한국인 구강편평상피세포암종 환자에서 CXCL1과 CXCL2 유전자의 다형성에 관한 연구

강상욱,김준열,조재오 대한구강악안면병리학회 2011 대한구강악안면병리학회지 Vol.35 No.3

Oral squamous cell carcinoma (OSCC) is the most common cancer of oral cancers. Recent data suggest that chemokines could be essential players in carcinogenesis and that tumor cells express chemokine receptors and use chemokines to metastasize to the target organ in many malignancies in humans. The aim of this study was to test the hypothesis that expression of SNPs in chemokine, CXCL1 and CXCL2 correlates with oral squamous cell carcinomas in Korean population. The CXCL1 and CXCL2 genotypes were determined in 21 subjects with oral squamous cell carcinoma and 90 control subjects without oral squamous cell carcinoma. The genotypes were determined by direct sequencing. The genotype distribution and allele frequency within the OSCC patients were not significantly different from those of control subjects. But among OSCC subjects, there was significant difference of CXCL1 gene in the degree of nuclear aberration. These findings suggest that CXCL1 -442C/T polymorphism and CXCL2 -264T/C polymorphism are not related to the development of OSCC but polymorphism of CXCL1 gene might have a relation with progression of OSCC in Korean population.

Expression of Endothelin-1 by Stimulation with CXCL8 in Mouse Peritoneal Macrophages

Bae, Jei-Jun,Kim, Jung-Hae,Kim, Hoon,Kim, Hee-Sun 대한미생물학회 2009 Journal of Bacteriology and Virology Vol.39 No.3

Endothelin-1 (ET-1) has been characterized as a potent vasoconstrictor secreted by the endothelium, and play a major role in the regulation of vascular tone. It has been also known to participate in inflammatory reactions. The production of ET-1 by macrophages during infection and inflammation is related to tissue perfusion and leukocyte extravasation. The aim of this study is to investigate the role of IL-8/CXCL8, as a major inflammatory chemokine, for ET-1 expression in macrophges. Expression of ET-1 mRNA in mouse peritoneal macrophages ($PeM{\phi}$) was weaker than that in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). However, expression of IL-8/CXCL8-induced ET-1 mRNA in $PeM{\phi}$ was much more stronger than that in SHR and WKY VSMCs. Maximum expression of ET-1 mRNA was observed at 50 ng/ml dose of IL-8/CXCL8 and occurred at 2 h after addition of IL-8/CXCL8. Expression of ET-1 by IL-8/CXCL8 was dependent on NF-${\kappa}B$ activation and ERK1/2 phosphorylation. Baicalein, a 12-lipoxygenase (LO) inhibitor, inhibited the expression of IL-8/CXCL8-induced ET-1 mRNA. This inhibitory action of baicalein was mediated via ERK1/2 inactivation. Induction of l2-LO mRNA by IL-8/CXCL8 and expression of ET-1 mRNA by 12-LO metabolite, 12(S)-HETE were also detected. The expression of IL-8/CXCL8-induced ET-1 mRNA was not detected in $PeM{\phi}$ transfected with 12-LO siRNA. These results suggest that IL-8/CXCL8 can act as one of main inducers of ET-1 in vascular inflammatory reactions, and ET-1 expression by IL-8/CXCL8 is related to 12-LO pathway in $PeM{\phi}$.

Chemokine (C-X-C Motif) Ligand 1 (CXCL1) Expression in the Minor Salivary Glands of Sjogren`s Syndrome Patients

( Kyung-eun Lee ),( Dong-jin Park ),( Sung-eun Choi ),( Ji-hyoun Kang ),( Yi-rang Yim ),( Ji-eun Kim ),( Jeong-won Lee ),( Lihui Wen ),( Tae-jong Kim ),( Yong-wook Park ),( Ji Shin Lee ),( Kyung Chul 대한류마티스학회 2016 대한류마티스학회지 Vol.23 No.5

Objective. To evaluate the laboratory and clinical manifestations of Sjogren`s syndrome (SS) association with chemokine (C-X-C motif) ligand 1 (CXCL1) expression in the ductal and acinar salivary gland epithelial cells (SGEC) of the minor salivary glands. Methods. The sociodemographic data of 106 SS patients was obtained, and the glandular and extraglandular manifestations of the disease documented. The minor salivary glands were biopsied and the laboratory findings analyzed. European League Against Rheumatism SS disease activity index (ESSDAI) and SS disease damage index (SSDDI) scores were obtained during biopsy. An immunohistochemical approach was used to define the expression of CXCL1 in the salivary glands. Results. Of 106 patients, the minor salivary glands of 22 patients (20.7%) stained positively for CXCL1. Such CXCL1-positive patients exhibited higher ESSDAI scores at the time of biopsy than the CXCL1-negative patients (3.86±2.27 vs. 2.64±1.62, p=0.015). Lymphadenopathy was more frequently observed in CXCL1-positive patients, compared with CXCL1-negative patients (31.8% vs. 9.5%, p=0.014). No differences between groups were identified in terms of sociodemographic characteristics, laboratory data, or the extent of the glandular manifestation of SS. Conclusion. The expression of CXCL1 within the ductal and acinar SGEC of SS patients is associated with lymphadenopathy and elevated clinical disease activity. CXCL1 may play an important role in the disease activity and prognosis of SS. (J Rheum Dis 2016;23:297-303)

CXCL1 and CXCL2 Polymorphisms of Oral Squamous Cell Carcinoma in Korean

강상욱,김준열,조재오 대한구강악안면병리학회 2011 대한구강악안면병리학회지 Vol.35 No.3

Oral squamous cell carcinoma (OSCC) is the most common cancer of oral cancers. Recent data suggest that chemokines could be essential players in carcinogenesis and that tumor cells express chemokine receptors and use chemokines to metastasize to the target organ in many malignancies in humans. The aim of this study was to test the hypothesis that expression of SNPs in chemokine, CXCL1 and CXCL2 correlates with oral squamous cell carcinomas in Korean population. The CXCL1 and CXCL2 genotypes were determined in 21 subjects with oral squamous cell carcinoma and 90 control subjects without oral squamous cell carcinoma. The genotypes were determined by direct sequencing. The genotype distribution and allele frequency within the OSCC patients were not significantly different from those of control subjects. But among OSCC subjects, there was significant difference of CXCL1 gene in the degree of nuclear aberration. These findings suggest that CXCL1 -442C/T polymorphism and CXCL2 -264T/C polymorphism are not related to the development of OSCC but polymorphism of CXCL1 gene might have a relation with progression of OSCC in Korean population.

고혈압 쥐와 정상혈압 쥐의 혈관 평활근 세포에서 케모카인 발현 비교

김정혜 ( Jung Hae Kim ),박소영 ( So Young Park ),김희선 ( Hee Sun Kim ) 영남대학교 기초/임상의학연구소 2007 Yeungnam University Journal of Medicine Vol.24 No.2S

Background:The action of chemokines to the vascular inflammation plays a pathogenic role in the development and maintenance of hypertension. 1) Materials and methods:In the present study, the expression of chemokine IL-8/CXCL8, MCP-1/CCL2 and RANTES/CCL5 was investigated in cultured vascular smooth muscle cells (VSMC) obtained from the thoracic aorta of normotensive Wister-Kyoto rat (WKY) and spontaneously hypertensive rat (SHR). We used real-time PCR and western blotting. Result:The expressions of IL-8/CXCL8, and MCP-1/CCL2 mRNA were stronger in VSMC from SHR than in WKY. However, the expression of RANTES/CCL5 was stronger in VSMC from WKY than in SHR. Expressions of CXCR1, CCR2, CD14 and PPARγ mRNA were stronger in VSMC from WKY than in SHR. Expressions of LPS-induced IL-8/CXCL8 and MCP-1/CCL2 mRNA were stronger in VSMC from SHR, but expression of LPS-induced RANTES/CCL5 was stronger in VSMC from WKY. A PPAR-γ ligand, 15-deoxy-Δ12, 14- prostaglandin J2 (15d-PGJ2) which possesses anti-inflammatory activity suppressed the expressions of LPS-induced IL-8/CXCL8, MCP-1/CCL2 and RANTES/CCL5 in VSMC from WKY and the expressions of LPS-induced MCP-1/CCL2 and RANTES/CCL5 expressions in SHR. But, the expression of LPS-induced IL-8/CXCL8 mRNA in SHR was increased by 15d- PGJ2. Angiotensin II (AngII) also induced IL-8/CXCL8 and MCP-1/CCL2 mRNA expressions in VSMC from SHR, but inhibited the expression of RANTES/CCL5 mRNA. Activities of LPS, or AngII-induced MAP kinases were stronger in VSMC from SHR than in WKY. Expression of AngII-induced IL-8/CXCL8 mRNA was associated with ERK phathway, and the expression of AngII-induced MCP-1/CCL2 mRNA was associated with p38 pathway, and the inhibition of RANTES/CCL5 mRNA by AngII was not associated with MAP Kinases pathways. Conclusion:Chemokine IL-8/CXCL8 and MCP-1/CCL2, not RANTES/CCL5, has a possibility to play a critical role in the pathogenesis of hypertension in the SHR.

CXCL12/CXCR4 Axis is Involved in the Recruitment of NK Cells by HMGB1 Contributing to Persistent Airway Inflammation and AHR During the Late Stage of RSV Infection

Chen Sisi,Tang Wei,Yu Guangyuan,Tang Zhengzhen,Liu Enmei 한국미생물학회 2023 The journal of microbiology Vol.61 No.4

We previously showed that both high-mobility group box-1 (HMGB1) and natural killer (NK) cells contribute to respiratory syncytial virus (RSV)-induced persistent airway inflammation and airway hyperresponsiveness (AHR). Meanwhile, Chemokine (C-X-C motif) ligand 12 (CXCL12) and its specific receptor (chemokine receptor 4, CXCR4) play important roles in recruitment of immune cells. CXCL12 has been reported to form a complex with HMGB1 that binds to CXCR4 and increases inflammatory cell migration. The relationship between HMGB1, NK cells and chemokines in RSV-infected model remains unclear. An anti-HMGB1 neutralizing antibody and inhibitor of CXCR4 (AMD3100) was administered to observe changes of NK cells and airway disorders in nude mice and BALB/c mice. Results showed that the mRNA expression and protein levels of HMGB1 were elevated in late stage of RSV infection and persistent airway inflammation and AHR were diminished after administration of anti-HMGB1 antibodies, with an associated significant decrease in CXCR4+ NK cells. In addition, CXCL12 and CXCR4 were reduced after HMGB1 blockade. Treatment with AMD3100 significantly suppressed the recruitment of NK cells and alleviated the airway disorders. Thus, CXCL12/CXCR4 axis is involved in the recruitment of NK cells by HMGB1, contributing to persistent airway inflammation and AHR during the late stage of RSV infection.

구강편평상피암종에서 stromal cell-derived factor-1의 발현

김경욱(Kyung-Wook Kim),한세진(Se-Jin Han),노규섭(Kyu-Seob Roh) 대한구강악안면외과학회 2010 대한구강악안면외과학회지 Vol.36 No.1

Purpose: Chemokines are structurally related, small polypeptide signaling molecules that bind to and activate a family of transmembrane G proteincoupled receptors, the chemokine receptors. Recently, interaction between the chemokine receptor CXCR4 and its ligand, stromal cell-derived factor 1(SDF-1 or CXCL12), has been found to play an important role in tumorigenicity, proliferation, metastasis and angiogenesis in many cancers such as lung cancer, breast cancer, melanoma, glioblastoma, pancreatic cancer and cholangiocarcinoma. Hence, the goal of this study is to identify the correlation of clinicopathological factors and the up-regulation of SDF-1 expression in oral squamous cell carcinoma. Material and methods: We studied the immunohistochemical staining of SDF-1, quantitative RT-PCR (qRT-PCR) of SDF-1 gene in 20 specimens of 20 patients with oral squamous cell carcinoma. Results: 1. In the immunohistochemical study of poor differentiated and invasive oral squamous cell carcinoma, the high level staining of SDF-1 was observed. And the correlation between immunohistochemical SDF-1 expression and tumor nodes metastases (TNM) classification of specimens was significant.(x2 test, P < 0.05) 2. In the SDF-1 gene qRT-PCR analysis, SDF-1 expression was more in tumor tissue than in carcinoma in situ tissue. Paired-samples analysis determined the difference of SDF-1 mRNA expression level between the cancer tissue and the carcinoma in situ tissue.(Student’s t-test, P < 0.05) Conclusion: These findings suggest that up-regulation of the SDF-1 may play a role in progression and invasion of oral squamous cell carcinoma.

Expression and functional roles of the chemokine receptor CXCR7 in acute myeloid leukemia cells

Ha-Yon Kim,So-YeonLee,Deog-Young Kim,Ji-Young Moon,Yoon-Seok Choi,송익찬,이효진,Hwan Jung Yun,Samyong Kim,조덕연 대한혈액학회 2015 Blood Research Vol.50 No.4

BackgroundThe C-X-C chemokine receptor 7 (CXCR7) has been shown to be a decoy receptor for CXCR4 in certain cell types. We investigated the expression status and functional roles of CXCR7 in acute myeloid leukemia (AML) cells in vitro.MethodsCXCR7 mRNA was knocked down in AML cells by using small interfering RNA (siRNA) technology, and subsequent biological alterations in the cells were evaluated in vitro. ResultsAll AML cell lines examined in this study (U937, K562, KG1a, HL-60, and MO7e) and pri-mary CD34+ cells obtained from patients with AML expressed CXCR7 mRNA at various levels. Western blotting showed that all AML cells produced CXCR7. Furthermore, all AML cells expressed CXCR7 in both the cytoplasm and on the cell surface at various levels. Stromal cell-derived factor-1 (SDF-1; C-X-C motif ligand 12 (CXCL12)) induced internal-ization of cell surface CXCR7. However, neither hypoxia nor the examined hematopoietic growth factors (interleukin-1 (IL-1), IL-3, IL-6, granulocyte-colony-stimulating factor, granulocyte, macrophage-colony-stimulating factor, and stem cell factor) and proin-flammatory cytokines (interferon-, transforming growth factor-, and tumor necrosis factor-) were found to alter cell surface CXCR7 expression. The transfection of AML cells with CXCR4 siRNA, but not CXCR7 siRNA, significantly impaired the CXCL12-induced transmigration of the cells. The transfection of AML cells with CXCR7 siRNA did not affect the survival or proliferation of these cells. Knockdown of CXCR7, but not CXCR4, induced the upregulation of CXCL12 mRNA expression and CXCL12 production in AML cells.ConclusionCXCR7 is involved in the regulation of autocrine CXCL12 in AML cells.

Histamine Induced Production of Chemokine CXCL8 Through H1R/PLC and NF-κB Signaling Pathways in Nasal Fibroblasts

강병진,박주후,이흥만 대한비과학회 2020 Journal of rhinology Vol.27 No.2

Background and Objectives: Histamine has been suggested to play an important role during allergic and inflammatory reactions, affecting allergic rhinitis and chronic rhinosinusitis. CXCL8 is a pro-inflammatory chemokine and a critical factor that causes many airway inflammatory diseases including allergic rhinitis and chronic rhinosinusitis.Materials and Method: Histamine cytotoxicity was measured by MTT assay. Real-time polymerase chain reaction was used to identify histamine type 1 receptor in nasal fibroblasts. The fibroblasts were then treated with histamine with or without a histamine type 1 receptor antagonist and the CXCL8 protein was assessed using an enzyme-linked immunosorbent assay (ELISA). The downstream signaling molecules, including phospholipase C and phospho-p50, were evaluated by western blot and immunofluorescent staining.Results: Histamine had no significant cytotoxic effect until the concentration reached 1,000 μM. Histamine type 1 receptor mRNA was expressed in nasal fibroblasts. CXCL8 protein expression level was significantly increased following histamine stimulation. However, the expression level of CXCL8 decreased when phospholipase C was inhibited by U73122. Histamine increased phospho-p50 expression as seen in western blot results. The BAY11-7082, NF-κB inhibitor significantly reduced CXCL8 production in histamine-stimulated nasal fibroblasts.Conclusion: Histamine can induce the production of NF-κB controlled-chemokine CXCL8 by nasal fibroblasts, which supports a role for histamine in upper airway inflammatory diseases.

Molecular Imaging of CXCL12 Promoter-driven HSV1-TK Reporter Gene Expression

Lina Alon,Dara L. Kraitchman,Michael Schär,Angel Cortez,Nirbhay N. Yadav,Rebecca Krimins,Peter V. Johnston,Michael T. McMahon,Peter C. M. van Zijl,Sridhar Nimmagadda,Martin G. Pomper,Jeff W. M. Bulte 한국생물공학회 2018 Biotechnology and Bioprocess Engineering Vol.23 No.2

The C-X-C motif chemokine 12 (CXCL12, SDF1a) and its receptor, CXCR4, play a fundamental role in several biological processes, including hematopoiesis, cardiogenesis, cancer progression, and stem cell migration. Noninvasive monitoring of CXCL12 is highly desirable for optimizing strategies that combine mobilization of therapeutic cells to combat cancer or to assist in cardiac tissue repair after myocardial infarction. Here, we report on an MRI reporter gene system for directly monitoring CXCL12 expression in vivo. Glioma cells and human adipose-derived stem cells (hADSC) were transduced with the herpes simplex virus type-1-thymidine kinase (HSV1- tk) reporter gene expressed under the CXCL12 promoter. HSV1-tk expression resulted in accumulation of the PET tracer [125I]FIAU in vitro and in vivo and induced cell death after ganciclovir treatment. Furthermore, the results show that conditional expression of the reporter gene can be induced by hypoxia in transduced cells. Transduced hADSC were incubated with the CEST MRI probe 5-methyl-5, 6- dihydrothymidine (5-MDHT) and transplanted into swine heart. Transplanted cells were clearly visible on Chemical Exchange Saturation Transfer (CEST) MRI using a 3T clinical scanner. Therefore, we conclude that it is possible to image CXCL12 expression with MRI in a large animal model, opening up a possible route to clinical translation.