju,Lee, Yong Chul,Yoo, Wan-Hee Kluwer Academic/Plenum Publishers 2011 INFLAMMATION Vol.34 No.5

<P>To determine the effects of adrenomedullin (AM) on interleukin (IL)-1관-induced proliferation of rheumatoid synovial fibroblasts (RASFs) and production of matrix metalloproteinases (MMPs), cyclooxygenase (COX) and prostaglandin E2 (PGE2) by RASFs. The RASFs proliferation was evaluated with CCK-8 reagent in the presence of IL-1관 with/without AM (1-52) and AM inhibitor (AM (22-52)). MMPs, tissue inhibitor of metalloproteinase (TIMP-1), COXs, PGE2 and intracellular mitogen-activated protein kinase (MAPK) signalings, including p-ERK, p-p38, p-JNK were examined by immunoblotting or semiquantitative RT-PCR and ELISA. AM (1-52) inhibited IL-1관-induced RASFs proliferation and inhibited MMP-1, 3, COX-2 and PGE2 production. AM (1-52) also inhibited IL-1관-induced phosphorylation of ERK-1/2, p38, JNK. AM 22-52 inhibited the effects of AM (1-52) on proliferation of RASFs and production of MMP-1, 3, COX-2 via MAPKs. These results suggest that AM might involved joint destruction in rheumatoid arthritis and indicate that it might be a new therapeutic modality for management of this disease.</P>

Characterization of IL-3, IL-5, GM-CSF - induced Eosinophils from Human CD34+ Cord Blood Cells

( Kwang Shin Lee ),( Kang Mo Ahn ),( Seung Yeon Nam ),( Dae Yeul Son ),( Se Chang Han ),( Man Yong Han ),( Sang Il Lee ) 대한 소아알레르기 호흡기학회(구 대한소아알레르기 및 호흡기학회) 1999 소아알레르기 및 호흡기학회지 Vol.9 No.4

Streptococcus dysgalactiae로부터 분리된 히알루론산과 황화된 유도체의 구조와 항염증 활성

홍창일(Chang-Il Hong),정의길(Eui-Gil Jung),한국일(Kook-Il Han),김용현(Yong Hyun Kim),이성희(Sung Hee Lee),이홍섭(Hong Sub Lee),한만덕(Man-Deuk Han) 한국생명과학회 2016 생명과학회지 Vol.26 No.5

히알루론산(HA, Hyaluronic acid)은 β-1, 3-N-acetyl glucosamine과 β-1, 4-glucuronic acid가 반복된 선형 폴리머 고분자로서 생물학적 활성 및 생체친화성 특성 때문에 의약 및 약학분야에서 중요한 분자로 여겨지고 있다. 본 연구는 HA을 S. dysgalactiae으로 얻고, 화학적 방법을 통해 황화된 히알루론산(S-HA, Sulfated hyaluronic acid)유도체를 합성하여 그 구조와 항염증 활성을 비교하였다. HA의 생산은 S. dysgalactiae를 5 l 생물반응기를 이용하여 대량 배양하여 수용성 히알루론산(HA-WS, water soluble hyaluronic acid)과 비수용성 히알루론산(HA-WI, water insoluble hyaluronic acid)을 분리 정제하였다. 특히 HA-WI를 황화시켜 황화된 히알루론산(S-HA) 유도체를 합성하였으며, 그 수율은 90%로 나타났다. 합성된 S-HA의 구조를 FT-IR 및 ¹H/<SUP>13</SUP>C-NMR를 통해 S. dysgalactiae 로부터 생산된 표준 HA, HA-WS 및 HA-WI와 비교 분석한 결과, 황으로 치환된 양상을 확인하였다. 또한, S-HA의 항염증 활성을 RAW 264.7 대식세포를 통해 확인한 결과, S-HA는 천연 형태의 HA (HA, HA-WS)보다 nitric oxide (NO)와 COX-2 및 PGE₂ 유전자 발현이 유의하게 낮게 발현되었다. 염증 매개 cytokine인 TNF-α (<80 pg/ml) 및 IL-6 (<100 pg/ml)의 생성도 S-HA가 천연 HA보다 낮은 수준으로 정량되었다. 이 같은 결과에서 황화된 S-HA은 천연 히알루론산보다 용해성이 우수하고 염증관련 사이토카인의 생성 억제를 통해 항염증 효과를 나타내므로 염증치료제, 성형 및 생체 적용 약물전달 소재로 그 활용이 기대된다. Hyaluronic acid (HA) is an important macromolecule in medical and pharmaceutical fields. HA is a natural and linear polymer composed of repeating disaccharide units of β-1, 3-N-acetyl glucosamine and β-1, 4-glucuronic acid. This work aimed to confirm the structural characteristics and anti-inflammatory activities of HA and its chemically sulfated-HA. HA was produced from a fed-batch fermentation process using Streptococcus dysgalactiae in a 5 l bioreactor. HA was isolated water-soluble form (HA-WS) and water-insoluble form (HA-WI) from culture medium, and was obtained chemically sulfated-derivative (S-HA) that resulted in a 90% yield from HA-WI. The structural features of the sulfated- HA (S-HA) were investigated by FT-IR and ¹H-NMR spectroscopy. The FT-IR and NMR patterns revealed the similarity in both the FTIR spectrum as well as NMR spectrum of both reference standard and purified HA from S. dysgalactiae. The anti-inflammatory activities of HA and S-HA were examined on LPS-induced RAW 264.7 cells. S-HA was significantly inhibited production of pro-inflammatory mediators such as nitric oxide (NO) and PGE₂ and the gene levels of iNOS and COX-2, which are responsible for the production of NO and PGE₂, respectively. Furthermore, S-HA also suppressed the overproduction of pro-inflammatory cytokine TNF-α (<80 pg/ml) and IL-6 (<100 pg/ml) compared to that of HA-WI. The present study clearly demonstrates that HA-S exhibits anti-inflammatory activities in RAW 264.7 macrophage cells.

The Effect of Extract from Sea Buckthorn on DNCB-induced Atopic Dermatitis in NC/Nga Mice

Park, Sang-Yong,Shin, Heon-Sub,Yang, Jung-Eun,Han, Sang-No,Kim, Dae-Sung,Kim, Myong-Jo,Heo, Seong-Il,Yi, Tae-Hoo,Lee, Jung-Min The Plant Resources Society of Korea 2012 한국자원식물학회지 Vol.25 No.6

Sea Buckthorn (Hippophae rhamnoides L.) has been used in traditional medicine for the treatment of cough, indigestion, circulatory problems and pain. The associated anti-inflammatory effect of this agent is achieved via the inhibition of Nf-${\kappa}B$ signaling, a property that has been demonstrated to effectively control the symptoms of various skin disorders, including atopic dermatitis. Accordingly, the purpose of this study was to assess the efficacy of Sea Buckthorn in reducing the production of lipopolysaccharide (LPS) activated nitric oxide (NO) by inhibiting the Nf-${\kappa}B$ pathway, as measured by the symptoms of atopic dermatitis (AD) occurring secondarily to inflammation and immune dysregulation. Our data demonstrate that Sea Buckthorn significantly decreased the LPS-induced production of NO (p<0.001). Atopic dermatitis was induced by repeated application of 2,4-dinitrochlorobenzene to the dorsal skin of mice. Topical application of 5% Sea Buckthorn extract improved the symptoms of AD, specifically reducing disease severity scores, scratching behaviors and epidermal thickness. When compared to the control group, animals treated with Sea Buckthorn exhibited increased serum IL-12 levels and decreased serum TNF-${\alpha}$, IL-4 and IL-5 levels. Such a modulation of biphasic T-helper (Th)1/Th2 cytokines may result in a reduction in serum IgE levels. Our findings suggest that mechanism of action of Sea Buckthorn in the treatment of AD is associated with a marked anti-inflammatory effect as well as an inhibition of Th2-mediated IgE overproduction via the modulation of biphasic Th1/Th2 cytokines. Such results suggest that topical Sea Buckthorn extract may prove to be a novel therapy for AD symptoms with few side effects.

Comparison of inflammatory markers for the prediction of neointimal hyperplasia after drug-eluting stent implantation

Kang, Woong Chol,Il Moon, Chan,Lee, Kyounghoon,Han, Seung Hwan,Suh, Soon Yong,Moon, Jeonggeun,Shin, Mi Seung,Ahn, Taehoon,Shin, Eak Kyun Lippincott Williams Wilkins, Inc. 2011 Coronary artery disease Vol.22 No.8

BACKGROUND: We compared the relationship between inflammatory markers and neointimal hyperplasia (NIH) after drug-eluting stent (DES) implantation. METHODS: We implanted a single DES in 42 consecutive patients with stable angina. The plasma high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and matrix metalloproteinase-9 (MMP-9) levels were measured before, and 24 and 72 h after the procedure. Angiography and intravascular ultrasound were performed. RESULTS: No relationship was noted between the baseline hs-CRP level and NIH. A significant positive correlation was noted between NIH and the hs-CRP level obtained at 24 h (r=0.435, P=0.004), and 72 h (r=0.334, P=0.031) after the procedure. Interestingly, there was a positive correlation between the change (&Dgr;) in the hs-CRP level and NIH at 24 h (r=0.414, P=0.006). The fourth quartile of the hs-CRP at 24 h after percutaneous coronary intervention (PCI) had significantly larger volume of NIH than the first quartile (20.1±25.1 vs. 2.7±6.4 mm, P<0.05). Moreover, NIH in the fourth quartile (20.9±26.4 mm) was higher than the first quartile (3.3±8.6 mm) of the &Dgr; hs-CRP level at 24 h (P<0.05) after the procedure. Although the IL-6 level at the baseline and 72 h after the procedure were positively correlated with NIH (r=0.337, P=0.029 and r=0.435, P=0.004, respectively), the &Dgr; IL-6 level at any stage was not correlated with NIH. Neither the MMP-9 level nor the &Dgr; MMP-9 level at any stage was correlated with NIH. CONCLUSION: This prospective intravascular ultrasound study showed the inflammatory response after PCI, as measured by hs-CRP levels, but not the baseline hs-CRP level, predict NIH after DES implantation. Neither a change in the IL-6 nor MMP-9 levels at any stage after PCI reflected NIH.

헬리코박터 파이로리 균 진단용 ^13C-요소 캅셀의 개발

용철순,김용일,김지만,강성훈,권기철,이종달,김종국,사홍기,최한곤 한국약제학회 2002 Journal of Pharmaceutical Investigation Vol.32 No.1

The purpose of this study was to develop a new ^13C-urea- containing capsule for diagnosis of H. pylori. The urea-containing capsules were prepared with various diluents such as polyethylene glycol (PEG), microcrystalline cellulose, sodium lauryl sulfate and citric acid. The dissolution test, ^13C-urea breath test and stability test were then performed on the capsules. Microcrystalline cellulose and sodium lauryl sulfate retarded the initial dissolution rates of urea. However, PEG increased the initial dissolution rates of urea. Furthermore, two formulae composed of PEG, [^13C-urea/PEG (38/1.9 mg/cap)] and [^13C-urea/PEG/citric acid (38/1.9/1.9 mg/cap)] had the maximum DOB value, about 16 at 20 mim, while the formula composed of only 38 mg ^13C-urea had the maximum DOB value at 30 min. The results indicated that PEG improved the sensitivity of ^13C-urea in the human volunteers. The capsule [^13C-urea/PEG (38/1.9 mg/cap)] was stable for at least six months in 25 and 37℃. Thus, a PEG-containing capsule, [^13C-urea/PEG (38/1.9 mg/cap)] would be a more economical, sensitive and stable preparation for diagnosis of H. pylori.

헬리코박터 파이로리 균 진단용 ^13C-요소 캅셀의 개발

용철순,김용일,김지만,강성훈,권기철,이종달,김종국,사홍기,최한곤 영남대학교 약품개발연구소 2002 영남대학교 약품개발연구소 연구업적집 Vol.11 No.-

The purpose of this study was to develop a new ^13C-urea-containing capsule for diagnosis of H.pylori. The urea-containing capsules were prepared with various diluents such as polyethylene glycol (PEG), microcrystaline cellulose, sodium lauryl sulfate and citric acid. The dissolution test, ^13C-urea breath test and stability test were then performed on the capsules. Microcrystalline cellulose and sodium lauryl sulfate retarded the initial dissolution rates of urea. However, PEG increased the initial dissolution rates of urea. Furthermore, two formulae composed of PEG,[^13C-urea/PEG (38/1.9 mg/cap)] and [^13C-urea/PEG (38/1.9/1.9 mg/cap)] had the maximum DOB value. about 16 at 20 min, while the formula composed of only 38 mg ^13C-urea had the maximum DOB value at 30 min. The results indicated that PEG improved the sensitivity of ^13C-urea in the human volunteers. The capsule [^13C-urea/PEG (38/1.9 mg/cap)] was stable for at least six months in 25 and 37℃. Thus, a PEG-containing capsule, [^13C-urea/PEG (38/1.9 mg/cap)] would be a more economical, sensitive and stable perparation for diagnosis of H. pylori.