• 한국발생생물학회지:발생과생식
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• 제22권4호
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• pp.341-350
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• 2018

Chemokines is a small protein that plays a major role in inflammatory reactions and viral infections as a chemotactic factor of cytokines involved in innate immunity. Most of the chemokines belong to the chemokine groups CC and CXC. To investigate the immune system of the olive flounder (Paralichthys olivaceus), an expression pattern specifically induced in the early developmental stages of analysis is examined using qRT-PCR. We also examined tissue-specific expression of both CC and CXC chemokine in healthy olive flounder samples. CC and CXC chemokine shows increased expression after immune-related organs are formed compared to expression during early development. CC chemokine was more highly expressed in the fin, but CXC chemokine showed higher expression in the gills, spleen, intestines, and stomach. Spatial and temporal expression analysis of CC and CXC chemokine were performed following viral hemorrhagic septicemia virus (VHSV) infection. CC chemokine showed high expression in the gills, which are respiratory organs, whereas CXC chemokine was more highly expressed in the kidneys, an immune-related organ. These results suggest that CC and CXC chemokine play an important role in the immune response of the olive flounder, and may be used as basic data for the immunological activity and gene analysis of it as well as other fish.

• IMMUNE NETWORK
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• 제7권1호
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• pp.18-25
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• 2007

Background: Although glucocorticoids (GCs) are effective in controlling asthma in the majority of patients, a subset of asthmatics fails to demonstrate a satisfactory response, even to systemic GC therapy. This population is referred to as being "steroid-resistant". The actual mechanism underlying steroid resistance in asthma remains to be elucidated. Methods: We have investigated how dexamethasone (DEX) regulates asthmatic phenotypes in a murine model of asthma, in which mice received i.p. immunization twice, followed by two bronchoprovocations with aerosolized OVA with a one-week interval, which we have recently described. Results: Pretreatment with DEX resulted in an inhibition of NF-${\kappa}B$ activation in asthmatic lungs, and also inhibited bronchoalveolar lavage (BAL) levels of NF-${\kappa}B$-dependent cytokines such as TNF-${\alpha}$ and CC chemokines [eotaxin and monocyte chemotactic protein (MCP)-1]. DEX was effective in suppressing airway hyperresponsiveness (AHR) at 10 h, Th2-dependent asthmatic phenotypes such as airway eosinophilia, BAL levels of Th2 cytokines (IL-5 and IL-13), and mucin production. However, DEX failed to suppress BAL levels of CXC chemokines [macrophage inflammatory protein-2 (MIP-2) and keratinocyte-derived chemokine (KC)] and airway neutrophilia. Conclusion: Airway neutrophilia is among the phenomena observed in patients with severe GC-resistant asthma. This study will provide insight into the molecular basis for airway neutrophila seen in steroid-resistant asthma. Further studies are required to delineate the underlying mechanism of CXC chemokine expression in asthma.

• Tuberculosis and Respiratory Diseases
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• 제52권2호
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• pp.145-155
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• 2002

연구배경 : 혈관내피세포와 호중구의 상호작용은 급성염증반응의 생리 및 병리학적 핵심적인 과정으로서 특별한 분자들에 의해서 매개되고 있다. 적절한 자극이 주어질 때 혈관 내피세포에서는 부착 및 신호인자가 표현되며 이들은 호중구의 수용체에 의해 인지된다. 본 연구에서는 IL-1과 LPS로 혈관내피세포를 자극하였을 때 CXC chemokine family에 속하는 GRO-${\alpha}$, IL-8 및 ENA-78이 내피세포에서 분비되는 양상을 관찰하였고, ENA-78과 GRO-${\alpha}$가 호중구-내피세포의 부착에 미치는 영향을 평가하였다. 방 법 : 인제대혈관 내피세포를 배양하여 다양한 농도로 IL-1과 LPS로 자극하였다. 자극된 내피세로로부터 분비 되어진 GRO-${\alpha}$, IL-8 및 ENA-78의 농도는 ELISA로 측정하였다. recombinant human ENA-78 및 GRO-${\alpha}$로 자극된 내피세포에 동위원소가 부착된 정상백혈구를 이용하여 부착능을 측정하였다. 결 과 : IL-1a과 LPS로 자극된 내피세포에서 GRO-${\alpha}$ IL-8 및 ENA-78의 분비는 자극의 농도와 지속시간에 비례하여 증가되었고, recombinant human ENA-78과 GRO-${\alpha}$의 농도가 증가함에 따라 호중구의 부착율이 더욱 증가하였다. 결 론 : ENA-78과 GRO-${\alpha}$는 CXC chemokine family에 속하며 주로 상피세포에서 발현되어 백혈구의 화학적 주성을 유발하며 염증성 반응을 매개하는 중요한 물질로 알려져 있다. 본 연구에서는 다양한 농도의 IL-1과 LPS로 자극된 내피세포에서 농도에 비례하여 GRO-${\alpha}$, IL-8 및 ENA-78이 분비됨을 확인할 수 있었으며, 또한 ENA-78과 GRO-${\alpha}$를 각각 다른 농도로 배양한 후 호중구 부착능이 농도에 따라 증가함을 알 수 있었다. 따라서 본 연구의 결과는 염증성 자극으로 혈관내피세포에서 분비되는 ENA-78과 GRO-${\alpha}$ 등의 CXC chemokine 이 염증반응의 진행 기전에서 중요한 역할을 담당할 것임을 시사하며, 향후 염증성 질환의 발병기전 규명이나 치료법개발을 위한 기초적 자료를 제공하는데 도움이 될 것으로 생각된다.

• Molecules and Cells
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• 제22권3호
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• pp.308-313
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• 2006

Stromal cell-derived factor (SDF-1) is a CXC chemokine that selectively activates the CXCR4 chemokine receptor. Fibronectin is an intracellular matrix component that binds integrin and mediates cell-matrix adhesion. Activation of the integrin receptor can occur in two ways: by ligand binding (outside-in signaling), and in response to intracellular events (inside-out signaling). In the current study we showed that SDF-$1{\alpha}$ inhibited adhesion of T lymphocyte Jurkat cells resulting from binding high concentrations of fibronectin as well as that of THP-1 monocytes. The effect of SDF-$1{\alpha}$ on fibronectin-mediated adhesion was partly reversed by the CXCR4 receptor antagonist T140. Our results suggest that an SDF-1/CXCR4 signal pathway modulates fibronectin-mediated lymphocytes adhesion.

• 대한병리학회지
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• 제52권6호
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• pp.369-377
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• 2018

Background: Chemokine receptor CXC chemokine receptor type 4 (CXCR4) and its ligand CXC motif chemokine 12 (CXCL12; stromal cell-derived factor-1) are implicated in tumor growth, metastasis, and tumor cell-microenvironment interaction. A number of studies have reported that increased CXCR4 expression is associated with worse prognosis in triple-negative breast cancer (TNBC), but its prognostic significance has not been studied in TNBC patients treated with adjuvant chemotherapy. Methods: Two hundred eighty-three TNBC patients who received adjuvant chemotherapy were retrospectively analyzed. Tissue microarray was constructed from formalin-fixed, paraffin-embedded tumor tissue and immunohistochemistry for CXCR4 and CXCL12 was performed. Expression of each marker was compared with clinicopathologic characteristics and outcome. Results: High cytoplasmic CXCR4 expression was associated with younger age (p=.008), higher histologic grade (p=.007) and lower pathologic stage (p=.045), while high CXCL12 expression was related to larger tumor size (p=.045), positive lymph node metastasis (p=.005), and higher pathologic stage (p=.017). The patients with high cytoplasmic CXCR4 experienced lower distant recurrence (p=.006) and better recurrence-free survival (RFS) (log-rank p=.020) after adjuvant chemotherapy. Cytoplasmic CXCR4 expression remained an independent factor of distant recurrence (p=.019) and RFS (p=.038) after multivariate analysis. Conclusions: High cytoplasmic CXCR4 expression was associated with lower distant recurrence and better RFS in TNBC patients treated with adjuvant chemotherapy. This is the first study to correlate high CXCR4 expression to better TNBC prognosis, and the underlying mechanism needs to be elucidated in further studies.

• Journal of Pharmaceutical Investigation
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• 제33권4호
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• pp.281-286
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• 2003

To design gene deliver systems which can deliver higher amounts of genes into stem cells, we studied the expression of receptors involved in the receptor-mediated endocytosis of bone marrow stromal stem cells. Bone marrow was isolated from ICR mice, and bone marrow stromal stem cells were isolated based on their plastic adherence property. Several culture conditions were screened for effective and continuous culture of marrow stromal stem cells. MesenCult medium was finally used to cultivate marrow stromal stem cells in vitro. As candidate receptors, various chemokine receptors were studied. Both bone marrow cells ad marrow-derived stromal stem cells showed expression of CC chemokine receptors (CCR) and CXC chemokine receptors (CXCR). Marrow stromal stem cells showed higher expression of CCR5 ad CXCR4 chemokine receptors as compared to other types of chemokine receptors. Moreover, though the expression of chemokine receptors generally decreased in most chemokine receptors with the cultivaton of marrow stromal stem cells, CCR5 and CXCR4 chemokine receptors retained the higher level of receptor expressions over prolonged periods. These results suggest that the ligands exhibiting specific binding to CCR5 or CXCR4 might be used to modify gene delivery systems for increased levels of receptor-mediated gene delivery into stromal stem cells.

• 통합자연과학논문집
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• 제9권2호
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• pp.121-127
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• 2016

CXC chemokine receptor 2 (CXCR2) is a prominent chemokine receptor on neutrophils. The neutrophilic inflammation in the lung diseases is found to be largely regulated through CXCR2 receptor. Antagonist of CXCR2 may reduce the neutrophil chemotaxis and alter the inflammatory response. Hence, in the present study, ligand based Comparative molecular field analysis (CoMFA) was performed on a series of CXCR2 antagonist named pyrimidine-5-carbonitrile-6-alkyl derivatives. The optimum CoMFA model was obtained with statistically significant cross-validated coefficients ($q^2$) of 0.568 and conventional coefficients ($r^2$) of 0.975. The contour maps suggest the important structural modifications and this study can be used to guide the development of potent CXCR2 antagonist.

• 통합자연과학논문집
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• 제10권4호
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• pp.209-215
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• 2017

CXC chemokine receptor 2 (CXCR2) is a prominent chemokine receptor on neutrophils. CXCR2 antagonist may reduce the neutrophil chemotaxis and alter the inflammatory response because the neutrophilic inflammation in the lung diseases is found to be largely regulated through CXCR2 receptor. Hence, in the present study, Topomer based Comparative Molecular Field Analysis (Topomer CoMFA) was performed on a series of CXCR2 antagonist named pyrimidine-5-carbonitrile-6-alkyl derivatives. The best Topomer COMFA model was obtained with significant cross-validated correlation coefficient ($q^2$ = 0.487) and non cross-validated correlation coefficients ($r^2$ = 0.980). The model was evaluated with six external test compounds and its $r^2{_{pred}}$ was found to be 0.616. The steric and electrostatic contribution map show that presence of bulkier and electropositive group around cyclopropyl ring may contribute more for improving the biological activities of these compounds. The generated Topomer CoMFA model could be helpful for future design of novel and structurally related CXCR2 antagonists.

• 통합자연과학논문집
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• 제9권3호
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• pp.177-184
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• 2016

CXC chemokine receptor 2 (CXCR2) is a prominent chemokine receptor on neutrophils and it regulates the neutrophilic inflammation in the lung diseases. CXCR2 antagonist may reduce the neutrophil chemotaxis and alter the inflammatory response. Hence, in the present study, ligand based Comparative Molecular Similar Indices Analysis (CoMSIA) was performed on a series of CXCR2 antagonist named pyrimidine-5-carbonitrile-6-alkyl derivatives. The optimum CoMSIA model was obtained with statistically significant cross-validated coefficients ($q^2$) of 0.582 and conventional coefficients ($r^2$) of 0.987 with steric, electrostatic, hydrophobic, donor and acceptor fields. The contour maps suggest the important structural modifications and this study can be used to guide the development of potent CXCR2 antagonist.

• Clinical and Experimental Pediatrics
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• 제64권1호
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• pp.37-43
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• 2021

Background: Animal studies have shown that a leukocyte influx precedes the development of bronchopulmonary dysplasia (BPD) in premature sheep. The CXC chemokine receptor 2 (CXCR2) pathway has been implicated in the pathogenesis of BPD because of the predominance of CXCR2 ligands in tracheal aspirates of preterm infants who later developed BPD. Purpose: To test the effect of CXCR2 antagonist on postnatal systemic and pulmonary inflammation and alveolarization in a newborn Sprague-Dawley rat model of BPD. Methods: Lipopolysaccharide (LPS) was injected intraperitoneally (i.p.) into the newborn rats on postnatal day 1 (P1), P3, and P5 to induce systemic inflammation and inhibit alveolarization. In the same time with LPS administration, CXCR2 antagonist (SB-265610) or vehicle was injected i.p. to investigate whether CXCR2 antagonist can alleviate the detrimental effect of LPS on alveolarization by attenuating inflammation. On P7 and P14, bronchoalveolar lavage fluid (BALF) and peripheral blood (PB) were collected from the pups. To assess alveolarization, mean cord length and alveolar surface area were measured on 4 random nonoverlapping fields per animal in 2 distal lung sections at ×100 magnification. Results: Early postnatal LPS administration significantly increased neutrophil counts in BALF and PB and inhibited alveolarization, which was indicated by a greater mean cord length and lesser alveolar surface area. CXCR2 antagonist significantly attenuated the increase of neutrophil counts in BALF and PB and restored alveolarization as indicated by a decreased mean cord length and increased alveolar surface area in rat pups exposed to early postnatal systemic LPS. Conclusion: CXCR2 antagonist preserved alveolarization by alleviating pulmonary and systemic inflammation induced by early postnatal systemic LPS administration. These results suggest that CXCR2 antagonist can be considered a potential therapeutic agent for BPD that results from disrupted alveolarization induced by inflammation.