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IL-5는 여러 경로를 통하여 호산구의 기능에 결정적인 역할을 하고 혈액이나 조직에서 호산구의 수적인 증가를 고려할 때 호산구 증다증을 동반하는 여러 질환과 깊게 연관되어 있다. 본 실험에서 IL-5로 자극된 호산구와 자극되지 않은 호산구의 활성을 pro-inflammatory cytokines(IL-1β , IL-6, TNF-α )과 Th1(IFN- γ), Th2(IL-4, IL-13) 그리고 Tr cytokines(IL-10)이 억제할 수 있는지를 eosinophil shape change를 통해서 알아보았다. 시간과 투여량에 따라 IL-6와 TNF- 는 자극되지 않은 호산구의 크기를 증가시키는 반면, IFN- γ와 IL-4 그리고 IL-13은 호산구의 크기를 유의하게 감소시켰다. 또한 IL-13을 제외한 IFN- γ와 IL-4는 IL-5로 자극된 호산구의 shapec hange를 억제했다. 최대 억제를 위해서 IFN- γ와 IL-4로 30~60분 정도 전처리 하였다. cyclohexamide에 의한 억제 효과의 제거는 cytokine에 의한 신호전달과 IFN- γ의 효과에 있어서 새로운 단백질이 필요함을 제시하였다. IFN- γ의 전처치는 IL-5에 의하여 유도된 ERK1/2의 인산화를 유의하게 억제하였다. 결론적으로 IFN- γ는 새로운 단백질의 생성으로 MAP kinase 활성을 억제하여 IL-5로 자극된 호산구의 기능을 조절할 수 있다. (J Asthma Allergy Clin Immunol 23: 759-72, 2003)
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>
Objective: Interleukin-15 (IL-15) recruits and activates synovial T cells, and IL-15 plays an important role in amplifying and perpetuating inflammation in the pathogenesis of rheumatoid arthritis (RA). Stromal cell-derived factor-1 (SDF-1) is a potent chemoattractant for memory T cells in the inflamed RA synovium. This study investigated the effect of IL-15 on SDF-1 production in RA fibroblast-like synoviocytes (FLS). Methods: The expressions of IL-15 and SDF-1 were determined from the synovium of patients with RA and osteoarthritis (OA) by performing immunohistochemistry. The expressions of SDF-1 was measured from the RA FLS that were cultured with IL-15 and IL-17 by real-time RT-PCR and ELISA. The SDF-1 expression was also measured, via ELISA, from the RA FLS stimulated by IL-15 together with the inhibitors of such intracellular signal molecules as phosphatidylinositol 3-kinase (PI 3-kinase, LY294002), STAT3 (AG490), MAP Kinase (PD98059), NF-κB (parthenolide) and activator protein 1 (AP-1, curcumin). Results: IL-15 and SDF-1 were mainly expressed in the RA synovium compared to that of the OA synovium. IL-15 increased the SDF-1 expressions and it, and had an additive effect with IL-17 on the SDF-1 expressions in the cultured RA FLS. The IL-15 induced increase of the SDF-1 expression in the cultured RA FLS was blocked by the inhibitors of PI 3-kinase, NF-κB and AP-1. Conclusion: The SDF-1 expression was increased in the RA synovium and it was up-regulated by IL-15 in the RA FLS through the PI 3-kinase, NF-κB, and AP-1 pathways. These results imply that the IL-15 induced increase of the SDF-1 expressions may be involved in the immunopathogenesis of RA.
Kang, Kwi Young,Kim, Hyun-Ok,Kwok, Seung-Ki,Ju, Ji Hyeon,Park, Kyung-Su,Sun, Dong-Il,Jhun, Joo Yeon,Oh, Hye Jwa,Park, Sung-Hwan,Kim, Ho-Youn BioMed Central 2011 ARTHRITIS RESEARCH AND THERAPY Vol.13 No.5
<P><B>Introduction</B></P><P>Interleukin (IL)-21 is a cytokine that controls the functional activity of effector T helper cells and the differentiation of Th17 cells, and promotes B-cell differentiation. To test whether IL-21 participates in the pathogenesis of primary Sjögren's syndrome (SS), serum IL-21 level was measured and IL-21 expression in the labial salivary glands (LSG) was examined.</P><P><B>Methods</B></P><P>Serum IL-21 levels in 40 primary SS, 40 rheumatoid arthritis (RA), and 38 systemic lupus erythematosus (SLE) patients and 20 healthy controls were measured. Serum IL-21 levels of SS patients were assessed for correlations with laboratory data, including anti-nuclear antibody, anti-Ro/La antibodies, globulin, immunoglobulin (Ig) class, and IgG subclass. LSGs from 16 primary SS and 4 controls with sicca symptoms were evaluated for IL-21 and IL-21 receptor (IL-21R) expression by immunohistochemistry. Confocal microscopy was performed to further characterize the IL-21 positive cells.</P><P><B>Results</B></P><P>Primary SS patients had significantly higher serum IL-21 levels than controls, and these increments correlated positively with levels of IgG, IgG1. Serum IgG1 levels correlated with anti-Ro antibody titers. Immunohistochemical analyses showed that lymphocytic foci and the periductal area of the LSGs from SS patients expressed high levels of IL-21 and lower levels of IL-21R, whereas the control LSGs showed minimal expression of both antigens. The more the lymphocyte infiltrated, IL-21expression in LSGs showed a tendency to increase. Confocal microscopic analyses revealed that IL-21 expressing infiltrating lymphocytes in the LSGs of SS patients also expressed CXCR5.</P><P><B>Conclusions</B></P><P>Primary SS is associated with high serum IL-21 levels that correlate positively with serum IgG, especially IgG1, levels. The expression of IL-21 is increased as more lymphocytes infiltrated in LSGs. These observations suggest that IL-21 may play an important role in primary SS pathogenesis.</P>
Recently a B cell surface molecule, CD40, has emerged as a receptor mediating a co-stimulatory signal for B cell proliferation and differentiation. To investigate the mechanism of synergy between interleukin-4(IL-4) and CD40 ligation in B cell activation we have examined the effect of CD40 cross-linking on the IL-40 receptor expression in human B cells using anti-CD40 antibody. We observed that IL-4 and anti-CD40 both induce IL-40 receptor gene expression with a rapid kinetics resulting in a noticeable accumulation of IL-4 receptor mRNA within 4 h. While IL-4 caused a dose-dependent induction of surface IL-4 receptor expression, the inclusion of anti-CD40 in the IL-4-treated culture, further up-regulated the IL-4-induced IL-4 receptor expression as analyzed by flow cytometry. Pretreatment of B cells with inhibitors of protein tyrosine kinase (PTK) resulted in asignificant inhibition of both the IL-4- and anti-CD40-induced IL-4 receptor mRNA levels, while protein kinase C (PKC) inhibitors had no effects. These results suggest that IL-4 and CD40 ligation generate B cell signals, which via PTK-dependent pathways, lead to the synergistic induction of IL-4 receptor gene expression. The rapid induction of IL-4 receptor gene expression through the tyrosine kinase-mediated signal transduction by B cell activating stimuli, would provide cells capacity for an efficient response to IL-4 in the early phase of IL-4action, and may in part constitute the molecular basis of the reported anti-CD40 co-stimulatory effect on the IL-4-induced response.
Chang, Young-Woon,Jang, Jae-Young,Kim, Nam-Hoon,Lee, Jae Won,Lee, Hyo Jung,Jung, Woon Won,Dong, Seok-Ho,Kim, Hyo-Jong,Kim, Byung-Ho,Lee, Joung-Il,Rin Chang KYUNG HEE UNIVERSITY MEDICAL CENTER 2006 고황의학상 수상논문집 Vol.21-22 No.-
Interleukin-1B and IL-1 receptor antagonist gene polymorphisms are associated with an increased risk of gastric cancer (GC) in Caucasian populations. However, recent studies could not find any association between IL-1B-511T polymorphism and the risk of GC in Asians. We tested for an association between IL-1 loci polymorphisms with increased gastric mucosal levels of IL-1β and an increased risk of developing GC in a Korean population. Polymorphisms of IL-1A-889, IL-1B-31, IL-1B-511 and IL-1RN were genotyped in 434 controls and 234 patients with GC. Mucosal IL-1β cytokine was measured using an ELISA. The frequencies of IL-1A, IL-1B-511, IL-1B-31 and IL-1RN were not statistically different between controls and all patients with GC. After subclassification of GC, only patients with intestinal-type GC showed a higher frequency of IL-1B-31T homozygotes (OR = 2.2; 95% CI = 1.1-4.3) compared with controls. Risk was also significantly increased in these patients for IL-1B-31T homozygotes compared with patients with diffuse-type GC (OR = 3.4; 95% CI = 1.5-7.7). As in Caucasian populations, linkage disequilibrium between IL-1B-31 and IL-1B-511 was nearly complete, but the pattern of haplotype related to the risk of GC (IL-1B-31T/IL-1B-511C) was opposite (IL-1B-511T/IL-1B-31C). Mucosal IL-1β levels in H. pylori-infected GC patients were higher in patients homozygous for IL-1B-31T compared with IL-1B-31C/T and IL-1B-31C/C. Thus, the combined effects of H. pylori infection and IL-1B-31T/IL-1B-511C polymorphisms with enhanced mucosal IL-1β production contributed to the development of intestinal-type GC in this Korean population.
목적 : 본 연구는 화상환자에서 면역이상의 기전을 조사코져 T-세포의 활성을 나타내는 가용성 interleukin-2 수용체(IL-2R), 대식세포의 활성을 나타내는 neopterin, tumor necrosis factor(TNF) 및 interleukin-6 (IL-6), 그리고 호중구의 활성을 반영하는 elastase-α1-antitrypsin을 측정하였다. 또한 lipopolysaccharide(LPS)가 이들 면역세포의 활성화에 미치는 영향을 조사하였다. 대상 및 방법 : 30예의 화상환자를 대상으로 화상후 1일, 7일, 14일, 21일, 28일에 각각 혈액을 채취하여 혈청중 가용성 IL-2R, TNF, IL-6, 그리고 elastase-α1-antitrypsin은 각각 효소면역법으로, 혈청중 neopterin은 radioimmunoassay법으로 측정하였다. LPS가 말초 단핵세포에 미치는 영향은 역전사 중합효소 연쇄반응을 통하여 각종 cytokines의 mRNA 발현을 측정하였다. 결과 : 화상환자에서 혈청중 가용성 IL-2R은 화상후 1일째부터 대조군에 비하여 유의성 있게 증가되어 7일과 14일째에 최고치를 나타냈으며 그 이후에는 다소 감소하였으나 대조군보다는 유의한 증가를 나타냈다. 화상환자를 중화상, 중등도화상, 경도화상으로 분류하여 혈청중 가용성 IL-2R 치를 비교해본 결과 중증 화상일수록 더욱 높은 치를 나타냈다. 화상환자에서 혈청중 neopterin 역시 화상후 1일째부터 증가되어 전 관찰기간 동안 대조군에 비해 유의한 높은 치를 나타냈다. 경도화상과 중등도 화상에서는 서로 유의한 차이를 보이지 않았으나 중환자에서는 경도 혹은 중등도 화상환자에 비해 유의한 증가를 보였다. 화상환자에서 혈청중 TNF 농도는 화상후 1일부터 증가되어 관찰전기간에 걸쳐 유의한 증가를 나타냈으며 중등도 화상환자에서 가장 높은 치를 보였다. 혈청중 IL-6치 역시 화상 전기간에 걸쳐 대조군보다 유의한 증가를 나타냈으며 중화상 환자에서 가장 높은 치를 나타냈다. 화상은 또한 혈청중 elastase-α1-antitrypsin 농도를 현저히 증가시켰다. 즉 화상후 1일에 elastase-α1-antitrypsin 농도는 정상인보다 5배 높았으며 그 이후 약 4주간 계속 높은 농도를 유지하다가 환자가 회복되면서 감소하는 경향을 나타내었다. 중등도화상 및 중화상환자의 혈청중 elastase-α1-antitrypsin 농도는 경도 화상환자에서 비해 유의한 증가를 보였다. 한편 화상환자에서 면역이상을 초래하는 주된 요인으로 여겨지는 lipopolysaccharide는 면역세포를 총체적으로 활성화시켜 IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, TNF, IFN-γ, TGF-β, GM-CSF, IL-2R의 유전자발현을 현저히 증가시켰다. 결론 : 화상환자에서 T-세포, 대식세포, 호중구의 활성화를 반영하는 가용성 IL-2R, neopterin, ,TNF, IL-6, elastase-α1-antitrypsin치가 혈중에 증가되어 있으며 화상의 정도가 심할수록 더 높았다. Cell-mediated immunity frequently becomes severely impaired after thermal injury. However, the cause of postburn immune dysfunction is unclear and controversy exists over both pathophysiology and clinical relevance of these abnormalities. This study was undertaken to investigate the immune responses in vivo of patients with burn. Levels of soluble IL-2R, a sensitive marker of T-cell activation, levels of serum TNF, IL-6, and neopterin, an index of macrophage activation, and levels of serum elastase-α1-antitrypsin, an index of neutrophil activation, were measured in serial serum samples taken from 30 burned patients. In patients with burn, soluble IL-2R levels were increased over a 4-week interval with peak concentrations reached during the 2nd week after burn. Patients with severe burn showed a higher soluble IL-2R levels than those with mild or moderate burn. In addition soluble IL-2R significantly correlated with burn size. The levels of serum neopterin were already increased at the first day following burn, and remained at a high level throughout the total period studied (28 days). Patients with severe burn showed significantly higher concentration of serum neopterin than mild or moderate burn. There was positive relationship between the burn sizes and the levels of neopterin. A significant positive correlation was also found between serum soluble IL-2R levels and neopterin levels in burn patients. Levels of serum TNF and IL-6 were also significantly increased over a 4-week interval in burn patients. The levels of serum elastase-α1-antitrypsin were also already increased at the first day following burn, and remained at a high level over a 4-week. Patients with moderate or severe burn showed significantly higher concentration of serum elastase-α1-antitrypsin than those with mild burn. There was no significant relationship between the burn extent and the level of elastase-α1-antitrypsin. LPS increased the transcription of all the cytokines we examined in peripheral mononuclear cells, i.e., IL-1α, IL-1β, IL-2, IL-4, IL-5_IL-6, IL-8, IL-10, TNF, TGF-β, GM-CSF, and IL-2R. We conclude that soluble IL-2R, neopterin, TNF, IL-6, and elastase-α1-antitrypsin might be useful parameters for monitoring of the clinical course in burn patients. Moreover, they indicate that T-cell, macrophage, and neutrophil activation might play the central role in the pathogenesis of the immuno-logic and metabolic disturbance that follows thermal injury.
Recently a B cell surface molecule, CD40, has emerged as a receptor mediating a co-stimulatory signal for B cell proliferation and differentiation. To investigate the mechanism of synergy between interleukin-4 (IL-4) and CD40 ligation in B cell activation, we have examined the effect of CE40 cross-linking on the IL-4 receptor expression in human B cells using anti-CE40 antibody. We observed that IL-4 and anti-CD40 both induce IL-4 receptor gene expression with a rapid kinetics resulting in a noticeable accumulation of IL-4 receptor mRNA within 4 h. While IL-4 caused a dose-dependent induction of surface IL-4 receptor expression, the inclusion of anti-CD40 in the IL-4-treated culture, further up-regulated the IL-4-induced IL-4 receptor expression as analyzed by flow cytometry. Pretreatment of B cells with inhibitors of protein tyrosine kinase (PTK) resulted in a significant inhibition of both the IL-4- and anti-CD40-induced IL-4 receptor mRNA levels, while protein kinase C (PKC) inhibitors had no effects. These results suggest that IL-4 and CD40 ligation generate B cell signals, which via PTK-dependent pathways, lead to the synergistic induction of IL-4 receptor gene expression. The rapid induction of IL-4 receptor gene expression through the tyrosine kinase-mediated signal transduction by B cell activating stimuli, would provide cells capacity for an efficient response to IL-4 in the early phase of IL-4 action, and may in part constitute the molecular basis of the reported anti-CD40 co-stimulatory effect on the IL-4-induced response.
Interleukin 6 (IL-6)은 여러종류의 세포에서 분화 및 주화인자로 작용하는 사이토카인이다. 사람 IL-6의 분자구조는 21에서 28 kDa의 분자량을 갖는 하나의 폴리펩타이드 단백질로서 N-형과 O-형당부가반응과 세린잔기에 인산화를 수반하여 수식되어 있다. 이 사이토카인은 수성의 28-아미노산 자기로 구성된 시그날배열을 가진 212 아미노산의 전구체 단백질로서 생합성된다. IL-6와 가장 밀접한 분자구조를 갖는 물질로는 granulocyte colony-stimulating factor (G-CSF)가 있으며 사람 IL-6의 유전자는 염색체 7p21에 암호화되어 있다. IL-6는 IL-6수용체 (80 kDa subunit, IL-6Ra)의 a-사슬의 세포의 영역과 상호작용을 거쳐 세포표면에 결합하게 되며 이렇게 생성된 결합체는 gp130수용체와 상호작용하며, 이때 gp130 subunit는 JAK/STAT signaling cascade의 계속적인 활성화능력을 보유하도록 리간드-의존적인 2량화 형성이 유도된다. IL-6Ra의 세포내 영역도메인은 신호전달반응에 아무런 역할을 하지 않으며 IL-6Ra의 세포막통과와 세포질도메인이 결여된 수용성 IL-6수용체도 마찬가지로 IL-6와 반웅하며 상승제로서 가능을 하게 된다. 이러한 광범위한 발현과 효과 때문에 IL-6생성의 생체내에서의 부적절한 발현과 조절은 중요한 생리적인 변화를 야기시킨다. 본 총설에서는 생리적이고 병태생리적인 조건에서의 IL-6의 역할과 기능을 검토하였으며 한의학에서의 면역, 천식, 골대사, 당뇨, 암, 순환기계질환, 신경계질환의 약물개발과 기전해석의 수단으로서 검토하였다. Interleukin 6 (IL-6) is a cytokine that functions as a trophic and differentiating factor in cells of many types. Human IL-6 is a single-chain protein with a molecular mass ranging from 21 to 28 kDa. IL-6 is modified by N- and O-glycosylations, as well as by phosphorylation on serine residues. The cytokine is synthesized as a precursor protein of 212 amino acids with a hydrophobic 28-residue signal sequence. Its closest homolog is granulocyte colony-stimulating factor (G-CSF). The gene for human IL-6 is located on chromosome 7p21. IL-6 binds to the cell surface via an interaction with the extracellular region of the a-chain of the IL-6 receptor (80 kDa subunit, IL-6Ra). This complex then associates with the gp130 receptor. The gpl30 subunit undergoes ligand-dependent dimerization with subsequent activation of the JAK/STAT signaling cascade. The intracellular domain of IL-6Ra does not play a role in signal transduction. The soluble IL-6 receptor, which lacks the transmembrane and cytoplasmic domain of IL-6Ra, is also responsive to IL-6 and acts as an agonist. Because of its wide-ranging expression and effects, the inappropriate expression and modulation of IL-6 production has important physiological consequences. Presently, it was examined that role of IL-6 under physiological and pathophysiological conditions, and its feasibility as a drug discovery target are meaningful in fields of oriental medical research.
LEE, JUN-HEE,CHO, MI-LA,KIM, JU-IN,MOON, YOUNG-MEE,OH, HYE-JWA,KIM, GEUN-TAE,RYU, SUN,BAEK, SEUNG-HOON,LEE, SUN-HEE,KIM, HO-YOUN,KIM, SUNG-IL The Journal of Rheumatology 2009 The Journal of rheumatology Vol.36 No.4
<B>Objective.</B><P>To examine the effect of interleukin 17 (IL-17) on the expression of Toll-like receptor (TLR)-2, 4, and 9 in collagen-induced arthritis (CIA) in mice.</P><B>Methods.</B><P>On Days 28 and 32 after induction of CIA in mice, phosphate-buffered saline (PBS group) or IL-17 (IL-17 group) was injected into both knee joints. On Day 35, mice were sacrificed. The severity of knee joint arthritis, synovial inflammation, and bone destruction was measured by a scoring system using macrography and histological analysis. Synovial expression of TLR-2, 4, 9, IL-17, IL-1ß, tumor necrosis factor-α (TNF-α), and IL-6 was determined by real-time PCR and immunohistochemistry. Synoviocytes of CIA mice were cultured with IL-17 and with neutralizing antibodies to cytokine, and the expression of TLR-2, 4, 9, IL-1ß, TNF-α, and IL-6 was determined by real-time RT-PCR.</P><B>Results.</B><P>In CIA mice, knee arthritis scores, synovial inflammation, bone destruction scores, and expression of synovial TLR-2, 4, and 9, IL-17, IL-1ß, TNF-α and IL-6 were higher in the IL-17 and PBS groups than in normal DBA1 mice. These variables were also significantly higher in the IL-17 group than in the PBS group. In CIA synoviocytes, IL-17 increased the expression of TLR-2, 4, and 9, and this effect was significantly alleviated by neutralizing antibodies to IL-17, IL-1ß, and IL-6.</P><B>Conclusion.</B><P>IL-17 aggravates joint inflammation and destruction, and increases the synovial expression of TLR-2, 4, and 9 by increasing IL-1ß and IL-6. These results imply that the IL-17-induced increase in expression of TLR-2, 4, and 9, and IL-1ß and IL-6 production are involved in the IL-17-induced aggravation of arthritis.</P>