A CXC chemokine gene, CXCL12, from rock bream, Oplegnathus fasciatus: Molecular characterization and transcriptional profile

Thulasitha, W.S.,Umasuthan, N.,Whang, I.,Lim, B.S.,Jung, H.B.,Noh, J.K.,Lee, J. Academic Press 2015 FISH AND SHELLFISH IMMUNOLOGY Vol.45 No.2

Chemokines are small, structurally related chemotactic cytokines characterized by the presence of conserved cysteine residues. In the present study, we identified the cDNA of a CXC chemokine from Oplegnathus fasciatus, designated as OfCXCL12. An open reading frame of 297 bp encoded a 98 amino acid peptide with a putative signal peptide of 23 amino acids. The CXC family-specific small cytokine domain (SCY), which is highly conserved among vertebrates, was located between residues 29 and 87. The characteristic conserved cysteine residues in the CXC motif of OfCXCL12 were separated by tyrosine (Y). Similar to other vertebrate CXCL12 proteins, OfCXCL12 also lacked the ELR motif and hence belongs to ELR<SUP>-</SUP> subfamily. Phylogenetic analysis revealed two distinct clades, consisting of fish and tetrapod CXCL12 homologs. Constitutive expression with significantly higher levels of OfCXCL12 mRNA transcription was detected in immune-related organs, including the head kidney, spleen, and kidney. Infection with bacterial and viral agents led to significant upregulation of mRNA expression in both the head kidney and spleen, in a stimulant-specific manner. Stimulation of peripheral blood leukocytes by the mitogen concanavalin-A significantly induced OfCXCL12 transcription. Results from the present study suggest an important role for OfCXCL12 in immune defense against bacterial and viral infection in rock bream.

LPS-Induced Migration of Peritoneal B-1 Cells is Associated with Upregulation of CXCR4 and Increased Migratory Sensitivity to CXCL12

문하나,이재기,신상혁,김태진 대한의학회 2012 Journal of Korean medical science Vol.27 No.1

B-1 cells, which constitute a predominant lymphocyte subset in serosal cavities and produce most of natural antibodies, are subdivided into the CD5+ B-1a and CD5- B-1b cell subpopulations, but the differential roles of B-1a and B-1b cells are not well understood. We report that B-1a cells preferentially migrate out of the peritoneal cavity and upregulate the expression of CXCR4 with heightened sensitivity to CXCL12 and CXCL13 upon LPS treatment compared to B-1b and B-2 cells. Whereas B-1a cells were slightly more abundant than B-1b and B-2 cells in the homeostatic condition, the number of B-1a cells preferentially decreased 48 hr after LPS treatment. The decrease in the peritoneal B-1a cell number was accompanied with increased migration of B-1a cells toward CXCL-12 and CXCL-13 in in vitro transmigration assay using peritoneal B cells from LPS treated mice. The expression level of CXCR4, but not of CXCR5, was also more prominently increased in B-1a cells upon LPS stimulation. LPS-stimulated B-1a cells did not accumulate in omental milky spots in contrast to B-2 cells. These results suggest that B-1a cells actively migrate out of the peritoneal cavity through the regulation of the migratory responsiveness to chemokines and actively participate in systemic immune responses.

LPS-Induced Migration of Peritoneal B-1 Cells is Associated with Upregulation of CXCR4 and Increased Migratory Sensitivity to CXCL12

Moon, Hana,Lee, Jae-Ghi,Shin, Sang Hyuck,Kim, Tae Jin The Korean Academy of Medical Sciences 2012 JOURNAL OF KOREAN MEDICAL SCIENCE Vol.27 No.1

<P>B-1 cells, which constitute a predominant lymphocyte subset in serosal cavities and produce most of natural antibodies, are subdivided into the CD5<SUP>+</SUP> B-1a and CD5<SUP>-</SUP> B-1b cell subpopulations, but the differential roles of B-1a and B-1b cells are not well understood. We report that B-1a cells preferentially migrate out of the peritoneal cavity and upregulate the expression of CXCR4 with heightened sensitivity to CXCL12 and CXCL13 upon LPS treatment compared to B-1b and B-2 cells. Whereas B-1a cells were slightly more abundant than B-1b and B-2 cells in the homeostatic condition, the number of B-1a cells preferentially decreased 48 hr after LPS treatment. The decrease in the peritoneal B-1a cell number was accompanied with increased migration of B-1a cells toward CXCL-12 and CXCL-13 in in vitro transmigration assay using peritoneal B cells from LPS treated mice. The expression level of CXCR4, but not of CXCR5, was also more prominently increased in B-1a cells upon LPS stimulation. LPS-stimulated B-1a cells did not accumulate in omental milky spots in contrast to B-2 cells. These results suggest that B-1a cells actively migrate out of the peritoneal cavity through the regulation of the migratory responsiveness to chemokines and actively participate in systemic immune responses.</P>

REWIEW : Role of the CXC12-CXCR4 Axis and CXCL16 in Inflammatory Bowel Disease

( Hiroshi Nakase ),( Minoru Matsuura ),( Sakae Mikami ),( Norimitsu Uza ),( Tsutomu Chiba ) 대한장연구학회 2012 Intestinal Research Vol.10 No.2

Numerous studies of colitis in IBD (inflammatory bowel diseases) patients and in animal models have demonstrated that both inflammatory cytokines and chemokines are up-regulated in settings of active inflammation. Blockade or absence of various cytokines and chemokines attenuates the disease in murine models of IBD. Therefore, identifying cytokines and chemokines involved in intestinal inflammation provide promising targets for the development of new drugs in the treatment of IBD. In general, chemokines have been implicated in many fundamental immune processes including lymphoid organogenesis, immune cell differentiation, development and positioning. Many chemokines are markedly increased in intestinal tissue from patients with IBD. In this study, we focused on the role of CXCL12-CXCR4 and CXCL16. CXCL12-CXCR4 axis plays a crucial role in the pathophysiology of IBD, especially UC, while SR-PSOX/CXCL16 plays a significant role in the pathophysiology of CD. Our present data suggest new insights into the etiology of IBD and we hope that the manipulation of these chemokines may have therapeutic value. (Intest Res 2012;10:125-133)

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.

An Investigation of SDF1/CXCR4 Gene Polymorphisms in Autism Spectrum Disorder: A Family-Based Study

Tayfun Kara,İ,smail Akaltun,Bedia Cakmakoglu,İ,lyas Kaya,Salih Zoroğ,lu 대한신경정신의학회 2018 PSYCHIATRY INVESTIGATION Vol.15 No.3

Objective-Autism spectrum disorders (ASD) have a complex pathophysiology including genetic, inflammatory and neurodevelopmental components. We aim to investigate the relationship between ASD and gene polymorphisms of stromal cell-derived factor-1 (SDF-1) and its receptor CXC chemokine receptor-4 (CXCR4), which may affect inflammatory and neurodevelopmental processes. Methods-101 children diagnosed with ASD aged 2–18 and their biological parents were included in the study. All participants were assessed using an information form and the Children were assessed using Childhood Autism Rating Scale (CARS). SDF-1 G801→A and CXCR4 C13→T polymorphisms were detected by genetic techniques. The results were evaluated using the transmission disequilibrium test (TDT) and haplotype relative risk (HRR). Results-Following TDT evaluation for CXCR4, the assumption of equality was not rejected (χ2=1.385, p=0.239). HRR for the C allele was 1.037 [HRR (95%CI)=0.937 (0.450-2.387), χ2=0.007, p=0.933] and HRR for the T allele was 0.965 [HRR (95%CI)=0.965 (0.419-2.221), χ2=1.219, p=0.270], but the findings were statistically insignificant. Based on TDT evaluation for SDF1, the assumption of equality cannot be rejected (χ2=0, p=0.999). HRR for the A allele was 0.701 [HRR (95%CI)=0.701 (0.372-1.319), χ2=1.219, p=0.270] and HRR for the G allele was 1.427 [HRR (95%CI)=1.427 (0.758-2.686), χ2=1.219, p=0.270], but the findings were statistically insignificant. Conclusion-The genetic screening of blood samples from mother, father and child trios could not show a significant association between SDF1/CXCR4 genes and ASD on the basis of TDT and HRR tests. More extensive genetic studies are now needed to investigate the relationship between SDF1/CXCR4 gene polymorphisms and ASD.

Inhibitory effect of CXC chemokine receptor 4 antagonist AMD3100 on bleomycin induced murine pulmonary fibrosis

Song, Jeong-Sup,Kang, Chun-Mi,Kang, Hyeon-Hui,Yoon, Hyung-Kyu,Kim, Young-Kyoon,Kim, Kwan-Hyung,Moon, Hwa-Sik,Park, Sung-Hak Korean Society for Biochemistry and Molecular Bion 2010 Experimental and molecular medicine Vol.42 No.6

CXC chemokine receptor 4 (CXCR4), which binds the stromal cell-derived factor-1 (SDF-1), has been shown to play a critical role in mobilizing the bone marrow (BM)-derived stem cells and inflammatory cells. We studied the effects of AMD3100, CXCR4 antagonist, on a murine bleomycin-induced pulmonary fibrosis model. Treatment of mice with AMD3100 in bleomycin-treated mice resulted in the decrease of SDF-1 in bronchoalveolar lavage (BAL) fluids at an early stage and was followed by the decrease of fibrocytes in the lung. AMD3100 treatment decreased the SDF-1 mRNA expression, fibrocyte numbers in the lung at an early stage (day 3) and CXCR4 expression at the later stage (day 7 and 21) after bleomycin injury. The collagen content and pulmonary fibrosis were significantly attenuated by AMD3100 treatment in later stage of bleomycin injury. AMD3100 treatment also decreased the murine mesenchymal and hematopoietic stem cell chemotaxis when either in the stimulation with bleomycin treated lung lysates or SDF-1 in vitro. In BM stem cell experiments, the phosphorylation of p38 MAPK which was induced by SDF-1 was significantly blocked by addition of AMD3100. Our data suggest that AMD3100 might be effective in preventing the pulmonary fibrosis by inhibiting the fibrocyte mobilization to the injured lung via blocking the SDF-1/CXCR4 axis.

Inhibitory effect of CXC chemokine receptor 4 antagonist AMD3100 on bleomycin induced murine pulmonary fibrosis

송정섭,Chun Mi Kang,Hyeon Hui Kang,윤형규,김영균,김관형,문화식,박성학 생화학분자생물학회 2010 Experimental and molecular medicine Vol.42 No.6

CXC chemokine receptor 4 (CXCR4), which binds the stromal cell-derived factor-1 (SDF-1), has been shown to play a critical role in mobilizing the bone marrow (BM)-derived stem cells and inflammatory cells. We studied the effects of AMD3100, CXCR4 antagonist, on a murine bleomycin-induced pulmonary fibrosis model. Treatment of mice with AMD3100 in bleomycin-treated mice resulted in the decrease of SDF-1 in bronchoalveolar lavage (BAL) fluids at an early stage and was followed by the decrease of fibrocytes in the lung. AMD3100 treatment decreased the SDF-1 mRNA expression, fibrocyte numbers in the lung at an early stage (day 3) and CXCR4 expression at the later stage (day 7 and 21) after bleomycin injury. The collagen content and pulmonary fibrosis were significantly attenuated by AMD3100 treatment in later stage of bleomycin injury. AMD3100 treatment also decreased the murine mesenchymal and hematopoietic stem cell chemotaxis when either in the stimulation with bleomycin treated lung lysates or SDF-1 in vitro. In BM stem cell experiments, the phosphorylation of p38 MAPK which was induced by SDF-1 was significantly blocked by addition of AMD3100. Our data suggest that AMD3100might be effective in preventing the pulmonary fibrosis by inhibiting the fibrocyte mobilization to the injured lung via blocking the SDF-1/CXCR4 axis.

Expression of CXCR4 and SDF-1αin Primary Breast Cancers and Metastatic Lymph Nodes

Jong-Ok Kim,Kwang-Sun Suh,Dong-Ho Lee,Hae-Joung Sul,Jung-Uee Lee,Kyu-Sang Song 한국유방암학회 2009 Journal of breast cancer Vol.12 No.4

Purpose: A CXCR4/stroma derived factor-1α(SDF-1α, CXCL12) interaction is involved in many metastatic cancer mechanisms, including breast cancer. The primary objectives of this study were to investigate the correlation between CXCR4 and axillary lymph node metastasis and to clarify the interaction between CXCR4 in primary tumor cells and SDF-1αin metastatic lymph nodes. An analysis of the correlation between CXCR4, SDF-1αand clinicopathologic features was also performed. Methods: Representative areas from 44 invasive ductal carcinomas were selected for construction of tissue microarrays using a 5 mm punch. Breast cancers (n=44), metastatic axillary lymph nodes (n=18) and non-metastatic axillary lymph nodes (n=26) were immunohistochemically stained for CXCR4, SDF-1α, estrogen receptor (ER), progesterone receptor (PR) and HER2. The parameters of age, tumor size, nuclear grade, histologic grade, lymph node status and pathologic node (pN) stage pN0 to pN3 were evaluated. Results: CXCR4 expression was negatively correlated with increased age (p=0.005) and positively correlated with a large tumor size (p=0.043) and PR expression (p=0.027). CXCR4 expression was not correlated with metastatic lymph nodes (p=0.079) and SDF-1αexpression in metastatic lymph nodes (p=0.062). However, CXCR4 nuclear positivity is correlated with lymph node metastasis (p=0.044). SDF-1αwas not correlated with any clinicopathologic feature in a statistically significant manner. Conclusion: An evaluation of young age, large tumor size and PR expression helps predict lymph node metastasis and poor prognosis. Expression of CXCR4 nuclear positivity is correlated with a poor prognosis.

Stromal-cell-derived Factor 1-α Promotes Tumor Progression in Colorectal Cancer

박세준,안태성,조성우,김창진,정동준,손명원,배상호,신응진,이문수,김창호,백무준 대한대장항문학회 2012 Annals of Coloproctolgy Vol.28 No.1

Purpose: Although stromal-cell-derived factor (SDF)-1α is suggested to be involved in tumorigenicity and tumor angiogenesis,the clinicopathological significance of its expression in colorectal cancers is not fully understood. We examined SDF-1α expression in colorectal cancers and investigated its relationship to clinicopathological features such as tumor staging, lymph-node metastasis, vascular invasion (VI), lymphatic invasion (LI) and neural invasion (NI). Methods: Specimens of 83 primary colorectal cancers were examined immunohistochemically, and the relationships between clinicopathological features and SDF-1α expression were analyzed. To compare the expressions between the normal colon tissue and colorectal cancer tissues, we performed Western blot analyses. Results: According to the Western blot analyses, SDF-1α was more highly expressed in colorectal carcinoma tissues than in normal colonic mucosa (20/21). According to the immunohistochemical stain, SDF-1α was associated with nodal status,distant metastasis, tumor staging, VI and LI. SDF-1α expression had a significant prognostic value for overall survival. Kaplan-Meier plots of survival in patients with high SDF-1α showed that high SDF-1α expression was associated with a shorter overall survival. However, no association was found between SDF-1α expression and other pathologic or clinical variables, including age, gender, degree of differentiation, and presence of perineural invasion. Conclusion: The expression of SDF-1α might be associated with tumor progression in colorectal cancer. Inhibition of SDF-1α could be a therapeutic option in colorectal cancer patients.