BACKGROUND: Chemokines have strong chemoattractant effects and are involved in a variety of immune and inflammatory reactions, such as attracting activated T lymphocytes, neutrophils, monocytes and natural killer cell...BACKGROUND: Chemokines have strong chemoattractant effects and are involved in a variety of immune and inflammatory reactions, such as attracting activated T lymphocytes, neutrophils, monocytes and natural killer cells via the pathway of G protein-coupled receptors to sites of inflammatory injury and contribute to wound repair. This investigation was designed to assess the levels of chemokine interferon-gamma inducible protein-10 (IP-10) and IP-10 mRNA, and the relationship between IP-10 mRNA and HBV-DNA and alanine aminotransferase (ALT) in patients with chronic hepatitis B. METHODS: The levels of IP-10 mRNA in peripheral blood mononuclear cells (PBMCs) were kinetically detected by real-time polymerase chain reaction (PCR). The rate of chemokine/GAPDH was regarded as the extreme level of chemokine. The level of IP-10 in serum was measured by enzyme linked immunosorbent assay (ELISA), and the expression of IP-10 in hepatic biopsy tissue was detected by streptavidin-peroxidase (SP) immunohistochemistry. RESULTS: The level of IP-10 mRNA in the PBMCs of patients was 0.7387 +/- 0.0768 (lg cDNA/lg GAPDH); it was significantly higher in patients with chronic hepatitis B than that in normal controls (P<0.001). The level of IP-10 in the serum of patients was 660.9 +/- 75.5 pg/ml. There was a significant difference between patients with chronic hepatitis B and normal controls (P<0.05). In patients with chronic hepatitis B, the level of IP-10 mRNA in PBMCs was correlated with the IP-10 plasma level (r=0.7312, P<0.001), and the IP-10 plasma level was fairly correlated with the levels of ALT and HBV-DNA plasma (r=0.7235, P<0.001; r=0.7371, P<0.001). IP-10 was found by immunohistochemical analysis to be selectively upregulated on sinusoidal endothelium. CONCLUSIONS: The expression of IP-10 mRNA in PBMCs, IP-10 plasma concentration and the expression of IP-10 in sinusoidal endothelium are all high in patients with chronic hepatitis B. Chemokine IP-10 may play an important role in trafficking inflammatory cells to the local focus in the liver and induce the development of the chronicity of hepatitis B.展开更多
AIM: To investigate the effect of secreted frizzledrelated proteins(s FRPs) on CXC chemokine expression in human mesenchymal stem cells(h MSCs).METHODS: CXC chemokines such as CXCL5 and CXCL8 are induced in h MSCs dur...AIM: To investigate the effect of secreted frizzledrelated proteins(s FRPs) on CXC chemokine expression in human mesenchymal stem cells(h MSCs).METHODS: CXC chemokines such as CXCL5 and CXCL8 are induced in h MSCs during differentiation with osteogenic differentiation medium(OGM) and may be involved in angiogenic stimulation during bone repair. h MSCs were treated with conditioned medium(CM) from L-cells expressing non-canonical Wnt5 a protein, or with control CM from wild type L-cells, or directly with s FRPs for up to 10 d in culture. m RNA expression levels of both CXCL5 and CXCL8 were quantitated by real-time reverse transcriptase-polymerase chain reaction and secreted protein levels of these proteins determined by ELISA. Dose-(0-500 ng/m L) and time-response curves were generated for treatment with s FRP1. Signal transduction pathways were explored by western blot analysis with pan- or phosphorylation-specific antibodies, through use of specific pathway inhibitors, and through use of si RNAs targeting specific frizzled receptors(Fzd)-2 and 5 or thereceptor tyrosine kinase-like orphan receptor-2(Ro R2) prior to treatment with s FRPs. RESULTS: CM from L-cells expressing Wnt5 a, a noncanonical Wnt, stimulated an increase in CXCL5 m RNA expression and protein secretion in comparison to control L-cell CM. s FRP1, which should inhibit both canonical and non-canonical Wnt signaling, surprisingly enhanced the expression of CXCL5 at 7 and 10 d. Dickkopf1, an inhibitor of canonical Wnt signaling prevented the s FRPstimulated induction of CXCL5 and actually inhibited basal levels of CXCL5 expression at 7 but not at 10 d post treatment. In addition, all four s FRPs isoforms induced CXCL8 expression in a dose- and time-dependent manner with maximum expression at 7 d with treatment at 150 ng/m L. The largest increases in CXCL5 expression were seen from stimulation with s FRP1 or s FRP2. Analysis of mitogen-activated protein kinase signaling pathways in the presence of OGM showed s FRP1-induced phosphorylation of extracellular signal-regulated kinase(ERK)(p44/42) maximally at 5 min after s FRP1 addition, earlier than that found in OGM alone. Addition of a phospholipase C(PLC) inhibitor also prevented s FRPstimulated increases in CXCL8 m RNA. si RNA technology targeting the Fzd-2 and 5 and the non-canonical Fzd co-receptor Ro R2 also significantly decreased s FRP1/2-stimulated CXCL8 m RNA levels.CONCLUSION: CXC chemokine expression in h MSCs is controlled in part by s FRPs signaling through noncanonical Wnt involving Fzd2/5 and the ERK and PLC pathways.展开更多
Breast cancer is the most frequently diagnosed cancer in women under 60, and the second most diagnosed cancer in women over 60. While significant </span><span style="font-family:Verdana;">progres...Breast cancer is the most frequently diagnosed cancer in women under 60, and the second most diagnosed cancer in women over 60. While significant </span><span style="font-family:Verdana;">progress has been made in developing targeted therapies for breast cancer,</span> <span style="font-family:Verdana;">advanced breast cancer continues to have high mortality, with poor 5-year</span> <span style="font-family:Verdana;">survival rates. Thus, current therapies are insufficient in treating advanced</span><span style="font-family:Verdana;"> stages of breast cancer;new treatments are sorely needed to address the complexity of advanced-stage breast cancer. Oncolytic virotherapy has been explored as a therapeutic approach capable of systemic administration, targeting cancer cells, and sparing normal tissue. In particular, oncolytic adenoviruses have been exploited as viral vectors due to their ease of manipulation, production, and demonstrated clinical safety profile. In this study, we engineered an oncolytic adenovirus to target the chemokine receptors CXCR4 and CXCR7. The overexpression of CXCR4 and CXCR7 is implicated in the initiation, survival, progress, and metastasis of breast cancer. Both receptors bind to the ligand, CXCL12 (SDF-1), which has been identified to play a crucial role in the metastasis of breast cancer cells. This study incorporated a T4 fibritin protein fused to CXCL12 into the tail domain of an adenovirus fiber </span><span style="font-family:Verdana;">to retarget the vector to the CXCR4 and CXCR7 chemokine receptors. We</span> <span style="font-family:Verdana;">showed that the modified virus targets and infects CXCR4- and CXCR7-</span><span style="font-family:Verdana;">overexpressing breast cancer cells more efficiently than a wild-type control</span><span style="font-family:Verdana;"> vector. In addition, the substitution of the wild-type fiber and knob with the modified chimeric fiber did not interfere with oncolytic capability. Overall, the results of this study demonstrate the feasibility of retargeting adenovirus vectors to chemokine receptor-positive tumors.展开更多
Objective:Colorectal cancer(CRC)is a major cause of cancer-related deaths worldwide.The class of chemokines known as cysteine-x-cysteine(CXC)motif ligands(CXCL)is thought to have a significant role in inflammation.A p...Objective:Colorectal cancer(CRC)is a major cause of cancer-related deaths worldwide.The class of chemokines known as cysteine-x-cysteine(CXC)motif ligands(CXCL)is thought to have a significant role in inflammation.A previous study implicated that CXCL family may play a role in angiogenesis and tumor development.In this comprehensive study,16 CXCLs in CRC will be analyzed for their prognostic values and expression patterns.Methods:To investigate CXCLs expression,immune cell infiltration,prognostic value significance,and genetic alteration among CRC patients,Gene Expression Profiling Interactive Analysis 2(GEPIA2),Kaplan-Meier plotter(K-M plotter),Gene Set Cancer Analysis(GSCA),STRING,GeneMANIA,and Sangerbox3.0 were employed.Results:As a result of our study,there was a significant increase in the levels of CXCL1/2/3/4/5/8/9/10/11/13/14/16 in CRC tissues,whereas CXCL12 was reduced.The expression of CXCL1/2/3/9/10/11 in CRC was linked to tumor stage.High expression of CXCL2/3/14 was associated with longer overall survival(OS)in colon adenocarcinoma(COAD)patients,and the overexpression of CXCL2/6/9/11/13 was related to long OS in rectum adenocarcinoma(READ)patients.Additionally,patients with CRC who expressed high levels of CXCL9/10/11 tended to have a longer disease-free survival(DFS).Furthermore,the functions of differentially expressed CXCLs were mainly involved in cytokine activity and chemokine effects.A significant correlation has been found between CXCLs expression and the infiltration of diverse immune cells in COAD and READ,including six types of CD4+T cells,macrophages,neutrophils,B cells,CD8+T cells,and dendritic cells.Conclusions:According to our study,CXCLs may not only serve as prognostic markers for CRC patients but also affect the immune status of CRC tissues,thereby providing new ideas for immunotherapy.展开更多
To review the implication of CXCR4 for gastrointestinal cancer, a "Pubmed" analysis was performed in order to evaluate the relevance of CXCR4 and its ligands for gastrointestinal cancers. Search terms applie...To review the implication of CXCR4 for gastrointestinal cancer, a "Pubmed" analysis was performed in order to evaluate the relevance of CXCR4 and its ligands for gastrointestinal cancers. Search terms applied were "cancer, malignoma, esophageal, gastric, colon, colorectal, hepatic, pancreatic, CXCR4, SDF-1α, and SDF-1b". CXCR4 expression correlated with dissemination of diverse gastrointestinal malignomas. The CXCR4 ligand SDF-1α might act as "chemorepellent" while SDF-1b might act as "chemorepellent" for CTLs, inducing tumor rejection. The paracrine expression of SDF-1α was furthermore closely associated with neoangiogenesis. CXCR4 and its ligands influence the dissemination, immune rejection, and neoangiogenesis of human gastrointestinal cancers. Inhibition of CXCR4 might be an interesting therapeutic option.展开更多
Recent evidence suggests that the chemokine axis of CXC chemokine ligand-12 and its receptor CXC chemokine receptor-4(CXCL12/CXCR4) is highly expressed in gynecological tumors and the axis of CXC chemokine ligand-16 a...Recent evidence suggests that the chemokine axis of CXC chemokine ligand-12 and its receptor CXC chemokine receptor-4(CXCL12/CXCR4) is highly expressed in gynecological tumors and the axis of CXC chemokine ligand-16 and CXC chemokine receptor-6(CXCL16/CXCR6) is overexpressed in inflammation-associated tumors.This study aimed to determine the relationship between CXCL12/CXCR4,CXCL16/CXCR6 and ovarian carcinoma's clinicopathologic features and prognosis.Accordingly,the expression of these proteins in ovarian tissues was detected by tissue microarray and immunohistochemistry.The expressions of CXCL12/CXCR4 and CXCL16/CXCR6 were significantly higher in epithelial ovarian carcinomas than in normal epithelial ovarian tissues or benign epithelial ovarian tumors.The expression of chemokines CXCL12 and CXCL16 were positively correlated with their receptors CXCR4 and CXCR6 in ovarian carcinoma,respectively(r = 0.300,P < 0.05;r = 0.395,P < 0.05).Moreover,the expression of CXCL12 was related to the occurrence of ascites(χ2 = 4.76,P < 0.05),the expression of CXCR4 was significantly related to lymph node metastasis(χ2 = 4.37,P < 0.05),the expression of CXCR6 was significantly related to lymph node metastasis(χ2 = 7.43,P < 0.05) and histological type(χ2 = 33.48,P < 0.05).In univariate analysis,the expression of CXCR4 and CXCL16 significantly correlated with reduced median survival(χ2 = 4.67,P < 0.05;χ2 = 4.48,P < 0.05).Therefore,we conclude that the chemokine axes CXCL12/CXCR4 and CXCL16/CXCR6 may play important roles in the growth,proliferation,invasion,and metastasis of epithelial ovarian carcinoma.展开更多
Objective: To examine expressions of chemokine receptor CXCR4 and its ligand CXCL12 in primary focus and lymphogenous metastasis of salivary adenoid cystic carcinoma (ACC) with lung metastasis. Methods: Using immunohi...Objective: To examine expressions of chemokine receptor CXCR4 and its ligand CXCL12 in primary focus and lymphogenous metastasis of salivary adenoid cystic carcinoma (ACC) with lung metastasis. Methods: Using immunohistochemical hypersensitivity catalyzed signal amplification (CSA), expressions of chemokine receptor CXCR4 and ligand CXCL12 were detected in tissue specimens from 20 cases of primary cancer focus and lymphogenous metastasis of salivary adenoid cystic carcinoma, of which 7 cases were associated with lung metastasis and 3 with lympogenous metastasis. Twenty cases of tongue carcinoma (including 10 cases with lymphogenous metastasis) and 15 cases of mucoepidermoid carcinoma (including 5 cases with lymphogenous metastasis) were used as the malignant control group;and salivary mixed tumor (n=10), tongue leukoceratosis (n=10) and cervical lymph node reactive hyperplasia (n=10) were used as the benign control group. Results: Expression of CXCR4 in the tissues and lymph metastases of oral and maxillofacial salivary ACC, mucoepidermoid carcinoma and tongue carcinoma was significantly higher than that of the benign control group (P<0.05); expression of CXCR4 in the primary focus of ACC was significantly higher than that of the malignant control group; and expression of CXCR4 in the ACC with lung metastasis was 87.1% (6/7), significantly higher than that without lung metastasis(P<0.01). There was evident positive expression of CXCL12 in endotheliocytes of microvessels within cancer and paracancer tissues and significantly high expression of CXCL12 in lymphogenous metastasis(P<0.05). Conclusion: Chemokine receptor CXCR4 and its ligand CXCL12 may be associated with local invasion and lymphogenous metastasis of oral and maxillofacial cancer, especially with lung metastasis of salivary ACC.展开更多
The role of chemokines in murine hepatitis virus strain 3 (MHV-3) induced fulminant hepatic failure (FHF) is not well defined. In this study, we investigated the role of the CXC chemokine receptor 3 (CXCR3)- associate...The role of chemokines in murine hepatitis virus strain 3 (MHV-3) induced fulminant hepatic failure (FHF) is not well defined. In this study, we investigated the role of the CXC chemokine receptor 3 (CXCR3)- associated chemokine [monokine induced by IFN-gamma (Mig/CXCL9) and interferon-gamma-inducible protein 10 (IP-10/CXCL10)] in the recruitment of intrahepatic lymphocytes and subsequent fulminant hepatic failure induced by MHV-3. Balb/cJ mice (6-8 weeks, female) were intraperitioneally injected with 100 PFU MHV-3.The proportions and numbers of T cells and NK cells as well as the expression of CXCR3 on T cells and NK cells in the liver, spleen and blood were analyzed by flow cytometry. The hepatic mRNA level of the CXCR3-associated chemokines (CXCL9 and CXCL10) was detected by realtime PCR. A transwell migration assay was used to assess the chemotactic effect of MHV-3-infected hepatocytes on the splenic lymphocytes. Following MHV-3 infection, the number of hepatic NK cells and T cells and the frequencies of hepatic NK cells and T cells expressing CXCR3 increased markedly; however, in the spleen and peripheral blood, they both decreased significantly. Moreover, the hepatic mRNAs levels of CXCL9 and CXCL10 were significantly elevated post infection. The transwell migration assay demonstrated that MHV-3-infected hepatocytes have the capacity to attract and recruit the splenic NK cells and T cells, and CXCL10 plays a key role in lymphocyte mobilization from the spleen. These results suggest that the CXCR3- associated chemokines (CXCL9 and CXCL10) may play animportant role in the recruitment of intrahepatic lymphocytes and subsequent necroinflammation and hepatic failure in MHV-3 infection.展开更多
Aflatoxin B_(1)(AFB_(1))is a naturally-occurring mycotoxin and recognized as the most toxic foodborne toxin,particularly causing damages to kidney.Glomerular podocytes are terminally differentiated epithelial cells.AF...Aflatoxin B_(1)(AFB_(1))is a naturally-occurring mycotoxin and recognized as the most toxic foodborne toxin,particularly causing damages to kidney.Glomerular podocytes are terminally differentiated epithelial cells.AFB_(1)induces podocyte inflammation,proteinuria and renal dysfunction.Studying the mechanism of AFB_(1)-induced podocyte inflammation and murine kidney dysfunction,we detected that AFB_(1)increased ubiquitindependent degradation of the transcription factor RelA through enhanced interaction of RelA with E3 ubiquitin ligase tripartite motif containing 7(TRIM7)in mouse podocyte clone-5(MPC-5)and mouse glomeruli.Reduction of RelA resulted in decreasing microRNA-9(miR-9)and activating the chemokine receptor 4(CXCR4),thioredoxin interacting protein(TXNIP),and NOD-like receptor pyrin domain-containing 3(NLRP3)signaling axis(CXCR4/TXNIP/NLRP3 pathway),leading to podocyte inflammation.We also determined that downregulation of miR-9 led to CXCR4 expression and the downstream TXNIP/NLRP3 pathway activation.Overexpression of miR-9 or deletion of CXCR4 suppressed AFB_(1)-induced CXCR4/TXNIP/NLRP3 pathway,resulting in alleviating podocyte inflammation and kidney dysfunction.Our findings indicated that ubiquitin-dependent proteolysis of RelA,downregulation of miR-9,and activation of CXCR4/TXNIP/NLRP3 pathway played an essential role in AFB_(1)-induced glomerular podocyte inflammation.Our study revealed a novel mechanism,via RelA,for the control of AFB_(1)’s nephrotoxicity,leading to an effective protection of food safety and public health.展开更多
Colorectal cancer(CRC) is the third most common cancer in men and the second most common cancer in women,worldwide. In the early stages of the disease, biomarkers predicting early relapse would improve survival rates....Colorectal cancer(CRC) is the third most common cancer in men and the second most common cancer in women,worldwide. In the early stages of the disease, biomarkers predicting early relapse would improve survival rates.In metastatic patients, the use of predictive biomarkers could potentially result in more personalized treatments and better outcomes. The CXC family of chemokines(CXCL1 to 17) are small(8 to 10 kDa) secreted proteins that attract neutrophils and lymphocytes. These chemokines signal through chemokine receptors(CXCR) 1 to 8.Several studies have reported that these chemokines and receptors have a role in either the promotion or inhibition of cancer, depending on their capacity to suppress or stimulate the action of the immune system, respectively.In general terms, activation of the CXCR1/CXCR2 pathway or the CXCR4/CXCR7 pathway is associated with tumor aggressiveness and poor prognosis; therefore,the specific inhibition of these receptors is a possible therapeutic strategy. On the other hand, the lesser known CXCR3 and CXCR5 axes are generally considered to be tumor suppressor signaling pathways, and their stimulation has been suggested as a way to fight cancer.These pathways have been studied in tumor tissues(using immunohistochemistry or measuring mRNA levels)or serum [using enzyme-linked immuno sorbent assay(ELISA) or multiplexing techniques], among other sample types. Common variants in genes encoding for the CXC chemokines have also been investigated as possible biomarkers of the disease. This review summarizes themost recent findings on the role of CXC chemokines and their receptors in CRC and discusses their possible value as prognostic or predictive biomarkers as well as the possibility of targeting them as a therapeutic strategy.展开更多
Gastric cancer is the fourth most common cancer,and the second-highest cause of cancer-related deaths worldwide.Despite extensive research to identify novel diagnostic and therapeutic agents,patients with advanced gas...Gastric cancer is the fourth most common cancer,and the second-highest cause of cancer-related deaths worldwide.Despite extensive research to identify novel diagnostic and therapeutic agents,patients with advanced gastric cancer suffer from a poor quality of life and poor prognosis,and treatment is dependent mainly on conventional cytotoxic chemotherapy.To improve the quality of life and survival of gastric cancer patients,a better understanding of the underlying molecular pathologies,and their application towards the development of novel targeted therapies,is urgently needed.Chemokines are a group of small proteins associated with cytoskeletal rearrangements,the directional migration of several cell types during development and physiology,and the host immune response via interactions with G-protein coupled receptors.There is also growing evidence to suggest that chemokines not only play a role in the immune system,but are also involved in the development and progression of tumors.In gastric cancer,CXC chemokines and chemokine receptors regulate the trafficking of cells in and out of the tumor microenvironment.CXC chemokines and their receptors can also directly influence tumorigenesis by modulating tumor transformation,survival,growth,invasion and metastasis,as well as indirectly by regulating angiogenesis,and tumor-leukocyte interactions.In this review,we will focus on the roles of CXC chemokines and their receptors in the development,progression,and metastasis of gastric tumors,and discuss their therapeutic potential for gastric cancer.展开更多
Spinal cord injury causes accumulation of a large number of leukocytes at the lesion site where they contribute to excessive inflammation.Overproduced chemokines are responsible for the migratory process of the leukoc...Spinal cord injury causes accumulation of a large number of leukocytes at the lesion site where they contribute to excessive inflammation.Overproduced chemokines are responsible for the migratory process of the leukocytes,but the regulatory mechanism underlying the production of chemokines from resident cells of the spinal cord has not been fully elucidated.We examined the protein levels of macrophage migration inhibitory factor and chemokine C-C motif chemokine ligand 2 in a spinal cord contusion model at different time points following spinal cord injury.The elevation of macrophage migration inhibitory factor at the lesion site coincided with the increase of chemokine C-C motif chemokine ligand 2 abundance in astrocytes.Stimulation of primary cultured astrocytes with different concentrations of macrophage migration inhibitory factor recombinant protein induced chemokine C-C motif chemokine ligand 2 production from the cells,and the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine attenuated the stimulatory effect.Further investigation into the underlying mechanism on macrophage migration inhibitory factor-mediated astrocytic production of chemokine C-C motif chemokine ligand 2 revealed that macrophage migration inhibitory factor activated intracellular JNK signaling through binding with CD74 receptor.Administration of the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine following spinal cord injury resulted in the reduction of chemokine C-C motif chemokine ligand 2-recruited microglia/macrophages at the lesion site and remarkably improved the hindlimb locomotor function of rats.Our results have provided insights into the functions of astrocyte-activated chemokines in the recruitment of leukocytes and may be beneficial to develop interventions targeting chemokine C-C motif chemokine ligand 2 for neuroinflammation after spinal cord injury.展开更多
Background: The allo-immune response following organ transplantation constitutes one of the main determinants concerning both short- and long- term outcomes in renal graft recipients. Chemokines and their receptors pl...Background: The allo-immune response following organ transplantation constitutes one of the main determinants concerning both short- and long- term outcomes in renal graft recipients. Chemokines and their receptors play a diversified and important role, either homeostatic or inflammatory and direct different immune-competent cell types to the allograft. While deeply studied in the last two decades, controversy persists as a result of chemokines’ pleiotropic actions. We report our analysis of CCR1, CCR3, CCR7, CCL5 and CX3CL1 expression or synthesis by graft-infiltrating cells in human kidney transplants (KTx). At the same time, we tested their robustness in diagnosing acute rejection. Methods: Fine-needle aspiration biopsies (Fnab) were performed either on days 7 or 14 post-transplantation among stable KTx and on the day of acute rejection (AR) diagnosis. Fnab cytopreparations were studied by the enzymatic avidin-biotin complex staining for CCR1, CCR3, CCR7 and CX3CL1. From another subgroup of cases, Fnab samples were cultured for 48 hours and the supernatants were analysed for CCL5 by ELISA. Results: The group of AR cases showed a significantly up-regulated expression of CCR1, CCR3, CCR7 and CX3CL1 and a significantly higher synthesis of CCL5. The positive predictive values were respectively 92%, 97%, 85%, 76% and 78% and negative predictive values were by the same order, 100%, 73%, 100%, 98% and 83%. Conclusions: Our study permits us to advance that CCR1 and CCR3 play a significant and non-redundant role in acute rejection, and it is the first report of CCR3 association with rejection, probably related to CCL5. The presence inside the graft of significant up-regulation for CCR7 surmises that part of antigen presentation may be performed there without being restricted to secondary lymphoid sites. Our results with CX3CL1 confirm other reports.展开更多
Chemokines are an indispensable component of our immune system through the regulation of directional migration and activation of leukocytes.CxCL8 is the most potent human neutrophil-attracting chemokine and plays cruc...Chemokines are an indispensable component of our immune system through the regulation of directional migration and activation of leukocytes.CxCL8 is the most potent human neutrophil-attracting chemokine and plays crucial roles in the response to infection and tissue injury.CXCL8 activity inherently depends on interaction with the human CXC chemokine receptors CXCR1 and CXCR2,the atypical chemokine receptor ACKR1,and glycosaminoglycans.Furthermore,(hetero)dimerization and tight regulation of transcription and translation,as well as post-translational modifications further fine-tune the spatial and temporal activity of CXCL8 in the context of inflammatory diseases and cancer.The CxCL8 interaction with receptors and glycosaminoglycans is therefore a promising target for therapy,as illustrated by multiple ongoing clinical trials.CXCL8-mediated neutrophil mobilization to blood is directly opposed by CXCL12,which retains leukocytes in bone marrow.CXCL12 is primarily a homeostatic chemokine that induces migration and activation of hematopoietic progenitor cells,endothelial cells,and several leukocytes through interaction with CXCR4,ACKR1,and ACKR3.Thereby,it is an essential player in the regulation of embryogenesis,hematopoiesis,and angiogenesis.However,CXCL12 can also exert inflammatory functions,as illustrated by its pivotal role in a growing list of pathologies and its synergy with CXCL8 and other chemokines to induce leukocyte chemotaxis.Here,we review the plethora of information on the CXCL8 structure,interaction with receptors and glycosaminoglycans,different levels of activity regulation,role in homeostasis and disease,and therapeutic prospects.Finally,we discuss recent research on CXCL12 biochemistry and biology and its role in pathology and pharmacology.展开更多
The interaction between some chemokines with tumoral and stromal cells can influence tumor progression. CXCL9, a monokine induced by interferon gamma (MIG), targets lymphocytes.The aim of our study was to identify and...The interaction between some chemokines with tumoral and stromal cells can influence tumor progression. CXCL9, a monokine induced by interferon gamma (MIG), targets lymphocytes.The aim of our study was to identify and quantify CD4+ and CD8+ T cells in the stroma of human breast cancer and correlate them with the presence of MIG/CXCL9. In 58 specimens of human breast carcinoma and 10 normal breast tissue from mammoplasty surgery, immunohistochemistry and ELISA methods were performed. The number of CD4+ and CD8+ T cells in breast cancer tissue was significantly increased compared with normal breast tissue with a clear predominance of CD8+ T cells. MIG/CXCL9 levels were significantly elevated respect normal breast tissue. This chemokine correlated with the number of CD8+ T cells only in non-metastatic tumors. These data suggest that MIG targets cytotoxic T cells. Their recruitment into breast carcinoma can play a critical role in malignant progression, inhibiting the production of metastasis.展开更多
Stromal cell-derived factor-1 and its receptor C-X-C chemokine receptor 4(CXCR4) have been shown to regulate neural regeneration after stroke.Howeve r,whether stromal cell-derived factor-1 receptor CXCR7,which is wide...Stromal cell-derived factor-1 and its receptor C-X-C chemokine receptor 4(CXCR4) have been shown to regulate neural regeneration after stroke.Howeve r,whether stromal cell-derived factor-1 receptor CXCR7,which is widely distributed in the develo ping and adult central nervous system,participates in neural regeneration remains poorly unde rstood.In this study,we established rat models of focal cerebral ischemia by injecting endothelin-1 into the cerebral co rtex and striatum.Starting on day 7 after injury,CXCR7-neutralizing antibody was injected into the lateral ventricle using a micro drug delivery system for 6 consecutive days.Our results showed that CXCR7-neutralizing antibody increased the total length and number of sprouting co rticospinal tra ct fibers in rats with cerebral ischemia,increased the expression of vesicular glutamate transporter 1 and growth-related protein 43,marke rs of the denervated spinal cord synapses,and promoted the differentiation and maturation of oligodendrocyte progenitor cells in the striatum.In addition,CXCR7 antibody increased the expression of CXCR4 in the striatum,increased the protein expression of RAS and ERK1/2 associated with the RAS/ERK signaling pathway,and im proved rat motor function.These findings suggest that CXCR7 improved neural functional recovery after ischemic stroke by promoting axonal regeneration,synaptogenesis,and myelin regeneration,which may be achieved by activation of CXCR4 and the RAS/ERK1/2 signaling pathway.展开更多
Classically,chemokines were described as small proteins driving leukocyte migration.Nonetheless,more and more studies are showing the great variety of cell functions and tissues in which they participate,including neu...Classically,chemokines were described as small proteins driving leukocyte migration.Nonetheless,more and more studies are showing the great variety of cell functions and tissues in which they participate,including neural cells.During the last years,research has highlighted the importance of chemokines in the nervous system,governing a wide range of processes (MesquidaVeny et al.,2021).This is evidenced for example by the crucial role played by CXCL12 during cortical development,or the homeostatic role of neuronal CX3CL1,preventing microglial activation.We are now certain that many chemokines and their receptors are widely expressed in neurons,and growing evidence has shown them as fundamental players in direct neuronal communication,both during homeostasis and after insult.展开更多
We previously reported that postsynaptic density-93 mediates neuron-microglia crosstalk by interacting with amino acids 357–395 of C-X3-C motif chemokine ligand 1(CX3 CL1) to induce microglia polarization. More impor...We previously reported that postsynaptic density-93 mediates neuron-microglia crosstalk by interacting with amino acids 357–395 of C-X3-C motif chemokine ligand 1(CX3 CL1) to induce microglia polarization. More importantly, the peptide Tat-CX3 CL1(comprising amino acids 357–395 of CX3 CL1) disrupts the interaction between postsynaptic density-93 and CX3 CL1, reducing neurological impairment and exerting a protective effect in the context of acute ischemic stroke. However, the mechanism underlying these effects remains unclear. In the current study, we found that the pro-inflammatory M1 phenotype increased and the anti-inflammatory M2 phenotype decreased at different time points. The M1 phenotype increased at 6 hours after stroke and peaked at 24 hours after perfusion, whereas the M2 phenotype decreased at 6 and 24 hours following reperfusion. We found that the peptide Tat-CX3 CL1(357–395 aa) facilitates microglial polarization from M1 to M2 by reducing the production of soluble CX3 CL1. Furthermore, the a disintegrin and metalloprotease domain 17(ADAM17) inhibitor GW280264 x, which inhibits metalloprotease activity and prevents CX3 CL1 from being sheared into its soluble form, facilitated microglial polarization from M1 to M2 by inhibiting soluble CX3 CL1 formation. Additionally, Tat-CX3 CL1(357–395 aa) attenuated long-term cognitive deficits and improved white matter integrity as determined by the Morris water maze test at 31–34 days following surgery and immunofluorescence staining at 35 days after stroke, respectively. In conclusion, Tat-CX3 CL1(357–395 aa) facilitates functional recovery after ischemic stroke by promoting microglial polarization from M1 to M2. Therefore, the Tat-CX3 CL1(357–395 aa) is a potential therapeutic agent for ischemic stroke.展开更多
基金a grant from the Nature Science Foundation of the Department of Education of Anhui Province (No. 2007kj019A).
文摘BACKGROUND: Chemokines have strong chemoattractant effects and are involved in a variety of immune and inflammatory reactions, such as attracting activated T lymphocytes, neutrophils, monocytes and natural killer cells via the pathway of G protein-coupled receptors to sites of inflammatory injury and contribute to wound repair. This investigation was designed to assess the levels of chemokine interferon-gamma inducible protein-10 (IP-10) and IP-10 mRNA, and the relationship between IP-10 mRNA and HBV-DNA and alanine aminotransferase (ALT) in patients with chronic hepatitis B. METHODS: The levels of IP-10 mRNA in peripheral blood mononuclear cells (PBMCs) were kinetically detected by real-time polymerase chain reaction (PCR). The rate of chemokine/GAPDH was regarded as the extreme level of chemokine. The level of IP-10 in serum was measured by enzyme linked immunosorbent assay (ELISA), and the expression of IP-10 in hepatic biopsy tissue was detected by streptavidin-peroxidase (SP) immunohistochemistry. RESULTS: The level of IP-10 mRNA in the PBMCs of patients was 0.7387 +/- 0.0768 (lg cDNA/lg GAPDH); it was significantly higher in patients with chronic hepatitis B than that in normal controls (P<0.001). The level of IP-10 in the serum of patients was 660.9 +/- 75.5 pg/ml. There was a significant difference between patients with chronic hepatitis B and normal controls (P<0.05). In patients with chronic hepatitis B, the level of IP-10 mRNA in PBMCs was correlated with the IP-10 plasma level (r=0.7312, P<0.001), and the IP-10 plasma level was fairly correlated with the levels of ALT and HBV-DNA plasma (r=0.7235, P<0.001; r=0.7371, P<0.001). IP-10 was found by immunohistochemical analysis to be selectively upregulated on sinusoidal endothelium. CONCLUSIONS: The expression of IP-10 mRNA in PBMCs, IP-10 plasma concentration and the expression of IP-10 in sinusoidal endothelium are all high in patients with chronic hepatitis B. Chemokine IP-10 may play an important role in trafficking inflammatory cells to the local focus in the liver and induce the development of the chronicity of hepatitis B.
基金Supported by Merit Review Award from the United States,Department of Veterans Affairs Biomedical Laboratory Research and Development Service of the VA Office of Research and Development,No.I01BX000170
文摘AIM: To investigate the effect of secreted frizzledrelated proteins(s FRPs) on CXC chemokine expression in human mesenchymal stem cells(h MSCs).METHODS: CXC chemokines such as CXCL5 and CXCL8 are induced in h MSCs during differentiation with osteogenic differentiation medium(OGM) and may be involved in angiogenic stimulation during bone repair. h MSCs were treated with conditioned medium(CM) from L-cells expressing non-canonical Wnt5 a protein, or with control CM from wild type L-cells, or directly with s FRPs for up to 10 d in culture. m RNA expression levels of both CXCL5 and CXCL8 were quantitated by real-time reverse transcriptase-polymerase chain reaction and secreted protein levels of these proteins determined by ELISA. Dose-(0-500 ng/m L) and time-response curves were generated for treatment with s FRP1. Signal transduction pathways were explored by western blot analysis with pan- or phosphorylation-specific antibodies, through use of specific pathway inhibitors, and through use of si RNAs targeting specific frizzled receptors(Fzd)-2 and 5 or thereceptor tyrosine kinase-like orphan receptor-2(Ro R2) prior to treatment with s FRPs. RESULTS: CM from L-cells expressing Wnt5 a, a noncanonical Wnt, stimulated an increase in CXCL5 m RNA expression and protein secretion in comparison to control L-cell CM. s FRP1, which should inhibit both canonical and non-canonical Wnt signaling, surprisingly enhanced the expression of CXCL5 at 7 and 10 d. Dickkopf1, an inhibitor of canonical Wnt signaling prevented the s FRPstimulated induction of CXCL5 and actually inhibited basal levels of CXCL5 expression at 7 but not at 10 d post treatment. In addition, all four s FRPs isoforms induced CXCL8 expression in a dose- and time-dependent manner with maximum expression at 7 d with treatment at 150 ng/m L. The largest increases in CXCL5 expression were seen from stimulation with s FRP1 or s FRP2. Analysis of mitogen-activated protein kinase signaling pathways in the presence of OGM showed s FRP1-induced phosphorylation of extracellular signal-regulated kinase(ERK)(p44/42) maximally at 5 min after s FRP1 addition, earlier than that found in OGM alone. Addition of a phospholipase C(PLC) inhibitor also prevented s FRPstimulated increases in CXCL8 m RNA. si RNA technology targeting the Fzd-2 and 5 and the non-canonical Fzd co-receptor Ro R2 also significantly decreased s FRP1/2-stimulated CXCL8 m RNA levels.CONCLUSION: CXC chemokine expression in h MSCs is controlled in part by s FRPs signaling through noncanonical Wnt involving Fzd2/5 and the ERK and PLC pathways.
文摘Breast cancer is the most frequently diagnosed cancer in women under 60, and the second most diagnosed cancer in women over 60. While significant </span><span style="font-family:Verdana;">progress has been made in developing targeted therapies for breast cancer,</span> <span style="font-family:Verdana;">advanced breast cancer continues to have high mortality, with poor 5-year</span> <span style="font-family:Verdana;">survival rates. Thus, current therapies are insufficient in treating advanced</span><span style="font-family:Verdana;"> stages of breast cancer;new treatments are sorely needed to address the complexity of advanced-stage breast cancer. Oncolytic virotherapy has been explored as a therapeutic approach capable of systemic administration, targeting cancer cells, and sparing normal tissue. In particular, oncolytic adenoviruses have been exploited as viral vectors due to their ease of manipulation, production, and demonstrated clinical safety profile. In this study, we engineered an oncolytic adenovirus to target the chemokine receptors CXCR4 and CXCR7. The overexpression of CXCR4 and CXCR7 is implicated in the initiation, survival, progress, and metastasis of breast cancer. Both receptors bind to the ligand, CXCL12 (SDF-1), which has been identified to play a crucial role in the metastasis of breast cancer cells. This study incorporated a T4 fibritin protein fused to CXCL12 into the tail domain of an adenovirus fiber </span><span style="font-family:Verdana;">to retarget the vector to the CXCR4 and CXCR7 chemokine receptors. We</span> <span style="font-family:Verdana;">showed that the modified virus targets and infects CXCR4- and CXCR7-</span><span style="font-family:Verdana;">overexpressing breast cancer cells more efficiently than a wild-type control</span><span style="font-family:Verdana;"> vector. In addition, the substitution of the wild-type fiber and knob with the modified chimeric fiber did not interfere with oncolytic capability. Overall, the results of this study demonstrate the feasibility of retargeting adenovirus vectors to chemokine receptor-positive tumors.
文摘Objective:Colorectal cancer(CRC)is a major cause of cancer-related deaths worldwide.The class of chemokines known as cysteine-x-cysteine(CXC)motif ligands(CXCL)is thought to have a significant role in inflammation.A previous study implicated that CXCL family may play a role in angiogenesis and tumor development.In this comprehensive study,16 CXCLs in CRC will be analyzed for their prognostic values and expression patterns.Methods:To investigate CXCLs expression,immune cell infiltration,prognostic value significance,and genetic alteration among CRC patients,Gene Expression Profiling Interactive Analysis 2(GEPIA2),Kaplan-Meier plotter(K-M plotter),Gene Set Cancer Analysis(GSCA),STRING,GeneMANIA,and Sangerbox3.0 were employed.Results:As a result of our study,there was a significant increase in the levels of CXCL1/2/3/4/5/8/9/10/11/13/14/16 in CRC tissues,whereas CXCL12 was reduced.The expression of CXCL1/2/3/9/10/11 in CRC was linked to tumor stage.High expression of CXCL2/3/14 was associated with longer overall survival(OS)in colon adenocarcinoma(COAD)patients,and the overexpression of CXCL2/6/9/11/13 was related to long OS in rectum adenocarcinoma(READ)patients.Additionally,patients with CRC who expressed high levels of CXCL9/10/11 tended to have a longer disease-free survival(DFS).Furthermore,the functions of differentially expressed CXCLs were mainly involved in cytokine activity and chemokine effects.A significant correlation has been found between CXCLs expression and the infiltration of diverse immune cells in COAD and READ,including six types of CD4+T cells,macrophages,neutrophils,B cells,CD8+T cells,and dendritic cells.Conclusions:According to our study,CXCLs may not only serve as prognostic markers for CRC patients but also affect the immune status of CRC tissues,thereby providing new ideas for immunotherapy.
文摘To review the implication of CXCR4 for gastrointestinal cancer, a "Pubmed" analysis was performed in order to evaluate the relevance of CXCR4 and its ligands for gastrointestinal cancers. Search terms applied were "cancer, malignoma, esophageal, gastric, colon, colorectal, hepatic, pancreatic, CXCR4, SDF-1α, and SDF-1b". CXCR4 expression correlated with dissemination of diverse gastrointestinal malignomas. The CXCR4 ligand SDF-1α might act as "chemorepellent" while SDF-1b might act as "chemorepellent" for CTLs, inducing tumor rejection. The paracrine expression of SDF-1α was furthermore closely associated with neoangiogenesis. CXCR4 and its ligands influence the dissemination, immune rejection, and neoangiogenesis of human gastrointestinal cancers. Inhibition of CXCR4 might be an interesting therapeutic option.
基金supported by grants from NationalNatural Science Foundation for Young Scholars of China(No. 30700763)Promotive Research Foundation forExcellent Young and Middle-aged Scientists of Shandong(No. BS2009SW002)
文摘Recent evidence suggests that the chemokine axis of CXC chemokine ligand-12 and its receptor CXC chemokine receptor-4(CXCL12/CXCR4) is highly expressed in gynecological tumors and the axis of CXC chemokine ligand-16 and CXC chemokine receptor-6(CXCL16/CXCR6) is overexpressed in inflammation-associated tumors.This study aimed to determine the relationship between CXCL12/CXCR4,CXCL16/CXCR6 and ovarian carcinoma's clinicopathologic features and prognosis.Accordingly,the expression of these proteins in ovarian tissues was detected by tissue microarray and immunohistochemistry.The expressions of CXCL12/CXCR4 and CXCL16/CXCR6 were significantly higher in epithelial ovarian carcinomas than in normal epithelial ovarian tissues or benign epithelial ovarian tumors.The expression of chemokines CXCL12 and CXCL16 were positively correlated with their receptors CXCR4 and CXCR6 in ovarian carcinoma,respectively(r = 0.300,P < 0.05;r = 0.395,P < 0.05).Moreover,the expression of CXCL12 was related to the occurrence of ascites(χ2 = 4.76,P < 0.05),the expression of CXCR4 was significantly related to lymph node metastasis(χ2 = 4.37,P < 0.05),the expression of CXCR6 was significantly related to lymph node metastasis(χ2 = 7.43,P < 0.05) and histological type(χ2 = 33.48,P < 0.05).In univariate analysis,the expression of CXCR4 and CXCL16 significantly correlated with reduced median survival(χ2 = 4.67,P < 0.05;χ2 = 4.48,P < 0.05).Therefore,we conclude that the chemokine axes CXCL12/CXCR4 and CXCL16/CXCR6 may play important roles in the growth,proliferation,invasion,and metastasis of epithelial ovarian carcinoma.
文摘Objective: To examine expressions of chemokine receptor CXCR4 and its ligand CXCL12 in primary focus and lymphogenous metastasis of salivary adenoid cystic carcinoma (ACC) with lung metastasis. Methods: Using immunohistochemical hypersensitivity catalyzed signal amplification (CSA), expressions of chemokine receptor CXCR4 and ligand CXCL12 were detected in tissue specimens from 20 cases of primary cancer focus and lymphogenous metastasis of salivary adenoid cystic carcinoma, of which 7 cases were associated with lung metastasis and 3 with lympogenous metastasis. Twenty cases of tongue carcinoma (including 10 cases with lymphogenous metastasis) and 15 cases of mucoepidermoid carcinoma (including 5 cases with lymphogenous metastasis) were used as the malignant control group;and salivary mixed tumor (n=10), tongue leukoceratosis (n=10) and cervical lymph node reactive hyperplasia (n=10) were used as the benign control group. Results: Expression of CXCR4 in the tissues and lymph metastases of oral and maxillofacial salivary ACC, mucoepidermoid carcinoma and tongue carcinoma was significantly higher than that of the benign control group (P<0.05); expression of CXCR4 in the primary focus of ACC was significantly higher than that of the malignant control group; and expression of CXCR4 in the ACC with lung metastasis was 87.1% (6/7), significantly higher than that without lung metastasis(P<0.01). There was evident positive expression of CXCL12 in endotheliocytes of microvessels within cancer and paracancer tissues and significantly high expression of CXCL12 in lymphogenous metastasis(P<0.05). Conclusion: Chemokine receptor CXCR4 and its ligand CXCL12 may be associated with local invasion and lymphogenous metastasis of oral and maxillofacial cancer, especially with lung metastasis of salivary ACC.
基金the National Key Basic Research Program of China (2007CB512900, 2005CB522901, 2005CB 522507)the National Science Fund of China (NSFC 30672380, 30571643)
文摘The role of chemokines in murine hepatitis virus strain 3 (MHV-3) induced fulminant hepatic failure (FHF) is not well defined. In this study, we investigated the role of the CXC chemokine receptor 3 (CXCR3)- associated chemokine [monokine induced by IFN-gamma (Mig/CXCL9) and interferon-gamma-inducible protein 10 (IP-10/CXCL10)] in the recruitment of intrahepatic lymphocytes and subsequent fulminant hepatic failure induced by MHV-3. Balb/cJ mice (6-8 weeks, female) were intraperitioneally injected with 100 PFU MHV-3.The proportions and numbers of T cells and NK cells as well as the expression of CXCR3 on T cells and NK cells in the liver, spleen and blood were analyzed by flow cytometry. The hepatic mRNA level of the CXCR3-associated chemokines (CXCL9 and CXCL10) was detected by realtime PCR. A transwell migration assay was used to assess the chemotactic effect of MHV-3-infected hepatocytes on the splenic lymphocytes. Following MHV-3 infection, the number of hepatic NK cells and T cells and the frequencies of hepatic NK cells and T cells expressing CXCR3 increased markedly; however, in the spleen and peripheral blood, they both decreased significantly. Moreover, the hepatic mRNAs levels of CXCL9 and CXCL10 were significantly elevated post infection. The transwell migration assay demonstrated that MHV-3-infected hepatocytes have the capacity to attract and recruit the splenic NK cells and T cells, and CXCL10 plays a key role in lymphocyte mobilization from the spleen. These results suggest that the CXCR3- associated chemokines (CXCL9 and CXCL10) may play animportant role in the recruitment of intrahepatic lymphocytes and subsequent necroinflammation and hepatic failure in MHV-3 infection.
基金funded by Suzhou Science and Technology Council(SNG201907)Universities Natural Science Foundation of Jiangsu Province(20KJB330002)+6 种基金General Program of China Postdoctoral Science Foundation(2022M711369)the Startup Funding of Soochow University,Jiangsu Province-Suzhou Science and Technology Planning Project(SL T201917)National Natural Science Foundation of China(32172922,31972741)Natural Science Foundation of Jiangsu Province of China(BK20211216,BK20221091)the Startup Funding of Hefei University of Technology(1302003712022058)China-CEEC Joint University Education Project(202010)the Excellence Project PrF UHK(2217/2022-2023)。
文摘Aflatoxin B_(1)(AFB_(1))is a naturally-occurring mycotoxin and recognized as the most toxic foodborne toxin,particularly causing damages to kidney.Glomerular podocytes are terminally differentiated epithelial cells.AFB_(1)induces podocyte inflammation,proteinuria and renal dysfunction.Studying the mechanism of AFB_(1)-induced podocyte inflammation and murine kidney dysfunction,we detected that AFB_(1)increased ubiquitindependent degradation of the transcription factor RelA through enhanced interaction of RelA with E3 ubiquitin ligase tripartite motif containing 7(TRIM7)in mouse podocyte clone-5(MPC-5)and mouse glomeruli.Reduction of RelA resulted in decreasing microRNA-9(miR-9)and activating the chemokine receptor 4(CXCR4),thioredoxin interacting protein(TXNIP),and NOD-like receptor pyrin domain-containing 3(NLRP3)signaling axis(CXCR4/TXNIP/NLRP3 pathway),leading to podocyte inflammation.We also determined that downregulation of miR-9 led to CXCR4 expression and the downstream TXNIP/NLRP3 pathway activation.Overexpression of miR-9 or deletion of CXCR4 suppressed AFB_(1)-induced CXCR4/TXNIP/NLRP3 pathway,resulting in alleviating podocyte inflammation and kidney dysfunction.Our findings indicated that ubiquitin-dependent proteolysis of RelA,downregulation of miR-9,and activation of CXCR4/TXNIP/NLRP3 pathway played an essential role in AFB_(1)-induced glomerular podocyte inflammation.Our study revealed a novel mechanism,via RelA,for the control of AFB_(1)’s nephrotoxicity,leading to an effective protection of food safety and public health.
基金the Institute of Health Carlos Ⅲ(ISCⅢ)No.PI16/01800 and PIE16/00011
文摘Colorectal cancer(CRC) is the third most common cancer in men and the second most common cancer in women,worldwide. In the early stages of the disease, biomarkers predicting early relapse would improve survival rates.In metastatic patients, the use of predictive biomarkers could potentially result in more personalized treatments and better outcomes. The CXC family of chemokines(CXCL1 to 17) are small(8 to 10 kDa) secreted proteins that attract neutrophils and lymphocytes. These chemokines signal through chemokine receptors(CXCR) 1 to 8.Several studies have reported that these chemokines and receptors have a role in either the promotion or inhibition of cancer, depending on their capacity to suppress or stimulate the action of the immune system, respectively.In general terms, activation of the CXCR1/CXCR2 pathway or the CXCR4/CXCR7 pathway is associated with tumor aggressiveness and poor prognosis; therefore,the specific inhibition of these receptors is a possible therapeutic strategy. On the other hand, the lesser known CXCR3 and CXCR5 axes are generally considered to be tumor suppressor signaling pathways, and their stimulation has been suggested as a way to fight cancer.These pathways have been studied in tumor tissues(using immunohistochemistry or measuring mRNA levels)or serum [using enzyme-linked immuno sorbent assay(ELISA) or multiplexing techniques], among other sample types. Common variants in genes encoding for the CXC chemokines have also been investigated as possible biomarkers of the disease. This review summarizes themost recent findings on the role of CXC chemokines and their receptors in CRC and discusses their possible value as prognostic or predictive biomarkers as well as the possibility of targeting them as a therapeutic strategy.
基金Supported by Basic Science Research Program through the National Research of Korea(NRF)funded by the Ministry of Education,Science and Technology,NRF-2009-0076540,NRF-2009-0067256
文摘Gastric cancer is the fourth most common cancer,and the second-highest cause of cancer-related deaths worldwide.Despite extensive research to identify novel diagnostic and therapeutic agents,patients with advanced gastric cancer suffer from a poor quality of life and poor prognosis,and treatment is dependent mainly on conventional cytotoxic chemotherapy.To improve the quality of life and survival of gastric cancer patients,a better understanding of the underlying molecular pathologies,and their application towards the development of novel targeted therapies,is urgently needed.Chemokines are a group of small proteins associated with cytoskeletal rearrangements,the directional migration of several cell types during development and physiology,and the host immune response via interactions with G-protein coupled receptors.There is also growing evidence to suggest that chemokines not only play a role in the immune system,but are also involved in the development and progression of tumors.In gastric cancer,CXC chemokines and chemokine receptors regulate the trafficking of cells in and out of the tumor microenvironment.CXC chemokines and their receptors can also directly influence tumorigenesis by modulating tumor transformation,survival,growth,invasion and metastasis,as well as indirectly by regulating angiogenesis,and tumor-leukocyte interactions.In this review,we will focus on the roles of CXC chemokines and their receptors in the development,progression,and metastasis of gastric tumors,and discuss their therapeutic potential for gastric cancer.
基金supported by the China Postdoctoral Science Foundation,No.2020M681689(to YMH)the Basic Scientific Research Projects of Nantong,Nos.JC2020015(to HX)and JC2020041(to YMH)。
文摘Spinal cord injury causes accumulation of a large number of leukocytes at the lesion site where they contribute to excessive inflammation.Overproduced chemokines are responsible for the migratory process of the leukocytes,but the regulatory mechanism underlying the production of chemokines from resident cells of the spinal cord has not been fully elucidated.We examined the protein levels of macrophage migration inhibitory factor and chemokine C-C motif chemokine ligand 2 in a spinal cord contusion model at different time points following spinal cord injury.The elevation of macrophage migration inhibitory factor at the lesion site coincided with the increase of chemokine C-C motif chemokine ligand 2 abundance in astrocytes.Stimulation of primary cultured astrocytes with different concentrations of macrophage migration inhibitory factor recombinant protein induced chemokine C-C motif chemokine ligand 2 production from the cells,and the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine attenuated the stimulatory effect.Further investigation into the underlying mechanism on macrophage migration inhibitory factor-mediated astrocytic production of chemokine C-C motif chemokine ligand 2 revealed that macrophage migration inhibitory factor activated intracellular JNK signaling through binding with CD74 receptor.Administration of the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine following spinal cord injury resulted in the reduction of chemokine C-C motif chemokine ligand 2-recruited microglia/macrophages at the lesion site and remarkably improved the hindlimb locomotor function of rats.Our results have provided insights into the functions of astrocyte-activated chemokines in the recruitment of leukocytes and may be beneficial to develop interventions targeting chemokine C-C motif chemokine ligand 2 for neuroinflammation after spinal cord injury.
文摘Background: The allo-immune response following organ transplantation constitutes one of the main determinants concerning both short- and long- term outcomes in renal graft recipients. Chemokines and their receptors play a diversified and important role, either homeostatic or inflammatory and direct different immune-competent cell types to the allograft. While deeply studied in the last two decades, controversy persists as a result of chemokines’ pleiotropic actions. We report our analysis of CCR1, CCR3, CCR7, CCL5 and CX3CL1 expression or synthesis by graft-infiltrating cells in human kidney transplants (KTx). At the same time, we tested their robustness in diagnosing acute rejection. Methods: Fine-needle aspiration biopsies (Fnab) were performed either on days 7 or 14 post-transplantation among stable KTx and on the day of acute rejection (AR) diagnosis. Fnab cytopreparations were studied by the enzymatic avidin-biotin complex staining for CCR1, CCR3, CCR7 and CX3CL1. From another subgroup of cases, Fnab samples were cultured for 48 hours and the supernatants were analysed for CCL5 by ELISA. Results: The group of AR cases showed a significantly up-regulated expression of CCR1, CCR3, CCR7 and CX3CL1 and a significantly higher synthesis of CCL5. The positive predictive values were respectively 92%, 97%, 85%, 76% and 78% and negative predictive values were by the same order, 100%, 73%, 100%, 98% and 83%. Conclusions: Our study permits us to advance that CCR1 and CCR3 play a significant and non-redundant role in acute rejection, and it is the first report of CCR3 association with rejection, probably related to CCL5. The presence inside the graft of significant up-regulation for CCR7 surmises that part of antigen presentation may be performed there without being restricted to secondary lymphoid sites. Our results with CX3CL1 confirm other reports.
基金KU Leuven(C1 grant C16/17/010),FWO-Vlaanderen(grant GOF8822N)the Rega Foundation.SC received a PhD fellowship from FWO-Vlaanderen(grant number 11A4220N).Figures 2-5 are created with BioRender.com.
文摘Chemokines are an indispensable component of our immune system through the regulation of directional migration and activation of leukocytes.CxCL8 is the most potent human neutrophil-attracting chemokine and plays crucial roles in the response to infection and tissue injury.CXCL8 activity inherently depends on interaction with the human CXC chemokine receptors CXCR1 and CXCR2,the atypical chemokine receptor ACKR1,and glycosaminoglycans.Furthermore,(hetero)dimerization and tight regulation of transcription and translation,as well as post-translational modifications further fine-tune the spatial and temporal activity of CXCL8 in the context of inflammatory diseases and cancer.The CxCL8 interaction with receptors and glycosaminoglycans is therefore a promising target for therapy,as illustrated by multiple ongoing clinical trials.CXCL8-mediated neutrophil mobilization to blood is directly opposed by CXCL12,which retains leukocytes in bone marrow.CXCL12 is primarily a homeostatic chemokine that induces migration and activation of hematopoietic progenitor cells,endothelial cells,and several leukocytes through interaction with CXCR4,ACKR1,and ACKR3.Thereby,it is an essential player in the regulation of embryogenesis,hematopoiesis,and angiogenesis.However,CXCL12 can also exert inflammatory functions,as illustrated by its pivotal role in a growing list of pathologies and its synergy with CXCL8 and other chemokines to induce leukocyte chemotaxis.Here,we review the plethora of information on the CXCL8 structure,interaction with receptors and glycosaminoglycans,different levels of activity regulation,role in homeostasis and disease,and therapeutic prospects.Finally,we discuss recent research on CXCL12 biochemistry and biology and its role in pathology and pharmacology.
文摘The interaction between some chemokines with tumoral and stromal cells can influence tumor progression. CXCL9, a monokine induced by interferon gamma (MIG), targets lymphocytes.The aim of our study was to identify and quantify CD4+ and CD8+ T cells in the stroma of human breast cancer and correlate them with the presence of MIG/CXCL9. In 58 specimens of human breast carcinoma and 10 normal breast tissue from mammoplasty surgery, immunohistochemistry and ELISA methods were performed. The number of CD4+ and CD8+ T cells in breast cancer tissue was significantly increased compared with normal breast tissue with a clear predominance of CD8+ T cells. MIG/CXCL9 levels were significantly elevated respect normal breast tissue. This chemokine correlated with the number of CD8+ T cells only in non-metastatic tumors. These data suggest that MIG targets cytotoxic T cells. Their recruitment into breast carcinoma can play a critical role in malignant progression, inhibiting the production of metastasis.
基金supported by the National Natural Science Foundation of China,Nos.81401002 (to SSZ),81801 053 (to XQZ)。
文摘Stromal cell-derived factor-1 and its receptor C-X-C chemokine receptor 4(CXCR4) have been shown to regulate neural regeneration after stroke.Howeve r,whether stromal cell-derived factor-1 receptor CXCR7,which is widely distributed in the develo ping and adult central nervous system,participates in neural regeneration remains poorly unde rstood.In this study,we established rat models of focal cerebral ischemia by injecting endothelin-1 into the cerebral co rtex and striatum.Starting on day 7 after injury,CXCR7-neutralizing antibody was injected into the lateral ventricle using a micro drug delivery system for 6 consecutive days.Our results showed that CXCR7-neutralizing antibody increased the total length and number of sprouting co rticospinal tra ct fibers in rats with cerebral ischemia,increased the expression of vesicular glutamate transporter 1 and growth-related protein 43,marke rs of the denervated spinal cord synapses,and promoted the differentiation and maturation of oligodendrocyte progenitor cells in the striatum.In addition,CXCR7 antibody increased the expression of CXCR4 in the striatum,increased the protein expression of RAS and ERK1/2 associated with the RAS/ERK signaling pathway,and im proved rat motor function.These findings suggest that CXCR7 improved neural functional recovery after ischemic stroke by promoting axonal regeneration,synaptogenesis,and myelin regeneration,which may be achieved by activation of CXCR4 and the RAS/ERK1/2 signaling pathway.
基金HDAC3-EAE-SCI Project with ref.PID2020-119769RA-I00 from MCIN/AEI/10.13039/501100011033 to AH。
文摘Classically,chemokines were described as small proteins driving leukocyte migration.Nonetheless,more and more studies are showing the great variety of cell functions and tissues in which they participate,including neural cells.During the last years,research has highlighted the importance of chemokines in the nervous system,governing a wide range of processes (MesquidaVeny et al.,2021).This is evidenced for example by the crucial role played by CXCL12 during cortical development,or the homeostatic role of neuronal CX3CL1,preventing microglial activation.We are now certain that many chemokines and their receptors are widely expressed in neurons,and growing evidence has shown them as fundamental players in direct neuronal communication,both during homeostasis and after insult.
基金supported by the National Natural Science Foundation of China,Nos. 82071304 (to QXZ), 81671149 (to QXZ),and 81971179 (to XML)the Natural Science Foundation of Jiangsu Province,Nos. BK20191463 (to XML) and BK20161167 (to QXZ)。
文摘We previously reported that postsynaptic density-93 mediates neuron-microglia crosstalk by interacting with amino acids 357–395 of C-X3-C motif chemokine ligand 1(CX3 CL1) to induce microglia polarization. More importantly, the peptide Tat-CX3 CL1(comprising amino acids 357–395 of CX3 CL1) disrupts the interaction between postsynaptic density-93 and CX3 CL1, reducing neurological impairment and exerting a protective effect in the context of acute ischemic stroke. However, the mechanism underlying these effects remains unclear. In the current study, we found that the pro-inflammatory M1 phenotype increased and the anti-inflammatory M2 phenotype decreased at different time points. The M1 phenotype increased at 6 hours after stroke and peaked at 24 hours after perfusion, whereas the M2 phenotype decreased at 6 and 24 hours following reperfusion. We found that the peptide Tat-CX3 CL1(357–395 aa) facilitates microglial polarization from M1 to M2 by reducing the production of soluble CX3 CL1. Furthermore, the a disintegrin and metalloprotease domain 17(ADAM17) inhibitor GW280264 x, which inhibits metalloprotease activity and prevents CX3 CL1 from being sheared into its soluble form, facilitated microglial polarization from M1 to M2 by inhibiting soluble CX3 CL1 formation. Additionally, Tat-CX3 CL1(357–395 aa) attenuated long-term cognitive deficits and improved white matter integrity as determined by the Morris water maze test at 31–34 days following surgery and immunofluorescence staining at 35 days after stroke, respectively. In conclusion, Tat-CX3 CL1(357–395 aa) facilitates functional recovery after ischemic stroke by promoting microglial polarization from M1 to M2. Therefore, the Tat-CX3 CL1(357–395 aa) is a potential therapeutic agent for ischemic stroke.