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Sample records for chemokine vmip-ii inhibits

  1. The Anti-inflammatory Protein TSG-6 Regulates Chemokine Function by Inhibiting Chemokine/Glycosaminoglycan Interactions*

    PubMed Central

    Dyer, Douglas P.; Salanga, Catherina L.; Johns, Scott C.; Valdambrini, Elena; Fuster, Mark M.; Milner, Caroline M.; Day, Anthony J.; Handel, Tracy M.

    2016-01-01

    TNF-stimulated gene-6 (TSG-6) is a multifunctional protein secreted in response to pro-inflammatory stimuli by a wide range of cells, including neutrophils, monocytes, and endothelial cells. It has been shown to mediate anti-inflammatory and protective effects when administered in disease models, in part, by reducing neutrophil infiltration. Human TSG-6 inhibits neutrophil migration by binding CXCL8 through its Link module (Link_TSG6) and interfering with the presentation of CXCL8 on cell-surface glycosaminoglycans (GAGs), an interaction that is vital for the function of many chemokines. TSG-6 was also found to interact with chemokines CXCL11 and CCL5, suggesting the possibility that it may function as a broad specificity chemokine-binding protein, functionally similar to those encoded by viruses. This study was therefore undertaken to explore the ability of TSG-6 to regulate the function of other chemokines. Herein, we demonstrate that Link_TSG6 binds chemokines from both the CXC and CC families, including CXCL4, CXCL12, CCL2, CCL5, CCL7, CCL19, CCL21, and CCL27. We also show that the Link_TSG6-binding sites on chemokines overlap with chemokine GAG-binding sites, and that the affinities of Link_TSG6 for these chemokines (KD values 1–85 nm) broadly correlate with chemokine-GAG affinities. Link_TSG6 also inhibits chemokine presentation on endothelial cells not only through a direct interaction with chemokines but also by binding and therefore masking the availability of GAGs. Along with previous work, these findings suggest that TSG-6 functions as a pluripotent regulator of chemokines by modulating chemokine/GAG interactions, which may be a major mechanism by which TSG-6 produces its anti-inflammatory effects in vivo. PMID:27044744

  2. The Anti-inflammatory Protein TSG-6 Regulates Chemokine Function by Inhibiting Chemokine/Glycosaminoglycan Interactions.

    PubMed

    Dyer, Douglas P; Salanga, Catherina L; Johns, Scott C; Valdambrini, Elena; Fuster, Mark M; Milner, Caroline M; Day, Anthony J; Handel, Tracy M

    2016-06-10

    TNF-stimulated gene-6 (TSG-6) is a multifunctional protein secreted in response to pro-inflammatory stimuli by a wide range of cells, including neutrophils, monocytes, and endothelial cells. It has been shown to mediate anti-inflammatory and protective effects when administered in disease models, in part, by reducing neutrophil infiltration. Human TSG-6 inhibits neutrophil migration by binding CXCL8 through its Link module (Link_TSG6) and interfering with the presentation of CXCL8 on cell-surface glycosaminoglycans (GAGs), an interaction that is vital for the function of many chemokines. TSG-6 was also found to interact with chemokines CXCL11 and CCL5, suggesting the possibility that it may function as a broad specificity chemokine-binding protein, functionally similar to those encoded by viruses. This study was therefore undertaken to explore the ability of TSG-6 to regulate the function of other chemokines. Herein, we demonstrate that Link_TSG6 binds chemokines from both the CXC and CC families, including CXCL4, CXCL12, CCL2, CCL5, CCL7, CCL19, CCL21, and CCL27. We also show that the Link_TSG6-binding sites on chemokines overlap with chemokine GAG-binding sites, and that the affinities of Link_TSG6 for these chemokines (KD values 1-85 nm) broadly correlate with chemokine-GAG affinities. Link_TSG6 also inhibits chemokine presentation on endothelial cells not only through a direct interaction with chemokines but also by binding and therefore masking the availability of GAGs. Along with previous work, these findings suggest that TSG-6 functions as a pluripotent regulator of chemokines by modulating chemokine/GAG interactions, which may be a major mechanism by which TSG-6 produces its anti-inflammatory effects in vivo. PMID:27044744

  3. Therapeutic potential of chemokine signal inhibition for metastatic breast cancer

    PubMed Central

    Kitamura, Takanori; Pollard, Jeffrey W.

    2015-01-01

    Metastatic breast cancer is incurable by current therapies including chemotherapy and immunotherapy. Accumulating evidence indicates that tumor-infiltrating macrophages promote establishment of the lethal metastatic foci and contribute to therapeutic resistance. Recent studies suggest that the accumulation of these macrophages is regulated by a chemokine network established in the tumor microenvironment. In this perspective paper, we elaborate on the chemokine signals that can attract monocytes/macrophages to the site of metastasis, and discuss whether inhibition of these chemokine signals can represent a new therapeutic strategy for metastatic breast cancer. PMID:26275794

  4. A20 regulates IL-1-induced tolerant production of CXC chemokines in human mesangial cells via inhibition of MAPK signaling

    PubMed Central

    Luo, Hongbo; Liu, Yuming; Li, Qian; Liao, Lingjuan; Sun, Ruili; Liu, Xueting; Jiang, Manli; Hu, Jinyue

    2015-01-01

    Chemokines and chemokine receptors are involved in the resolution or progression of renal diseases. Locally secreted chemokines mediated leukocyte recruitment during the initiation and amplification phase of renal inflammation. However, the regulation of chemokine induction is not fully understood. In this study, we found that IL-1 induced a significant up-regulation of CXC chemokines CXCL1, 2, and 8 at both mRNA and protein levels in human mesangial cells. The induction of chemokines was tolerant, as the pre-treatment of HMC with IL-1 down-regulated the induction of chemokines induced by IL-1 re-stimulation. IL-1 up-regulated the ubiquintin-editing enzyme A20. A20 over-expression down-regulated IL-1-induced up-regulation of chemokines, and A20 down-regulation reversed chemokine inhibition induced by IL-1 pre-treatment, suggested that A20 played important roles in the tolerant production of chemokines. Unexpectedly, A20 over- expression inhibited the activation of ERK, JNK, and P38, but did not inhibit the activation of NF-κB. In addition, both IL-1 treatment and A20 over-expression induced the degradation of IRAK1, an important adaptor for IL-1R1 signaling, and A20 inhibition by RNA interference partly reversed the degradation of IRAK1. Taken together, IL-1-induced A20 negatively regulated chemokine production, suggesting that A20 may be an important target for the prevention and control of kidney inflammation. PMID:26648169

  5. Inhibition of Chemokine-Glycosaminoglycan Interactions in Donor Tissue Reduces Mouse Allograft Vasculopathy and Transplant Rejection

    PubMed Central

    Dai, Erbin; Liu, Li-Ying; Wang, Hao; McIvor, Dana; Sun, Yun ming; Macaulay, Colin; King, Elaine; Munuswamy-Ramanujam, Ganesh; Bartee, Mee Yong; Williams, Jennifer; Davids, Jennifer; Charo, Israel; McFadden, Grant; Esko, Jeffrey D.; Lucas, Alexandra R.

    2010-01-01

    Background Binding of chemokines to glycosaminoglycans (GAGs) is classically described as initiating inflammatory cell migration and creating tissue chemokine gradients that direct local leukocyte chemotaxis into damaged or transplanted tissues. While chemokine-receptor binding has been extensively studied during allograft transplantation, effects of glycosaminoglycan (GAG) interactions with chemokines on transplant longevity are less well known. Here we examine the impact of interrupting chemokine-GAG interactions and chemokine-receptor interactions, both locally and systemically, on vascular disease in allografts. Methodology/Principal Findings Analysis of GAG or CC chemokine receptor 2 (CCR2) deficiency were coupled with the infusion of viral chemokine modulating proteins (CMPs) in mouse aortic allograft transplants (n = 239 mice). Inflammatory cell invasion and neointimal hyperplasia were significantly reduced in N-deacetylase-N-sulfotransferase-1 (Ndst1f/fTekCre+) heparan sulfate (GAG)-deficient (Ndst1−/−, p<0.044) and CCR2-deficient (Ccr2−/−, p<0.04) donor transplants. Donor tissue GAG or CCR2 deficiency markedly reduced inflammation and vasculopathy, whereas recipient deficiencies did not. Treatment with three CMPs was also investigated; Poxviral M-T1 blocks CC chemokine receptor binding, M-T7 blocks C, CC, and CXC GAG binding, and herpesviral M3 binds receptor and GAG binding for all classes. M-T7 reduced intimal hyperplasia in wild type (WT) (Ccr2+/+, p≤0.003 and Ccr2−/−, p≤0.027) aortic allografts, but not in Ndst1−/− aortic allografts (p = 0.933). M-T1 and M3 inhibited WT (Ccr2+/+ and Ndst1+/+, p≤0.006) allograft vasculopathy, but did not block vasculopathy in Ccr2−/− (p = 0.61). M-T7 treatment alone, even without immunosuppressive drugs, also significantly prolonged survival of renal allograft transplants (p≤0.001). Conclusions/Significance Interruption of chemokine-GAG interactions, even in the absence of

  6. Basic Research on Virus-Induced Asthma Exacerbation: Inhibition of Inflammatory Chemokine Expression by Fluticasone Propionate

    PubMed Central

    Matsukura, Satoshi; Kurokawa, Masatsugu; Homma, Tetsuya; Watanabe, Shin; Suzuki, Shintaro; Ieki, Koushi; Takeuchi, Hiroko; Notomi, Kyoko; Schleimer, Robert P.; Kawaguchi, Mio; Kokubu, Fumio

    2016-01-01

    Background Viral infection can exacerbate asthma by inducing the accumulation of inflammatory cells in the airway. We have previously reported that double-stranded RNA (dsRNA), a viral product and ligand of the Toll-like receptor-3 (TLR3), activates the transcription factors NF-κB and IRF-3 and upregulates the expression of inflammatory chemokines in airway epithelial cells. Here, we examined the effects of the glucocorticoid fluticasone propionate (FP) on the expression of the inflammatory chemokines CCL5, CXCL8 and CXCL10. Methods The airway epithelial cell line BEAS-2B was used for this study. Expression of CCL5, CXCL8 and CXCL10 mRNA and protein was quantified by real-time PCR and ELISA assay, respectively. To examine the association of FP with the physiology of chemokine production, we included several methods. Nuclear translocation of transcription factors was determined by performing Western blot analysis. Histone deacetylase (HDAC) activity in nuclear extracts was measured using a colorimetric assay. Stability of the chemokine mRNAs was examined in cells incubated with actinomycin D. The activities of the CCL5 promoter and the transcription factors NF-κB and IRF-3 were assessed using luciferase reporter assays. Results Treatment of BEAS-2B cells with FP significantly and dose-dependently (10−9 to 10−6 M) inhibited dsRNA-induced expression of CCL5, CXCL8 and CXCL10 protein and mRNA, but did not affect mRNA stability. FP also significantly inhibited dsRNA-stimulated CCL5 promoter activity. However, FP had no effect on the activity of HDAC or the nuclear translocation of NF-κB and IRF-3. Conclusions FP inhibits the dsRNA-stimulated expression of inflammatory chemokines in airway epithelial cells. FP may act by inhibiting chemokine transcription through an as yet Unidentified mechanism. PMID:23711858

  7. Inhibition of Intimal Hyperplasia in Transgenic Mice Conditionally Expressing the Chemokine-Binding Protein M3

    PubMed Central

    Pyo, Robert; Jensen, Kristian K.; Wiekowski, Maria T.; Manfra, Denise; Alcami, Antonio; Taubman, Mark B.; Lira, Sergio A.

    2004-01-01

    Chemokines have been implicated in the pathogenesis of a wide variety of diseases. This report describes the generation of transgenic mice that conditionally express M3, a herpesvirus protein that binds and inhibits chemokines. In response to doxycycline, M3 expression was induced in a variety of tissues and M3 was detectable in the blood by Western blotting. No gross or histological abnormalities were seen in mice expressing M3. To determine whether M3 expression could modify a significant pathophysiological response, we examined its effect on the development of intimal hyperplasia in response to femoral arterial injury. Intimal hyperplasia is thought to play a critical role in the development of restenosis after percutaneous transluminal coronary angioplasty and in the progression of atherosclerosis. Induction of M3 expression resulted in a 67% reduction in intimal area and a 68% reduction in intimal/medial ratio after femoral artery injury. These data support a role for chemokines in regulating intimal hyperplasia and suggest that M3 may be effective in attenuating this process. This transgenic mouse model should be a valuable tool for investigating the role of chemokines in a variety of pathological states. PMID:15161661

  8. Inhibition of intimal hyperplasia in transgenic mice conditionally expressing the chemokine-binding protein M3.

    PubMed

    Pyo, Robert; Jensen, Kristian K; Wiekowski, Maria T; Manfra, Denise; Alcami, Antonio; Taubman, Mark B; Lira, Sergio A

    2004-06-01

    Chemokines have been implicated in the pathogenesis of a wide variety of diseases. This report describes the generation of transgenic mice that conditionally express M3, a herpesvirus protein that binds and inhibits chemokines. In response to doxycycline, M3 expression was induced in a variety of tissues and M3 was detectable in the blood by Western blotting. No gross or histological abnormalities were seen in mice expressing M3. To determine whether M3 expression could modify a significant pathophysiological response, we examined its effect on the development of intimal hyperplasia in response to femoral arterial injury. Intimal hyperplasia is thought to play a critical role in the development of restenosis after percutaneous transluminal coronary angioplasty and in the progression of atherosclerosis. Induction of M3 expression resulted in a 67% reduction in intimal area and a 68% reduction in intimal/medial ratio after femoral artery injury. These data support a role for chemokines in regulating intimal hyperplasia and suggest that M3 may be effective in attenuating this process. This transgenic mouse model should be a valuable tool for investigating the role of chemokines in a variety of pathological states. PMID:15161661

  9. Calcitonin Gene-related Peptide Inhibits Chemokine Production by Human Dermal Microvascular Endothelial Cells

    PubMed Central

    Huang, Jing; Stohl, Lori L.; Zhou, Xi; Ding, Wanhong; Granstein, Richard D.

    2011-01-01

    This study examined whether the sensory neuropeptide calcitonin gene-related peptide (CGRP) inhibits release of chemokines by dermal microvascular endothelial cells. Dermal blood vessels are associated with nerves containing CGRP, suggesting that CGRP-containing nerves may regulate cutaneous inflammation through effects on vessels. We examined CGRP effects on stimulated chemokine production by a human dermal microvascular endothelial cell line (HMEC-1) and primary human dermal microvascular endothelial cells (pHDMECs). HMEC-1 cells and pHDMECs expressed mRNA for components of the CGRP and adrenomedullin receptors and CGRP inhibited LPS-induced production of the chemokines CXCL8, CCL2, and CXCL1 by both HMEC-1 cells and pHDMECs. The receptor activity-modifying protein (RAMP)1/calcitonin receptor-like receptor (CL)-specific antagonists CGRP8-37 and BIBN4096BS, blocked this effect of CGRP in a dose-dependent manner. CGRP prevented LPS-induced IκBα degradation and NF-κB binding to the promoters of CXCL1, CXCL8 and CCL2 in HMEC-1 cells and Bay 11-7085, an inhibitor of NF-κB activation, suppressed LPS-induced production of CXCL1, CXCL8 and CCL2. Thus, the NF-κB pathway appears to be involved in CGRP-mediated suppression of chemokine production. Accordingly, CGRP treatment of LPS-stimulated HMEC-1 cells inhibited their ability to chemoattract human neutrophils and mononuclear cells. Elucidation of this pathway may suggest new avenues for therapeutic manipulation of cutaneous inflammation. PMID:21334428

  10. Small neutralizing molecules to inhibit actions of the chemokine CXCL12.

    PubMed

    Hachet-Haas, Muriel; Balabanian, Karl; Rohmer, François; Pons, Françoise; Franchet, Christel; Lecat, Sandra; Chow, Ken Y C; Dagher, Rania; Gizzi, Patrick; Didier, Bruno; Lagane, Bernard; Kellenberger, Esther; Bonnet, Dominique; Baleux, Françoise; Haiech, Jacques; Parmentier, Marc; Frossard, Nelly; Arenzana-Seisdedos, Fernando; Hibert, Marcel; Galzi, Jean-Luc

    2008-08-22

    The chemokine CXCL12 and the receptor CXCR4 play pivotal roles in normal vascular and neuronal development, in inflammatory responses, and in infectious diseases and cancer. For instance, CXCL12 has been shown to mediate human immunodeficiency virus-induced neurotoxicity, proliferative retinopathy and chronic inflammation, whereas its receptor CXCR4 is involved in human immunodeficiency virus infection, cancer metastasis and in the rare disease known as the warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis (WHIM) syndrome. As we screened chemical libraries to find inhibitors of the interaction between CXCL12 and the receptor CXCR4, we identified synthetic compounds from the family of chalcones that reduce binding of CXCL12 to CXCR4, inhibit calcium responses mediated by the receptor, and prevent CXCR4 internalization in response to CXCL12. We found that the chemical compounds display an original mechanism of action as they bind to the chemokine but not to CXCR4. The highest affinity molecule blocked chemotaxis of human peripheral blood lymphocytes ex vivo. It was also active in vivo in a mouse model of allergic eosinophilic airway inflammation in which we detected inhibition of the inflammatory infiltrate. The compound showed selectivity for CXCL12 and not for CCL5 and CXCL8 chemokines and blocked CXCL12 binding to its second receptor, CXCR7. By analogy to the effect of neutralizing antibodies, this molecule behaves as a small organic neutralizing compound that may prove to have valuable pharmacological and therapeutic potential. PMID:18556651

  11. Inhibition of zymosan-induced cytokine and chemokine expression in human corneal fibroblasts by triptolide

    PubMed Central

    Liu, Yang; Li, Jing; Liu, Ye; Wang, Ping; Jia, Hui

    2016-01-01

    AIM To investigate the effects of triptolide on proinflammatory cytokine and chemokine expression induced by the fungal component zymosan in cultured human corneal fibroblasts (HCFs). METHODS HCFs were cultured in the absence or presence of zymosan or triptolide. The release of interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1) into culture supernatants was measured with enzyme-linked immunosorbent assays. The cellular abundance of the mRNAs for these proteins was determined by reverse transcription and real-time polymerase chain reaction analysis. The phosphorylation of mitogen-activated protein kinases (MAPKs) and the endogenous nuclear factor-κB (NF-κB) inhibitor IκB-α was examined by immunoblot analysis. The release of lactate dehydrogenase (LDH) activity from HCFs was measured with a colorimetric assay. RESULTS Triptolide inhibited the zymosan-induced release of IL-6, IL-8, and MCP-1 from HCFs in a concentration- and time-dependent manner. It also inhibited the zymosan-induced up-regulation of IL-6, IL-8, and MCP-1 mRNA abundance in these cells. Furthermore, triptolide attenuated zymosan-induced phosphorylation of the MAPKs extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 as well as the phosphorylation and degradation of IκB-α. Triptolide did not exhibit cytotoxicity for HCFs. CONCLUSION Triptolide inhibited proinflammatory cytokine and chemokine production by HCFs exposed to zymosan, with this action likely being mediated by suppression of MAPK and NF-κB signaling pathways. This compound might thus be expected to limit the infiltration of inflammatory cells into the cornea associated with fungal infection. PMID:26949603

  12. MiRNA-101 inhibits breast cancer growth and metastasis by targeting CX chemokine receptor 7

    PubMed Central

    Zhu, Xiao-Shan; Liu, Qin-Qin; Wang, Xiu-Li; Yu, Feng; Liu, Yan-Li; Yang, An-Gang; Gao, Chun-Fang

    2015-01-01

    Whereas miR-101 is involved in the development and progression of breast cancer, the underlying molecular mechanisms remain to be elucidated. Here, we report that miR-101 expression is inversely correlated with the clinical stage, lymph node metastasis and prognosis in breast cancers. Introduction of miR-101 inhibited breast cancer cell proliferation and invasion in vitro and suppressed tumor growth and lung metastasis of in vivo. CX chemokine receptor 7 (CXCR7) is a direct target of miR-101, positively correlating with the histological grade and the incidence of lymph node metastasis in breast cancer patients. The effects of miR-101 were mimicked and counteracted by CXCR7 depletion and overexpression, respectively. STAT3 signaling downstream of CXCR7 is involved in miR-101 regulation of breast cancer cell behaviors. These findings have implications for the potential application of miR-101 in breast cancer treatment. PMID:26360780

  13. Gambogic acid inhibits multiple myeloma mediated osteoclastogenesis through suppression of chemokine receptor CXCR4 signaling pathways.

    PubMed

    Pandey, Manoj K; Kale, Vijay P; Song, Chunhua; Sung, Shen-shu; Sharma, Arun K; Talamo, Giampaolo; Dovat, Sinisa; Amin, Shantu G

    2014-10-01

    Bone disease, characterized by the presence of lytic lesions and osteoporosis is the hallmark of multiple myeloma (MM). Stromal cell-derived factor 1α (SDF-1α) and its receptor, CXC chemokine receptor 4 (CXCR4), has been implicated as a regulator of bone resorption, suggesting that agents that can suppress SDF1α/CXCR4 signaling might inhibit osteoclastogenesis, a process closely linked to bone resorption. We, therefore, investigated whether gambogic acid (GA), a xanthone, could inhibit CXCR4 signaling and suppress osteoclastogenesis induced by MM cells. Through docking studies we predicted that GA directly interacts with CXCR4. This xanthone down-regulates the expression of CXCR4 on MM cells in a dose- and time-dependent manner. The down-regulation of CXCR4 was not due to proteolytic degradation, but rather GA suppresses CXCR4 mRNA expression by inhibiting nuclear factor-kappa B (NF-κB) DNA binding. This was further confirmed by quantitative chromatin immunoprecipitation assay, as GA inhibits p65 binding at the CXCR4 promoter. GA suppressed SDF-1α-induced chemotaxis of MM cells and downstream signaling of CXCR4 by inhibiting phosphorylation of Akt, p38, and Erk1/2 in MM cells. GA abrogated the RANKL-induced differentiation of macrophages to osteoclasts in a dose- and time-dependent manner. In addition, we found that MM cells induced differentiation of macrophages to osteoclasts, and that GA suppressed this process. Importantly, suppression of osteoclastogenesis by GA was mediated through IL-6 inhibition. Overall, our results show that GA is a novel inhibitor of CXCR4 expression and has a strong potential to suppress osteoclastogenesis mediated by MM cells. PMID:25034231

  14. (+)-Nootkatone inhibits tumor necrosis factor α/interferon γ-induced production of chemokines in HaCaT cells.

    PubMed

    Choi, Hyeon-Jae; Lee, Jin-Hwee; Jung, Yi-Sook

    2014-05-01

    Chemokines are important mediators of cell migration, and thymus and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22) are well-known typical inflammatory chemokines involved in atopic dermatitis (AD). (+)-Nootkatone is the major component of Cyperus rotundus. (+)-Nootkatone has antiallergic, anti-inflammatory, and antiplatelet activities. The purpose of this study was to investigate the effect of (+)-nootkatone on tumor necrosis factor α (TNF-α)/interferon γ (IFN-γ)-induced expression of Th2 chemokines in HaCaT cells. We found that (+)-nootkatone inhibited the TNF-α/IFN-γ-induced expression of TARC/CCL17 and MDC/CCL22 mRNA in HaCaT cells. It also significantly inhibited TNF-α/IFN-γ-induced activation of nuclear factor kappa B (NF-κB), p38 mitogen-activated protein kinase (MAPK), and protein kinase Cζ (PKCζ). Furthermore, we showed that PKCζ and p38 MAPK contributed to the inhibition of TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression by blocking IκBα degradation in HaCaT cells. Taken together, these results suggest that (+)-nootkatone may suppress TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression in HaCaT cells by inhibiting of PKCζ and p38 MAPK signaling pathways that lead to activation of NF-κB. We propose that (+)-nootkatone may be a useful therapeutic candidate for inflammatory skin diseases such as AD. PMID:24704449

  15. (+)-Nootkatone inhibits tumor necrosis factor α/interferon γ-induced production of chemokines in HaCaT cells

    SciTech Connect

    Choi, Hyeon-Jae; Lee, Jin-Hwee; Jung, Yi-Sook

    2014-05-02

    Highlights: • (+)-Nootkatone inhibits TNF-α/IFN-γ-induced TARC and MDC expression in HaCaT cells. • PKCζ, p38 MAPK, or NF-κB mediate TNF-α/IFN-γ-induced TARC and MDC expression. • (+)-Nootkatone inhibits TNF-α/IFN-γ-induced activation of PKCζ, p38 MAPK, or NF-κB. • (+)-Nootkatone suppresses chemokine expression by inhibiting of PKCζ and p38 pathways. - Abstract: Chemokines are important mediators of cell migration, and thymus and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22) are well-known typical inflammatory chemokines involved in atopic dermatitis (AD). (+)-Nootkatone is the major component of Cyperus rotundus. (+)-Nootkatone has antiallergic, anti-inflammatory, and antiplatelet activities. The purpose of this study was to investigate the effect of (+)-nootkatone on tumor necrosis factor α (TNF-α)/interferon γ (IFN-γ)-induced expression of Th2 chemokines in HaCaT cells. We found that (+)-nootkatone inhibited the TNF-α/IFN-γ-induced expression of TARC/CCL17 and MDC/CCL22 mRNA in HaCaT cells. It also significantly inhibited TNF-α/IFN-γ-induced activation of nuclear factor kappa B (NF-κB), p38 mitogen-activated protein kinase (MAPK), and protein kinase Cζ (PKCζ). Furthermore, we showed that PKCζ and p38 MAPK contributed to the inhibition of TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression by blocking IκBα degradation in HaCaT cells. Taken together, these results suggest that (+)-nootkatone may suppress TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression in HaCaT cells by inhibiting of PKCζ and p38 MAPK signaling pathways that lead to activation of NF-κB. We propose that (+)-nootkatone may be a useful therapeutic candidate for inflammatory skin diseases such as AD.

  16. Inhibition of metastasis of rhabdomyosarcoma by a novel neutralizing antibody to CXC chemokine receptor-4

    PubMed Central

    Kashima, Kenji; Watanabe, Miho; Sato, Yasuko; Hata, Junichi; Ishii, Nobuya; Aoki, Yuko

    2014-01-01

    Rhabdomyosarcoma is the most common soft tissue sarcoma affecting children, and the overall cure rate of children with metastatic disease remains below 30%. The CXC chemokine receptor-4 (CXCR4)/stromal cell-derived factor-1 (SDF1) axis has been implicated in the promotion of metastatic potential in several tumors. In this study, we developed a novel anti-CXCR4 mAb, CF172, and investigated its antimetastatic activity against rhabdomyosarcoma cells in vitro and in vivo, to evaluate its potential as a therapeutic antibody to treat rhabdomyosarcoma. The CF172 molecule showed a specific binding reactivity against human CXCR4, as well as a specific neutralizing activity against CXCR4/SDF1 signal transduction. Using CF172, we determined that SJCRH30 rhabdomyosarcoma cells expressed high levels of CXCR4. In addition, CF172 was found to inhibit the SDF1-induced migration activity of SJCRH30 cells in vitro. Using xenograft models of SJCRH30 cells, we carried out in vivo efficacy studies for peritoneal and lymph node metastasis, which were clinically observed in rhabdomyosarcoma. These studies indicated that CF172 significantly decreased both types of metastasis of SJCRH30. In conclusion, we found that a novel anti-CXCR4 mAb, CF172, with specific reactivity against human CXCR4, prevented peritoneal metastasis and lymph node metastasis of rhabdomyosarcoma in animal models. These results suggest that CF172 is a potential antimetastasis therapeutic antibody for rhabdomyosarcoma treatment. PMID:25154453

  17. Antagonism of chemokine receptor CXCR3 inhibits osteosarcoma metastasis to lungs.

    PubMed

    Pradelli, Emmanuelle; Karimdjee-Soilihi, Babou; Michiels, Jean-François; Ricci, Jean-Ehrland; Millet, Marie-Ange; Vandenbos, Fanny; Sullivan, Timothy J; Collins, Tassie L; Johnson, Michael G; Medina, Julio C; Kleinerman, Eugenie S; Schmid-Alliana, Annie; Schmid-Antomarchi, Heidy

    2009-12-01

    Metastasis continues to be the leading cause of mortality for patients with cancer. Several years ago, it became clear that chemokines and their receptors could control the tumor progress. CXCR3 has now been identified in many cancers including osteosarcoma and CXCR3 ligands were expressed by lungs that are the primary sites to which this tumor metastasize. This study tested the hypothesis that disruption of the CXCR3/CXCR3 ligands complexes could lead to a decrease in lungs metastasis. The experimental design involved the use of the CXCR3 antagonist, AMG487 and 2 murine models of osteosarcoma lung metastases. After tail vein injection of osteosarcoma cells, mice that were systematically treated with AMG487 according to preventive or curative protocols had a significant reduction in metastatic disease. Treatment of osteosarcoma cells in vitro with AMG487 led to decreased migration, decreased matrix metalloproteinase activity, decreased proliferation/survival and increased caspase-independent death. Taken together, our results support the hypothesis that CXCR3 and their ligands intervene in the initial dissemination of the osteosarcoma cells to the lungs and stimulate the growth and expansion of the metastatic foci in later stages. Moreover, these studies indicate that targeting CXCR3 may specifically inhibit tumor metastasis without adversely affecting antitumoral host response. PMID:19544560

  18. Antagonism of chemokine receptor CXCR3 inhibits osteosarcoma metastasis to lungs

    PubMed Central

    Pradelli, Emmanuelle; Karimdjee-Soilihi, Babou; Michiels, Jean-François; Ricci, Jean-Ehrland; Millet, Marie-Ange; Vandenbos, Fanny; Sullivan, Timothy J.; Collins, Tassie L.; Johnson, Michael G.; Medina, Julio C.; Kleinerman, Eugenie S.; Schmid-Alliana, Annie; Schmid-Antomarchi, Heidy

    2009-01-01

    Metastasis continues to be the leading cause of mortality for patients with cancer. Several years ago, it became clear that chemokines and their receptors could control the tumor progress. CXCR3 has now been identified in many cancers including osteosarcoma and CXCR3 ligands were expressed by lungs that are the primary sites to which this tumor metastasize. This study tested the hypothesis that disruption of the CXCR3/CXCR3 ligands complexes could lead to a decrease in lungs metastasis. The experimental design involved the use of the CXCR3 antagonist, AMG487 and 2 murine models of osteosarcoma lung metastases. After tail vein injection of osteosarcoma cells, mice that were systematically treated with AMG487 according to preventive or curative protocols had a significant reduction in metastatic disease. Treatment of osteosarcoma cells in vitro with AMG487 led to decreased migration, decreased matrix metalloproteinase activity, decreased proliferation/survival and increased caspase-independent death. Taken together, our results support the hypothesis that CXCR3 and their ligands intervene in the initial dissemination of the osteosarcoma cells to the lungs and stimulate the growth and expansion of the metastatic foci in later stages. Moreover, these studies indicate that targeting CXCR3 may specifically inhibit tumor metastasis without adversely affecting antitumoral host response. PMID:19544560

  19. Functional inhibition of chemokine receptor CCR2 by dicer-substrate-siRNA prevents pain development

    PubMed Central

    Midavaine, Élora; Dansereau, Marc-André; Tétreault, Pascal; Longpré, Jean-Michel; Jacobi, Ashley M; Rose, Scott D; Behlke, Mark A; Beaudet, Nicolas; Sarret, Philippe

    2016-01-01

    Background Accumulating evidence suggests that the C-C chemokine ligand 2 (CCL2, or monocyte chemoattractant protein 1) acts as a neuromodulator in the central nervous system through its binding to the C-C chemokine receptor 2 (CCR2). Notably, it is well established that the CCL2/CCR2 axis plays a key role in neuron-glia communication as well as in spinal nociceptive transmission. Gene silencing through RNA interference has recently emerged as a promising avenue in research and drug development, including therapeutic management of chronic pain. In the present study, we used 27-mer Dicer-substrate small interfering RNA (DsiRNA) targeting CCR2 and assessed their ability to reverse the nociceptive behaviors induced by spinal CCL2 injection or following intraplantar injection of complete Freund’s adjuvant. Results To this end, we first developed high-potency DsiRNAs designed to target different sequences distributed across the rat CCR2 (rCCR2) messenger RNA. For optimization, methyl groups were added to the two most potent DsiRNA candidates (Evader and M7 2′-O-methyl modified duplexes) in order to improve in vivo duplex stability and to reduce potential immunostimulatory activity. Our results demonstrated that all modified candidates formulated with the cell-penetrating peptide reagent Transductin showed strong RNAi activity following intrathecal delivery, exhibiting >50% rCCR2 knockdown in lumbar dorsal root ganglia. Accordingly, we found that these DsiRNA duplexes were able to reduce spinal microglia activation and were effective at blocking CCL2-induced mechanical hypersensitivity. Along with similar reductions of rCCR2 messenger RNA, both sequences and methylation patterns were similarly effective in inhibiting the CCL2 nociceptive action for the whole seven days testing period, compared to mismatch DsiRNA. DsiRNAs against CCR2 also reversed the hypernociceptive responses observed in the complete Freund’s adjuvant-induced inflammatory chronic pain model

  20. Pomolic Acid Inhibits Invasion of Breast Cancer Cells Through the Suppression of CXC Chemokine Receptor Type 4 Expression.

    PubMed

    Kim, Buyun; Kim, Ji-Hun; Park, Byoungduck

    2016-06-01

    High mortality of cancer-mediated deaths is due to metastasis. CXC chemokine receptor type 4 (CXCR4) signaling has been demonstrated to be involved in migration of breast cancer. Thus, identification of CXCR4 inhibitor has been challenged constantly as an anticancer drug. This study is aimed to investigate the CXCR4 inhibitor that could inhibit tumor metastasis from natural products. We demonstrated that pomolic acid (PA), a component of Euscaphis japonica, could downregulate CXCR4 expression in breast cancer cells. Treatment with proteasomal and lysosomal inhibitors did not show significant effects on PA's ability. When we further explored the molecular mechanism, suppression of CXCR4 occurred at transcriptional level and was correlated with inhibition of nuclear factor-kappaB (NF-κB) activation. Downregulation of CXCR4 by PA was accompanied by the inhibition of CXC motif chemokine 12 (CXCL12)-induced invasion of breast cancer cells. Overall, our results indicate that PA, as a novel inhibitor of CXCR4, can be a promising therapeutic agent for treatment of cancer metastasis. J. Cell. Biochem. 117: 1296-1307, 2016. © 2015 Wiley Periodicals, Inc. PMID:26495998

  1. Inhibition of chemokine-like factor 1 improves blood-brain barrier dysfunction in rats following focal cerebral ischemia.

    PubMed

    Kong, Ling-Lei; Wang, Zhi-Yuan; Hu, Jin-Feng; Yuan, Yu-He; Li, Hua; Chen, Nai-Hong

    2016-08-01

    Disruption of blood-brain barrier (BBB) and subsequent edema are major contributors to the pathogenesis of ischemic stroke, and the current clinical therapy remains unsatisfied. Chemokine-like factor 1 (CKLF1), as a novel C-C chemokine, plays important roles in immune response. The expression of CKLF1 increased after focal cerebral ischemia and inhibition of CKLF1 activity showed neuroprotective effect by alleviating infiltration of neutrophil and neuron apoptosis in cerebral ischemia. However, few studies have focused on the role of CKLF1 on BBB integrity. The objective of present study was to investigate the role of CKLF1 on BBB integrity by applying anti-CKLF1 antibodies in rat focal cerebral ischemia and reperfusion model. Brain water content, Evans blue leakage and the expression of aquaporin-4 (AQP-4), matrix metalloproteinase-9 (MMP-9), Zonula Occludens-1 (ZO-1) and Occludin were measured. After treatment with anti-CKLF1 antibody, brain water content and Evans blue leakage in ipsilateral hemisphere were decreased in a dose-dependent manner at 24h after reperfusion, but not changed in contralateral hemisphere. Anti-CKLF1 antibody reduced the expression of AQP-4 and MMP-9, and upregulated the expression of ZO-1 and Occludin. These results suggest that CKLF1 is involved in BBB disruption after reperfusion. Inhibition of CKLF1 protects against cerebral ischemia by maintaining BBB integrity, possibly via inhibiting the expression of AQP-4 and MMP-9, and increasing the expression of tight junction protein. PMID:27283776

  2. Progranulin inhibits expression and release of chemokines CXCL9 and CXCL10 in a TNFR1 dependent manner

    PubMed Central

    Mundra, Jyoti Joshi; Jian, Jinlong; Bhagat, Priyal; Liu, Chuan-ju

    2016-01-01

    Progranulin (PGRN), a pleiotrophic growth factor, is known to play an important role in the maintenance and regulation of the homeostatic dynamics of normal tissue development, proliferation, regeneration, and host-defense. PGRN also has potent anti-inflammatory functionality, and deregulated PGRN is associated with rheumatoid arthritis and inflammatory bowel disease. We have previously reported that PGRN directly binds to TNFR and significantly enhances Treg population and stimulatesIL-10 production. To further investigate PGRN’s function in the immune system we performed a gene array analysis on CD4+ T cells from wild type B6 mice and PGRN −/− mice. We identified many chemokines and their receptors, among which CXCL9 and CXCL10 were most prominent, that were significantly induced in PGRN null mice. Administration of recombinant PGRN protein strongly inhibited TNF and IFN-γ-induced CXCL9 and CXCL10 expression. In addition, CXCL9 expression is strongly upregulated in PGRN KO mice and its level is correlated with severity of inflammation in a dermatitis model. Further, we have demonstrated that PGRN-mediated inhibition of chemokine expression largely depends on TNFR1. Taken together, this study provides new insights into the mechanisms underlying PGRN mediated regulation of various inflammatory and autoimmune diseases. PMID:26892362

  3. Progranulin inhibits expression and release of chemokines CXCL9 and CXCL10 in a TNFR1 dependent manner.

    PubMed

    Mundra, Jyoti Joshi; Jian, Jinlong; Bhagat, Priyal; Liu, Chuan-Ju

    2016-01-01

    Progranulin (PGRN), a pleiotrophic growth factor, is known to play an important role in the maintenance and regulation of the homeostatic dynamics of normal tissue development, proliferation, regeneration, and host-defense. PGRN also has potent anti-inflammatory functionality, and deregulated PGRN is associated with rheumatoid arthritis and inflammatory bowel disease. We have previously reported that PGRN directly binds to TNFR and significantly enhances Treg population and stimulatesIL-10 production. To further investigate PGRN's function in the immune system we performed a gene array analysis on CD4+ T cells from wild type B6 mice and PGRN -/- mice. We identified many chemokines and their receptors, among which CXCL9 and CXCL10 were most prominent, that were significantly induced in PGRN null mice. Administration of recombinant PGRN protein strongly inhibited TNF and IFN-γ-induced CXCL9 and CXCL10 expression. In addition, CXCL9 expression is strongly upregulated in PGRN KO mice and its level is correlated with severity of inflammation in a dermatitis model. Further, we have demonstrated that PGRN-mediated inhibition of chemokine expression largely depends on TNFR1. Taken together, this study provides new insights into the mechanisms underlying PGRN mediated regulation of various inflammatory and autoimmune diseases. PMID:26892362

  4. Anti-phospholipid human monoclonal antibodies inhibit CCR5-tropic HIV-1 and induce β-chemokines

    PubMed Central

    Liao, Hua-Xin; Alam, S. Munir; Scearce, Richard M.; Plonk, M. Kelly; Kozink, Daniel M.; Drinker, Mark S.; Zhang, Ruijun; Xia, Shi-Mao; Sutherland, Laura L.; Tomaras, Georgia D.; Giles, Ian P.; Kappes, John C.; Ochsenbauer-Jambor, Christina; Edmonds, Tara G.; Soares, Melina; Barbero, Gustavo; Forthal, Donald N.; Landucci, Gary; Chang, Connie; King, Steven W.; Kavlie, Anita; Denny, Thomas N.; Hwang, Kwan-Ki; Chen, Pojen P.; Thorpe, Philip E.; Montefiori, David C.

    2010-01-01

    Traditional antibody-mediated neutralization of HIV-1 infection is thought to result from the binding of antibodies to virions, thus preventing virus entry. However, antibodies that broadly neutralize HIV-1 are rare and are not induced by current vaccines. We report that four human anti-phospholipid monoclonal antibodies (mAbs) (PGN632, P1, IS4, and CL1) inhibit HIV-1 CCR5-tropic (R5) primary isolate infection of peripheral blood mononuclear cells (PBMCs) with 80% inhibitory concentrations of <0.02 to ∼10 µg/ml. Anti-phospholipid mAbs inhibited PBMC HIV-1 infection in vitro by mechanisms involving binding to monocytes and triggering the release of MIP-1α and MIP-1β. The release of these β-chemokines explains both the specificity for R5 HIV-1 and the activity of these mAbs in PBMC cultures containing both primary lymphocytes and monocytes. PMID:20368576

  5. Inhibition of Chemokine (C-C Motif) Receptor 7 Sialylation Suppresses CCL19-Stimulated Proliferation, Invasion and Anti-Anoikis

    PubMed Central

    Su, Mei-Lin; Chang, Tsung-Ming; Chiang, Chi-Hsiang; Chang, Han-Chen; Hou, Ming-Feng; Li, Wen-Shan; Hung, Wen-Chun

    2014-01-01

    Chemokine (C-C motif) receptor 7 (CCR7) is involved in lymph-node homing of naive and regulatory T cells and lymphatic metastasis of cancer cells. Sialic acids comprise a group of monosaccharide units that are added to the terminal position of the oligosaccharide chain of glycoproteins by sialyation. Recent studies suggest that aberrant sialylation of receptor proteins contributes to proliferation, motility, and drug resistance of cancer cells. In this study, we addressed whether CCR7 is a sialylated receptor protein and tried to elucidate the effect of sialylation in the regulation of signal transduction and biological function of CCR7. Our results demonstrated that α-2, 3-sialyltransferase which catalyze sialylation reaction in vivo was overexpressed in breast tumor tissues and cell lines. Lectin blot analysis clearly demonstrated that CCR7 receptor was sialyated in breast cancer cells. Chemokine (C-C motif) ligand 19 (CCL19), the cognate ligand for CCR7, induced the activation of extracellular signal-regulated kinase (ERK) and AKT signaling and increased the expression of cell cycle regulatory proteins and proliferation of breast cancer cells. When cells were pre-treated with a sialyltransferase inhibitor AL10 or sialidase, CCL19-induced cell growth was significantly suppressed. CCL19 also increased invasion and prevented anoikis by up-regulating pro-survival proteins Bcl-2 and Bcl-xL. Inhibition of sialylation by AL10 totally abolished these effects. Finally, we showed that AL10 inhibited tumorigenicity of breast cancer in experimental animals. Taken together, we demonstrate for the first time that CCR7 receptor is a sialylated protein and sialylation is important for the paracrine stimulation by its endogenous ligand CCL19. In addition, inhibition of aberrant sialylation of CCR7 suppresses proliferation and invasion and triggers anoikis in breast cancer cells. Targeting of sialylation enzymes may be a novel strategy for breast cancer treatment. PMID:24915301

  6. Inhibition of infection-mediated preterm birth by administration of broad spectrum chemokine inhibitor in mice.

    PubMed

    Shynlova, Oksana; Dorogin, Anna; Li, Yunqing; Lye, Stephen

    2014-09-01

    Preterm birth (PTB) is the single most important cause of perinatal and infant mortality worldwide. Maternal infection can result in PTB. We investigated the ability of a Broad Spectrum Chemokine Inhibitor (BSCI) to prevent infection-induced PTB in mice. PTB was initiated in pregnant mice by intraperitoneal injection of lipopolysaccharide (LPS; 50 μg). Half the mice received BSCI (10 mg/kg) 24 hrs prior to and immediately before LPS administration. The impact of LPS alone or LPS plus BSCI was assessed on (i) injection-to-delivery interval, foetal survival rate, placental and neonates' weight; (ii) amniotic fluid and maternal plasma cytokine levels (by Luminex assay); foetal and maternal tissue cytokine gene expression levels (by Real-Time RT-PCR); (iii) immune cells infiltration into the uterine tissue (by stereological immunohistochemistry). Pre-treatment with BSCI (i) decreased LPS-induced PTB (64% versus 100%, P < 0.05); (ii) significantly attenuated cytokine/chemokine expression in maternal tissues (plasma, liver, myometrium, decidua); (iii) significantly decreased neutrophil infiltration in the mouse myometrium. BSCI-treated mice in which PTB was delayed till term had live foetuses with normal placental and foetal weight. BSCI represents a promising new class of therapeutics for PTB. In a mouse model of preterm labour, BCSI suppresses systemic inflammation in maternal tissues which resulted in the reduced incidence of LPS-mediated PTB. These data provide support for efforts to target inflammatory responses as a means of preventing PTB. PMID:24894878

  7. Inhibition of infection-mediated preterm birth by administration of broad spectrum chemokine inhibitor in mice

    PubMed Central

    Shynlova, Oksana; Dorogin, Anna; Li, Yunqing; Lye, Stephen

    2014-01-01

    Preterm birth (PTB) is the single most important cause of perinatal and infant mortality worldwide. Maternal infection can result in PTB. We investigated the ability of a Broad Spectrum Chemokine Inhibitor (BSCI) to prevent infection-induced PTB in mice. PTB was initiated in pregnant mice by intraperitoneal injection of lipopolysaccharide (LPS; 50 μg). Half the mice received BSCI (10 mg/kg) 24 hrs prior to and immediately before LPS administration. The impact of LPS alone or LPS plus BSCI was assessed on (i) injection-to-delivery interval, foetal survival rate, placental and neonates' weight; (ii) amniotic fluid and maternal plasma cytokine levels (by Luminex assay); foetal and maternal tissue cytokine gene expression levels (by Real-Time RT-PCR); (iii) immune cells infiltration into the uterine tissue (by stereological immunohistochemistry). Pre-treatment with BSCI (i) decreased LPS-induced PTB (64% versus 100%, P < 0.05); (ii) significantly attenuated cytokine/chemokine expression in maternal tissues (plasma, liver, myometrium, decidua); (iii) significantly decreased neutrophil infiltration in the mouse myometrium. BSCI-treated mice in which PTB was delayed till term had live foetuses with normal placental and foetal weight. BSCI represents a promising new class of therapeutics for PTB. In a mouse model of preterm labour, BCSI suppresses systemic inflammation in maternal tissues which resulted in the reduced incidence of LPS-mediated PTB. These data provide support for efforts to target inflammatory responses as a means of preventing PTB. PMID:24894878

  8. Omega-3 fatty acids inhibit the up-regulation of endothelial chemokines in maintenance hemodialysis patients

    PubMed Central

    Hung, Adriana M.; Booker, Cindy; Ellis, Charles D.; Siew, Edward D.; Graves, Amy J.; Shintani, Ayumi; Abumrad, Naji N.; Himmelfarb, Jonathan; Ikizler, Talat Alp

    2015-01-01

    Background Chronic systemic inflammation is common in patients with chronic kidney disease on dialysis (CKD5D) and has been considered a key mediator of the increased cardiovascular risk in this patient population. In this study, we tested the hypothesis that supplementation of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) will attenuate the systemic inflammatory process in CKD5D patients. Methods The design was a randomized, double-blinded, placebo controlled pilot trial (NCT00655525). Thirty-eight patients were randomly assigned in a 1 : 1 fashion to receive 2.9 g of eicosapentaenoic acid (C20:5, n-3) plus docosahexaenoic acid (C22:6, n-3) versus placebo for 12 weeks. The primary outcome was change in pro-inflammatory chemokines measured by lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs). Secondary outcomes were changes in systemic inflammatory markers. Analysis of covariance was used to compare percent change from baseline to 12 weeks. Results Thirty-one patients completed 12 weeks and three patients completed 6 weeks of the study. Median age was 52 (interquartile range 45, 60) years, 74% were African-American and 79% were male. Supplementation of ω-3 PUFAs effectively decreased the LPS-induced PBMC expression of RANTES (Regulated upon Activation, Normal T cell Expressed and Secreted) and MCP-1 (Monocyte Chemotactic Protein-1; unadjusted P = 0.04 and 0.06; adjusted for demographics P = 0.02 and 0.05, respectively). There was no significant effect of the intervention on serum inflammatory markers (C-reactive protein, interleukin-6 and procalcitonin). Conclusions The results of this pilot study suggest that supplementation of ω-3 PUFAs is beneficial in decreasing the levels of endothelial chemokines, RANTES and MCP-1. Studies of larger sample size and longer duration are required to further evaluate effects of ω-3 PUFAs on systemic markers of inflammation, other metabolic parameters and clinical outcomes, particularly

  9. Capacity of wild-type and chemokine-armed parvovirus H-1PV for inhibiting neo-angiogenesis

    SciTech Connect

    Lavie, Muriel; Struyf, Sofie; Stroh-Dege, Alexandra; Rommelaere, Jean; Van Damme, Jo; Dinsart, Christiane

    2013-12-15

    Anti-angiogenic therapy has been recognized as a powerful potential strategy for impeding the growth of various tumors. However no major therapeutic effects have been observed to date, mainly because of the emergence of several resistance mechanisms. Among novel strategies to target tumor vasculature, some oncolytic viruses open up new prospects. In this context, we addressed the question whether the rodent parvovirus H-1PV can target endothelial cells. We show that cultures of human normal (HUVEC) and immortalized (KS-IMM) endothelial cells sustain an abortive viral cycle upon infection with H-1PV and are sensitive to H-1PV cytotoxicity. H-1PV significantly inhibits infected KS-IMM tumor growth. This effect may be traced back by the virus ability to both kill proliferating endothelial cells and inhibit VEGF production Recombinant H-1PV vectors can also transduce tumor cells with chemokines endowed with anti-angiogenesis properties, and warrant further validation for the treatment of highly vascularized tumors. - Highlights: • The oncolytic parvovirus H-1PV can target endothelial cells. • Abortive viral cycle upon infection of endothelial cells with H-1PV. • Inhibition of VEGF expression and KS-IMM tumor growth by H-1PV.

  10. Investigation of Inhibition Mechanism of Chemokine Receptor CCR5 by Micro-second Molecular Dynamics Simulations

    PubMed Central

    Salmas, Ramin Ekhteiari; Yurtsever, Mine; Durdagi, Serdar

    2015-01-01

    Chemokine receptor 5 (CCR5) belongs to G protein coupled receptors (GPCRs) and plays an important role in treatment of human immunodeficiency virus (HIV) infection since HIV uses CCR5 protein as a co-receptor. Recently, the crystal structure of CCR5-bound complex with an approved anti-retroviral drug (maroviroc) was resolved. During the crystallization procedure, amino acid residues (i.e., Cys224, Arg225, Asn226 and Glu227) at the third intra-cellular loop were replaced by the rubredoxin for stability reasons. In the current study, we aimed to understand the impact of the incorporated rubredoxin on the conformations of TM domains of the target protein. For this reason, rubredoxin was deleted from the crystal structure and the missing amino acids were engineered. The resultant structure was subjected to long (μs) molecular dynamics (MD) simulations to shed light into the inhibitory mechanism. The derived model structure displayed a significant deviation in the cytoplasmic domain of TM5 and IC3 in the absence of rubredoxin. The principal component analyses (PCA) and MD trajectory analyses revealed important structural and dynamical differences at apo and holo forms of the CCR5. PMID:26299310

  11. Roflumilast inhibits the release of chemokines and TNF-α from human lung macrophages stimulated with lipopolysaccharide

    PubMed Central

    Buenestado, A; Grassin-Delyle, S; Guitard, F; Naline, E; Faisy, C; Israël-Biet, D; Sage, E; Bellamy, JF; Tenor, H; Devillier, P

    2012-01-01

    BACKGROUND AND PURPOSE Lung macrophages are critically involved in respiratory diseases. This study assessed the effects of the PDE4 inhibitor roflumilast and its active metabolite, roflumilast N-oxide on the release of a range of chemokines (CCL2, 3, 4, CXCL1, 8, 10) and of TNF-α, from human lung macrophages, stimulated with bacterial lipopolysaccharide LPS. EXPERIMENTAL APPROACH Lung macrophages isolated from resected human lungs were incubated with roflumilast, roflumilast N-oxide, PGE2, the COX inhibitor indomethacin, the COX-2 inhibitor NS-398 or vehicle and stimulated with LPS (24 h). Chemokines, TNF-α, PGE2 and 6-keto PGF1α were measured in culture supernatants by immunoassay. COX-2 mRNA expression was assessed with RT-qPCR. PDE activities were determined in macrophage homogenates. KEY RESULTS Expression of PDE4 in lung macrophages was increased after incubation with LPS. Roflumilast and roflumilast N-oxide concentration-dependently reduced the LPS-stimulated release of CCL2, CCL3, CCL4, CXCL10 and TNF-α from human lung macrophages, whereas that of CXCL1 or CXCL8 was not altered. This reduction by the PDE4 inhibitors was further accentuated by exogenous PGE2 (10 nM) but abolished in the presence of indomethacin or NS-398. Conversely, addition of PGE2 (10 nM), in the presence of indomethacin restored inhibition by roflumilast. LPS also increased PGE2 and 6-keto PGF1α release from lung macrophages which was associated with an up-regulation of COX-2 mRNA. CONCLUSIONS AND IMPLICATIONS Roflumilast and roflumilast N-oxide reduced LPS-induced release of CCL2, 3, 4, CXCL10 and TNF-α in human lung macrophages. PMID:21913898

  12. CC-chemokine ligand 2 inhibition in idiopathic pulmonary fibrosis: a phase 2 trial of carlumab.

    PubMed

    Raghu, Ganesh; Martinez, Fernando J; Brown, Kevin K; Costabel, Ulrich; Cottin, Vincent; Wells, Athol U; Lancaster, Lisa; Gibson, Kevin F; Haddad, Tarik; Agarwal, Prasheen; Mack, Michael; Dasgupta, Bidisha; Nnane, Ivo P; Flavin, Susan K; Barnathan, Elliot S

    2015-12-01

    The objective of this study was to determine the safety and efficacy of carlumab in the treatment of idiopathic pulmonary fibrosis (IPF).A phase 2, randomised, double-blind placebo-controlled dose-ranging study was conducted in patients with IPF (n=126). Patients were randomised to carlumab (1 mg·kg(-1), 5 mg·kg(-1), or 15 mg·kg(-1)) or placebo every 4 weeks. The primary endpoint was the rate of percentage change in forced vital capacity (FVC). Secondary endpoints were time to disease progression, absolute change in FVC, relative change in diffusing capacity of the lung for carbon monoxide (DLCO), and St George's Respiratory Questionnaire (SGRQ) total score.Due to a pre-planned, unfavourable interim benefit-risk analysis, dosing was suspended. The rate of percentage change in FVC showed no treatment effect (placebo -0.582%, 1 mg·kg(-1) -0.533%, 5 mg·kg(-1) -0.799% and 15 mg·kg(-1) -0.470%; p=0.261). All active treatment groups showed a greater decline in FVC (1 mg·kg(-1) -290 mL, 5 mg·kg(-1) -370 mL and 15 mg·kg(-1) -320 mL) compared with placebo (-130 mL). No effect on disease progression, DLCO, infection rates or mortality was observed. SGRQ scores showed a nonsignificant trend toward worsening with active treatment. Unexpectedly, free CC-chemokine ligand 2 levels were elevated above baseline at both 24 and 52 weeks. A higher proportion of patients with one or more serious adverse events was observed in the 5 mg·kg(-1) group (53.1%) compared with 1 mg·kg(-1) (15.2%), 15 mg·kg(-1) (21.9%) and placebo (46.4%), although no unexpected serious adverse events were noted.Although dosing was stopped prematurely, it is unlikely that carlumab provides benefit to IPF patients. PMID:26493793

  13. The phosphoinositide 3′-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia

    PubMed Central

    Hoellenriegel, Julia; Meadows, Sarah A.; Sivina, Mariela; Wierda, William G.; Kantarjian, Hagop; Keating, Michael J.; Giese, Neill; O'Brien, Susan; Yu, Albert; Miller, Langdon L.; Lannutti, Brian J.

    2011-01-01

    In lymphocytes, the phosphoinositide 3′-kinase (PI3K) isoform p110δ (PI3Kδ) transmits signals from surface receptors, including the B-cell receptor (BCR). CAL-101, a selective inhibitor of PI3Kδ, displays clinical activity in CLL, causing rapid lymph node shrinkage and a transient lymphocytosis. Inhibition of pro-survival pathways, the presumed mechanism of CAL-101, does not explain this characteristic pattern of activity. Therefore, we tested CAL-101 in assays that model CLL-microenvironment interactions in vitro. We found that CAL-101 inhibits CLL cell chemotaxis toward CXCL12 and CXCL13 and migration beneath stromal cells (pseudoemperipolesis). CAL-101 also down-regulates secretion of chemokines in stromal cocultures and after BCR triggering. CAL-101 reduces survival signals derived from the BCR or from nurse-like cells, and inhibits BCR- and chemokine-receptor–induced AKT and MAP kinase (ERK) activation. In stromal cocultures, CAL-101 sensitizes CLL cells toward bendamustine, fludarabine, and dexamethasone. These results are corroborated by clinical data showing marked reductions in circulating CCL3, CCL4, and CXCL13 levels, and a surge in lymphocytosis during CAL-101 treatment. Thus, CAL-101 displays a dual mechanism of action, directly decreasing cell survival while reducing interactions that retain CLL cells in protective tissue microenvironments. These data provide an explanation for the clinical activity of CAL-101, and a roadmap for future therapeutic development. PMID:21803855

  14. Atypical chemokine receptors in cancer: friends or foes?

    PubMed

    Massara, Matteo; Bonavita, Ornella; Mantovani, Alberto; Locati, Massimo; Bonecchi, Raffaella

    2016-06-01

    The chemokine system is a fundamental component of cancer-related inflammation involved in all stages of cancer development. It controls not only leukocyte infiltration in primary tumors but also angiogenesis, cancer cell proliferation, and migration to metastatic sites. Atypical chemokine receptors are a new, emerging class of regulators of the chemokine system. They control chemokine bioavailability by scavenging, transporting, or storing chemokines. They can also regulate the activity of canonical chemokine receptors with which they share the ligands by forming heterodimers or by modulating their expression levels or signaling activity. Here, we summarize recent results about the role of these receptors (atypical chemokine receptor 1/Duffy antigen receptor for chemokine, atypical chemokine receptor 2/D6, atypical chemokine receptor 3/CXC-chemokine receptor 7, and atypical chemokine receptor 4/CC-chemokine receptor-like 1) on the tumorigenesis process, indicating that their effects are strictly dependent on the cell type on which they are expressed and on their coexpression with other chemokine receptors. Indeed, atypical chemokine receptors inhibit tumor growth and progression through their activity as negative regulators of chemokine bioavailability, whereas, on the contrary, they can promote tumorigenesis when they regulate the signaling of other chemokine receptors, such as CXC-chemokine receptor 4. Thus, atypical chemokine receptors are key components of the regulatory network of inflammation and immunity in cancer and may have a major effect on anti-inflammatory and immunotherapeutic strategies. PMID:26908826

  15. Regulation of breast cancer metastasis by atypical chemokine receptors.

    PubMed

    Cheng, Xiaoyun; Hung, Mien-Chie

    2009-05-01

    The interaction between chemokines and their G-protein-coupled receptors plays an important role in promoting metastasis of different kinds of human cancers. However, the expression of an atypical chemokine receptor, CCX-CKR, which serves as a decoy receptor to attract chemokines, inhibits the growth and metastasis of breast cancer by sequestration of chemokines. PMID:19383808

  16. Inhibition of lung metastasis by chemokine CCL17-mediated in vivo silencing of genes in CCR4+ Tregs

    PubMed Central

    Biragyn, Arya; Bodogai, Monica; Olkhanud, Purevdorj B.; Denny-Brown, Sinan R.; Puri, Nitin; Ayukawa, Koichi; Kanegasaki, Shiro; Hogaboam, Cory M.; Wejksza, Katarzyna; Lee-Chang, Catalina

    2013-01-01

    Despite significant attractiveness of anti-sense oligonucleotide/RNAi technology, its clinical application has been precluded by a lack of methods for targeted delivery and transduction of primary immune cells in vivo. Here, we devised a chemokine CCL17-based strategy (TARC-arp) that transiently silences expression of genes in immune cells by delivering inhibitory oligonucleotides via their chemokine receptors. In modeling studies using mice with established 4T1.2 breast cancer, we show that IL10 produced by CCR4+ cells, in particular FoxP3+ regulatory T cells (Tregs), plays an important role in lung metastasis. As such, TARC-arp-mediated silencing of IL-10 or FoxP3 in CCR4+ Tregs is sufficient to block lung metastasis. Thus, we provide a simple solution that circumvents the problems of RNAi use in vivo, indicating that a disease outcome can be successfully controlled by delivering inhibitory oligonucleotides with chemokines to inactivate a selective subset of immune cells. PMID:23603860

  17. The good and the bad of chemokines/chemokine receptors in melanoma

    PubMed Central

    Richmond, Ann; Yang, Jinming; Su, Yingjun

    2010-01-01

    Summary Chemokine ligand/receptor interactions affect melanoma cell growth, stimulate or inhibit angiogenesis, recruit leukocytes, promote metastasis, and alter the gene expression profile of the melanoma associated fibroblasts. Chemokine/chemokine receptor interactions can protect against tumor development/growth or can stimulate melanoma tumor progression, tumor growth and metastasis. Metastatic melanoma cells express chemokine receptors that play a major role in the specifying the organ site for metastasis, based upon receptor detection of the chemokine gradient elaborated by a specific organ/tissue. A therapeutic approach that utilizes the protective benefit of chemokines involves delivery of angiostatic chemokines or chemokines that stimulate the infiltration of cytotoxic T cells and natural killer T cells into the tumor microenvironment. An alternative approach that tackles the tumorigenic property of chemokines uses chemokine antibodies or chemokine receptor antagonists to target the growth and metastatic properties of these interactions. Based upon our current understanding of the role of chemokine-mediated inflammation in cancer, it is important that we learn to appropriately regulate the chemokine contribution to the tumorigenic `cytokine/chemokine storm', and to metastasis. PMID:19222802

  18. Modulation of Chemokine Responses: Synergy and Cooperativity

    PubMed Central

    Proudfoot, Amanda E. I.; Uguccioni, Mariagrazia

    2016-01-01

    Chemokine biology is mediated by more complex interactions than simple monomolecular ligand–receptor interactions, as chemokines can form higher order quaternary structures, which can also be formed after binding to glycosaminoglycans (GAGs) on endothelial cells, and their receptors are found as dimers and/or oligomers at the cell surface. Due to the complexity of the chemokine binding and signaling system, several mechanisms have been proposed to provide an explanation for the synergy observed between chemokines in leukocyte migration. Pioneering studies on interactions between different chemokines have revealed that they can act as antagonists, or synergize with other chemokines. The synergism can occur at different levels, involving either two chemokine receptors triggered simultaneously or sequentially exposed to their agonists, or the activation of one type of chemokine receptor triggered by chemokine heterocomplexes. In addition to the several chemokines that, by forming a heterocomplex with chemokine receptor agonists, act as enhancers of molecules of the same family, we have recently identified HMGB1, an endogenous damage-associated molecular patterns (DAMPs) molecule, as an enhancer of the activity of CXCL12. It is now evident that synergism between chemokines is crucial at the very early stage of inflammation. In addition, the low-affinity interaction with GAGs has recently been shown to induce cooperativity allowing synergy or inhibition of activity by displacement of other ligands. PMID:27242790

  19. Anti-inflammatory actions of herbal formula Gyejibokryeong-hwan regulated by inhibiting chemokine production and STAT1 activation in HaCaT cells.

    PubMed

    Jeong, Soo-Jin; Lim, Hye-Sun; Seo, Chang-Seob; Jin, Seong-Eun; Yoo, Sae-Rom; Lee, Nari; Shin, Hyeun-Kyoo

    2015-01-01

    Gyejibokryeong-hwan (GJBRH; Keishi-bukuryo-gan in Japan and Guizhi Fuling Wan in China) is a traditional herbal formula comprising five medicinal herbs and is used to treat climacteric syndrome. GJBRH has been shown to exhibit biological activity against diabetes, diabetic nephropathy, atherosclerosis, ischemia, and cancer. However, there is no scientific evidence of its activities against skin inflammation, including atopic dermatitis. We used the HaCaT human keratinocyte cell line to investigate the effects of GJBRH on skin inflammation. No significant cytotoxicity was observed in cells treated with GJBRH up to a concentration of 1000 µg/mL. Exposure to the proinflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) significantly increased HaCaT cell production of the following chemokines: macrophage-derived chemokine (MDC)/CCL22; regulated on activation, normal T-cell expressed and secreted (RANTES)/CCL5; and interleukin-8 (IL-8). In contrast, GJBRH significantly reduced the production of MDC, RANTES, and IL-8 compared with control cells simulated with TNF-α and IFN-γ. Consistently, GJBRH suppressed the mRNA expression of MDC, RANTES, and IL-8 in TNF-α and IFN-γ-treated cells. Treatment with GJBRH markedly inhibited phosphorylation of signal transducer and activator of transcription 1 (STAT1) in HaCaT cells stimulated with TNF-α and IFN-γ. Our findings indicate that GJBRH impairs TNF-α and IFN-γ-mediated inflammatory chemokine production and STAT1 phosphorylation in keratinocytes. We suggest that GJBRH may be a potent therapeutic agent for inflammatory skin disorders. PMID:25757924

  20. Molecular Pharmacology of Chemokine Receptors.

    PubMed

    de Wit, Raymond H; de Munnik, Sabrina M; Leurs, Rob; Vischer, Henry F; Smit, Martine J

    2016-01-01

    Chemokine receptors are involved in various pathologies such as inflammatory diseases, cancer, and HIV infection. Small molecule and antibody-based antagonists have been developed to inhibit chemokine-induced receptor activity. Currently two small molecule inhibitors targeting CXCR4 and CCR5 are on the market for stem cell mobilization and the treatment of HIV infection, respectively. Antibody fragments (e.g., nanobodies) targeting chemokine receptors are primarily orthosteric ligands, competing for the chemokine binding site. This is opposed by most small molecules, which act as allosteric modulators and bind to the receptor at a topographically distinct site as compared to chemokines. Allosteric modulators can be distinguished from orthosteric ligands by unique features, such as a saturable effect and probe dependency. For successful drug development, it is essential to determine pharmacological parameters (i.e., affinity, potency, and efficacy) and the mode of action of potential drugs during early stages of research in order to predict the biological effect of chemokine receptor targeting drugs in the clinic. This chapter explains how the pharmacological profile of chemokine receptor targeting ligands can be determined and quantified using binding and functional experiments. PMID:26921959

  1. Sulindac, a nonsteroidal anti-inflammatory drug, selectively inhibits interferon-{gamma}-induced expression of the chemokine CXCL9 gene in mouse macrophages

    SciTech Connect

    Sakaeda, Yoshiichi; Hiroi, Miki; Shimojima, Takahiro; Iguchi, Mayumi; Kanegae, Haruhide; Ohmori, Yoshihiro . E-mail: ohmori@dent.meikai.ac.jp

    2006-11-17

    Sulindac, a non-steroidal anti-inflammatory drug, has been shown to exert an anti-tumor effect on several types of cancer. To determine the effect of sulindac on intracellular signaling pathways in host immune cells such as macrophages, we investigated the effect of the drug on interferon gamma (IFN{gamma})-induced expression of signal transducer and activator of transcription 1 (STAT1) and other genes in mouse macrophage-like cell line RAW264.7 cells. Sulindac, but not aspirin or sodium salicylate, inhibited IFN{gamma}-induced expression of the CXC ligand 9 (CXCL9) mRNA, a chemokine for activated T cells, whereas the interferon-induced expression of CXCL10 or IFN regulatory factor-1 was not affected by sulindac. Luciferase reporter assay demonstrated that sulindac inhibited IFN{gamma}-induced promoter activity of the CXCL9 gene. Surprisingly, sulindac had no inhibitory effect on IFN{gamma}-induced STAT1 activation; however, constitutive nuclear factor {kappa}B activity was suppressed by the drug. These results indicate that sulindac selectively inhibited IFN{gamma}-inducible gene expression without inhibiting STAT1 activation.

  2. Chemokine sequestration by atypical chemokine receptors.

    PubMed

    Hansell, C A H; Simpson, C V; Nibbs, R J B

    2006-12-01

    Leucocyte migration is essential for robust immune and inflammatory responses, and plays a critical role in many human diseases. Chemokines, a family of small secreted protein chemoattractants, are of fundamental importance in this process, directing leucocyte trafficking by signalling through heptahelical G-protein-coupled receptors expressed by the migrating cells. However, several mammalian chemokine receptors, including D6 and CCX-CKR (ChemoCentryx chemokine receptor), do not fit existing models of chemokine receptor function, and do not even appear to signal in response to chemokine binding. Instead, these 'atypical' chemokine receptors are biochemically specialized for chemokine sequestration, acting to regulate chemokine bioavailability and thereby influence responses through signalling-competent chemokine receptors. This is of critical importance in vivo, as mice lacking D6 show exaggerated cutaneous inflammatory responses and an increased susceptibility to the development of skin cancer. CCX-CKR, on the other hand, is predicted to modulate homoeostatic lymphocyte and dendritic cell trafficking, key migratory events in acquired immune responses that are directed by CCX-CKR-binding chemokines. Thus studies on 'atypical' chemokine receptors are revealing functional and biochemical diversity within the chemokine receptor family and providing insights into novel mechanisms of chemokine regulation. PMID:17073739

  3. Luteolin inhibits recruitment of monocytes and migration of Lewis lung carcinoma cells by suppressing chemokine (C-C motif) ligand 2 expression in tumor-associated macrophage.

    PubMed

    Choi, Hee-Jin; Choi, Hee-Jung; Chung, Tae-Wook; Ha, Ki-Tae

    2016-01-29

    Tumor-associated macrophages (TAMs) play pivotal roles in the progression of cancer. In order to investigate a novel candidate that inhibits the tumor-supporting M2-like phenotype of TAMs, a murine macrophage cell line RAW 264.7 cells were treated with interleukin (IL)-4. Luteolin inhibited phosphorylation of signal transducer and activator of transcription 6 (STAT6), a main downstream signal of IL-4, and reduced the expression of the M2-associated genes. In addition, Luminex multiplex analysis for secreted cytokines revealed that IL-4-enhanced secretion of chemokine (C-C motif) ligand 2 (CCL2) was reduced by luteolin treatment. IL-4-stimulated migration of monocyte, THP-1 cells, was inhibited by luteolin treatment and recovered by recombinant CCL2 supplement. Moreover, luteolin decreased migration of Lewis lung carcinoma cells in a CCL2-dependent manner. Given the important role of the TAM phenotype in the tumor microenvironment, inhibitory effect of luteolin on the monocyte recruitment and cancer migration via suppression of the TAM-secreted CCL2 may suggest a novel therapeutic approach to treat malignant tumors. PMID:26766793

  4. Chemokines and chemokine receptors in arthritis

    PubMed Central

    Szekanecz, Zoltan; Vegvari, Aniko; Szabo, Zoltan; Koch, Alisa E.

    2010-01-01

    Chemokines are involved in leukocyte recruitment to inflammatory sites, such as the synovial tissue in rheumatoid arthritis (RA). There is a structural and a functional classification of chemokines. The former includes four groups: CXC, CC, C and CX3C chemokines. Chemokines may also be either inflammatory or homeostatic, however, these functions often overlap. Anti-chemokine and anti-chemokine receptor targeting may be therapeutically used in the future biological therapy of arthritis. Most data in this field have been obtained from animal models of arthritis as only very few human RA trials have been completed. However, it is very likely that various specific chemokine and chemokine receptor antagonists will be developed and administered to RA patients. PMID:20036936

  5. IL-12– and IL-23–modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition

    PubMed Central

    Kroenke, Mark A.; Carlson, Thaddeus J.; Andjelkovic, Anuska V.; Segal, Benjamin M.

    2008-01-01

    The interleukin (IL)-12p40 family of cytokines plays a critical role in the development of experimental autoimmune encephalomyelitis (EAE). However, the relative contributions of IL-12 and IL-23 to the pathogenic process remain to be elucidated. Here, we show that activation of uncommitted myelin-reactive T cells in the presence of either IL-12p70 or IL-23 confers encephalogenicity. Adoptive transfer of either IL-12p70– or IL-23–polarized T cells into naive syngeneic hosts resulted in an ascending paralysis that was clinically indistinguishable between the two groups. However, histological and reverse transcription–polymerase chain reaction analysis of central nervous system (CNS) tissues revealed distinct histopathological features and immune profiles. IL-12p70–driven disease was characterized by macrophage-rich infiltrates and prominent NOS2 up-regulation, whereas neutrophils and granulocyte–colony-stimulating factor (CSF) were prominent in IL-23–driven lesions. The monocyte-attracting chemokines CXCL9, 10, and 11 were preferentially expressed in the CNS of mice injected with IL-12p70–modulated T cells, whereas the neutrophil-attracting chemokines CXCL1 and CXCL2 were up-regulated in the CNS of mice given IL-23–modulated T cells. Treatment with anti–IL-17 or anti–granulocyte/macrophage-CSF inhibited EAE induced by transfer of IL-23–polarized, but not IL-12p70–polarized, cells. These findings indicate that autoimmunity can be mediated by distinct effector populations that use disparate immunological pathways to achieve a similar clinical outcome. PMID:18573909

  6. Polyplex-mediated inhibition of chemokine receptor CXCR4 and chromatin-remodeling enzyme NCOA3 impedes pancreatic cancer progression and metastasis.

    PubMed

    Wang, Yan; Kumar, Sushil; Rachagani, Satyanarayana; Sajja, Balasrinivasa R; Xie, Ying; Hang, Yu; Jain, Maneesh; Li, Jing; Boska, Michael D; Batra, Surinder K; Oupický, David

    2016-09-01

    Pancreatic cancer (PC) is one of the most aggressive malignancies due to intense desmoplasia, extreme hypoxia and inherent chemoresistance. Studies have implicated the expression of chemokine receptor CXCR4 and nuclear receptor co-activator-3 (NCOA3) in the development of desmoplasia and metastatic spread of PC. Using a series of polymeric CXCR4 antagonists (PCX), we optimized formulation of PCX/siNCOA3 polyplexes to simultaneously target CXCR4 and NCOA3 in PC. Cholesterol-modified PCX showed maximum CXCR4 antagonism, NCOA3 silencing and inhibition of PC cell migration in vitro. The optimized PCX/siNCOA3 polyplexes were used in evaluating antitumor and antimetastatic activity in orthotopic mouse model of metastatic PC. The polyplexes displayed significant inhibition of primary tumor growth, which was accompanied by a decrease in tumor necrosis and increased tumor perfusion. The polyplexes also showed significant antimetastatic effect and effective suppression of metastasis to distant organs. Overall, dual-function PCX/siNCOA3 polyplexes can effectively regulate tumor microenvironment to decrease progression and dissemination of PC. PMID:27267632

  7. Computational analysis of the structural mechanism of inhibition of chemokine receptor CXCR4 by small molecule antagonists

    PubMed Central

    Kawatkar, Sameer P; Yan, Maocai; Gevariya, Harsukh; Lim, Mi Youn; Eisold, Steven; Zhu, Xuejun; Huang, Ziwei; An, Jing

    2014-01-01

    Understanding the structural mechanism of receptor–ligand interactions for the chemokine receptor CXCR4 is essential for determining its physiological and pathological functions and for developing new therapies targeted to CXCR4. We have recently reported a structural mechanism for CXCR4 antagonism by a novel synthetic CXCR4 antagonist RCP168 and compared its effectiveness against the natural agonist SDF-1α. In the present study, using molecular docking, we further investigate the binding modes of another seven small molecules known to act as CXCR4 antagonists. The predicted binding modes were compared with previously published mutagenesis data for two of these (AMD3100 and AMD11070). Four antagonists, including AMD3100, AMD11070, FC131 and KRH-1636, bound in a similar fashion to CXCR4. Two important acidic amino acid residues (Asp262 and Glu288) on CXCR4, previously found essential for AMD3100 binding, were also involved in binding of the other ligands. These four antagonists use a binding site in common with that used by RCP168, which is a novel synthetic derivative of vMIP-II in which the first 10 residues are replaced by D-amino acids. Comparison of binding modes suggested that this binding site is different from the binding region occupied by the N-terminus of SDF-1α, the only known natural ligand of CXCR4. These observations suggest the presence of a ligand-binding site (site A) that co-exists with the agonist (SDF-1α) binding site (site B). The other three antagonists, including MSX123, MSX202 and WZ811, are smaller in size and had very similar binding poses, but binding was quite different from that of AMD3100. These three antagonists bound at both sites A and B, thereby blocking both binding and signaling by SDF-1α. PMID:21697335

  8. Xanthohumol, a prenylated chalcone derived from hops, suppresses cancer cell invasion through inhibiting the expression of CXCR4 chemokine receptor.

    PubMed

    Wang, Y; Chen, Y; Wang, J; Chen, J; Aggarwal, B B; Pang, X; Liu, M

    2012-02-01

    Cancer metastasis is the main cause of death (90%), and only recently we have gained some insight into the mechanisms by which metastatic cells arise from primary tumors and target to specific organs. Cysteine X Cysteine (CXC) chemokine receptor 4 (CXCR4), initially linked with leukocyte trafficking, is overexpressed in various tumors and mediates homing of tumor cells to distant sites expressing its cognate ligand CXCL12. Therefore, identification of CXCR4 inhibitors has great potential to abrogate tumor metastasis. In this study, we demonstrated that xanthohumol (XN), a prenylflavonoid derived from the female flowers of the hops plant (Humulus lupulus. L), suppressed CXCR4 expression in various cancer cell types in a concentration- and time-dependent manner. Both proteasome and lysosomal inhibitors had no effect to prevent the XN-induced downregulation of CXCR4, suggesting that the inhibitory effect of XN was not due to proteolytic degradation but occurred at the transcriptional level. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay further confirmed that XN could block endogenous activation of nuclear factor kappa B, a key transcription factor regulates the expression of CXCR4 in cancer cells. Consistent with the above molecular basis, XN abolished cell invasion induced by CXCL12 in both breast and colon cancer cells. Interestingly, although co-exist in hops, XN is the only isoform that exhibited the inhibitory effect on the expression of CXCR4 compared with other isomers, isoxanthohumol and 8-prenylnaringenin. Together, our results suggested that XN, as a novel inhibitor of CXCR4, could be a promising therapeutic agent contributed to cancer treatment. PMID:22172099

  9. BTK inhibition results in impaired CXCR4 chemokine receptor surface expression, signaling and function in chronic lymphocytic leukemia.

    PubMed

    Chen, S-S; Chang, B Y; Chang, S; Tong, T; Ham, S; Sherry, B; Burger, J A; Rai, K R; Chiorazzi, N

    2016-04-01

    Bruton's tyrosine kinase (BTK) is involved in the regulation of B-cell growth, migration and adhesion. The importance of BTK in cell trafficking is emphasized by the clonal contraction proceeded by lymphocytosis typical for the enzyme inhibitor, ibrutinib, in B-cell malignancies, including chronic lymphocytic leukemia (CLL). Here, we investigated BTK regulation of leukemic B-cell trafficking in a mouse model of aggressive TCL1 CLL-like disease. Inhibiting BTK by ibrutinib reduced surface membrane (sm) levels of CXCR4 but not CXCR5, CD49d and other adhesion/homing receptors. Decreased smCXCR4 levels resulted from blocking receptor signal transduction, which in turn aborted cycling from and to the membrane. This resulted in rapid re-distribution of CLL cells from spleens and lymph nodes into the circulation. CLL cells with impaired smCXCR4 from BTK inhibition failed to home to spleens. These functional changes mainly resulted from inhibition of CXCR4 phosphorylation at Ser339, mediated directly by blocking BTK enzymatic activity and indirectly by affecting the function of downstream targets PLCγ2 and PKCμ, and eventually synthesis of PIM-1 and BTK itself. Our data identify CXCR4 as a key regulator in BTK-mediated CLL-cell retention and have elucidated a complex set of not previously described mechanisms responsible for these effects. PMID:26582643

  10. BTK inhibition results in impaired CXCR4 chemokine receptor surface expression, signaling and function in chronic lymphocytic leukemia

    PubMed Central

    Chen, S-S; Chang, B Y; Chang, S; Tong, T; Ham, S; Sherry, B; Burger, J A; Rai, K R; Chiorazzi, N

    2016-01-01

    Bruton's tyrosine kinase (BTK) is involved in the regulation of B-cell growth, migration and adhesion. The importance of BTK in cell trafficking is emphasized by the clonal contraction proceeded by lymphocytosis typical for the enzyme inhibitor, ibrutinib, in B-cell malignancies, including chronic lymphocytic leukemia (CLL). Here, we investigated BTK regulation of leukemic B-cell trafficking in a mouse model of aggressive TCL1 CLL-like disease. Inhibiting BTK by ibrutinib reduced surface membrane (sm) levels of CXCR4 but not CXCR5, CD49d and other adhesion/homing receptors. Decreased smCXCR4 levels resulted from blocking receptor signal transduction, which in turn aborted cycling from and to the membrane. This resulted in rapid re-distribution of CLL cells from spleens and lymph nodes into the circulation. CLL cells with impaired smCXCR4 from BTK inhibition failed to home to spleens. These functional changes mainly resulted from inhibition of CXCR4 phosphorylation at Ser339, mediated directly by blocking BTK enzymatic activity and indirectly by affecting the function of downstream targets PLCγ2 and PKCμ, and eventually synthesis of PIM-1 and BTK itself. Our data identify CXCR4 as a key regulator in BTK-mediated CLL-cell retention and have elucidated a complex set of not previously described mechanisms responsible for these effects. PMID:26582643

  11. Anti-inflammatory effects of an inflammatory chemokine: CCL2 inhibits lymphocyte homing by modulation of CCL21-triggered integrin-mediated adhesions.

    PubMed

    Flaishon, Liat; Hart, Gili; Zelman, Einat; Moussion, Christine; Grabovsky, Valentin; Lapidot Tal, Guy; Feigelson, Sara; Margalit, Raanan; Harmelin, Alon; Avin-Wittenberg, Tamar; Shoseyov, David; Alon, Ronen; Girard, Jean-Philippe; Shachar, Idit

    2008-12-15

    Our studies focus on the pathways that restrict homing of specific subsets of immune cells, and thereby fine-tune the immune response at specific lymphoid and peripheral tissues. Here, we report that CCL2 (at picomolar [pM] levels) renders both murine and human T cells defective in their ability to develop CCR7-triggered activation of LFA-1- and LFA-1-mediated adhesion strengthening to endothelial ICAM-1 both in vitro and in vivo. CCL2 also attenuated lymphocyte chemotaxis toward lymph node chemokines. Consequently, low-dose CCL2 inhibited lymphocyte homing to peripheral lymph nodes but did not affect lymphocyte trafficking through the spleen. Impaired homing of lymphocytes to peripheral lymph nodes resulted in attenuated progression of both asthma and adjuvant arthritis. Thus, pM levels of circulating CCL2 can exert global suppressive effects on T-cell trafficking and differentiation within peripheral lymph nodes, and may be clinically beneficial as an anti-inflammatory agent. PMID:18802011

  12. Targeting of TGF-β-activated protein kinase 1 inhibits chemokine (C-C motif) receptor 7 expression, tumor growth and metastasis in breast cancer

    PubMed Central

    Hung, Wen-Chun; Hou, Ming-Feng

    2015-01-01

    TGF-β-activated protein kinase 1 (TAK1) is a critical mediator in inflammation, immune response and cancer development. Our previous study demonstrated that activation of TAK1 increases the expression of chemokine (C-C motif) receptor 7 (CCR7) and promotes lymphatic invasion ability of breast cancer cells. However, the expression and association of activated TAK1 and CCR7 in breast tumor tissues is unknown and the therapeutic effect by targeting TAK1 is also unclear. We showed that activated TAK1 (as indicated by phospho-TAK1) and its binding protein TAB1 are strongly expressed in breast tumor tissues (77% and 74% respectively). In addition, increase of phospho-TAK1 or TAB1 is strongly associated with over-expression of CCR7. TAK1 inhibitor 5Z-7-Oxozeaenol (5Z-O) inhibited TAK1 activity, suppressed downstream signaling pathways including p38, IκB kinase (IKK) and c-Jun N-terminal kinase (JNK) and reduced CCR7 expression in metastatic MDA-MB-231 cells. In addition, 5Z-O repressed NF-κB- and c-JUN-mediated transcription of CCR7 gene. Knockdown of TAB1 attenuated CCR7 expression and tumor growth in an orthotopic animal study. More importantly, lymphatic invasion and lung metastasis were suppressed. Collectively, our results demonstrate that constitutive activation of TAK1 is frequently found in human breast cancer and this kinase is a potential therapeutic target for this cancer. PMID:25557171

  13. Chemokine Receptor Oligomerization and Allostery

    PubMed Central

    Stephens, Bryan; Handel, Tracy M.

    2014-01-01

    Oligomerization of chemokine receptors has been reported to influence many aspects of receptor function through allosteric communication between receptor protomers. Allosteric interactions within chemokine receptor hetero-oligomers have been shown to cause negative cooperativity in the binding of chemokines and to inhibit receptor activation in the case of some receptor pairs. Other receptor pairs can cause enhanced signaling and even activate entirely new, hetero-oligomer-specific signaling complexes and responses downstream of receptor activation. Many mechanisms contribute to these effects including direct allosteric coupling between the receptors, G protein mediated allostery, G protein stealing, ligand sequestration and recruitment of new intracellular proteins by exposing unique binding interfaces on the oligomerized receptors. These effects present both challenges as well as exciting opportunities for drug discovery. One of the most difficult challenges will involve determining if and when hetero-oligomers versus homo-oligomers are involved in specific disease states. PMID:23415099

  14. The opioid antagonist, β-funaltrexamine, inhibits NF-κB signaling and chemokine expression in human astrocytes and in mice.

    PubMed

    Davis, Randall L; Das, Subhas; Thomas Curtis, J; Stevens, Craig W

    2015-09-01

    Opioid-immune crosstalk occurs when opioid drugs alter the activity of the immune system. In this study, the opioid antagonist β-funaltrexamine (β-FNA) decreases the expression and release of an inflammatory chemokine, interferon-γ inducible protein-10 (CXCL10) from normal human astrocytes stimulated by interleukin 1β (IL-1β). β-FNA decreased CXCL10 by an unknown action that did not involve the mu opioid receptor (MOR). As IL-1β acts through its receptor to activate NF-κB/MAPK signaling pathways which leads to CXCL10 expression and release, key steps in the IL-1β signaling pathways were examined following β-FNA treatment. IL-1β-induced activation of p38 mitogen-activated protein kinases (p38 MAPK) was inhibited by β-FNA as shown by decreased p38 MAPK phosphorylation in treated cells. β-FNA also decreased the levels of activated subunits of NF-κB (p50 and p65) in treated astrocytes. The impact of β-FNA was also observed in proteins that act to negatively regulate NF-κB signaling. IL-1β upregulated the expression of A20, a ubiquitin (Ub)-editing enzyme that dampens NF-κB signaling by altering ubiquination patterns on IL-1 receptor second messengers, and the increase in A20 was significantly inhibited by β-FNA treatment. Inhibition of the Ub-activating enzyme E1 by the inhibitor PYR41 also decreased CXCL10 release, like β-FNA, and concurrent treatment with both PYR41 and β-FNA inhibited CXCL10 more than did either agent alone. In mice, lipopolysaccharide-induced CXCL10 expression in the brain was inhibited by treatment with β-FNA. These findings suggest that β-FNA exerts an anti-inflammatory action in vitro and in vivo that is MOR-independent and possibly due to the alkylating ability of β-FNA. PMID:26007645

  15. Proinflammatory chemokines during Candida albicans keratitis.

    PubMed

    Yuan, Xiaoyong; Hua, Xia; Wilhelmus, Kirk R

    2010-03-01

    Chemotactic cytokines mediate the recruitment of leukocytes into infected tissues. This study investigated the profile of chemokines during experimental Candida albicans keratitis and determined the effects of chemokine inhibition on leukocyte infiltration and fungal growth during murine keratomycosis. Scarified corneas of BALB/c mice were topically inoculated with C. albicans and monitored daily over one week for fungal keratitis. After a gene microarray for murine chemokines compared infected corneas to controls, real-time reverse transcription polymerase chain reaction (RT-PCR) and immunostaining assessed chemokine expression in infected and mock-inoculated corneas. An anti-chemokine antibody was then administered subconjunctivally and evaluated for effects on clinical severity, corneal inflammation, fungal recovery, and cytokine expression. Of 33 chemokine genes examined by microarray, 6 CC chemokines and 6 CXC chemokines were significantly (P<0.05) upregulated more than two-fold. Chemokine (CC-motif) ligand 3 (CCL3) was upregulated 108-fold (P=0.03) by real-time RT-PCR within one day after fungal inoculation and remained increased 28-fold (P=0.02) at one week, and its in situ expression increased in the epithelium and stroma of infected corneas. Compared to the control antibody-treated group, eyes treated with anti-CCL3 antibody showed reduced clinical severity (P<0.05), less corneal neovascularization (P=0.02), and fewer inflammatory cells infiltrating corneal tissue, but the amount of recoverable fungi was not significantly (P=0.4) affected. Anti-CCL3 treatment significantly (P=0.01) reduced the expression of tumor necrosis factor and interleukin-1beta in infected corneas. These results indicate that chemokines, especially the CC chemokine CCL3, play important roles in the acute inflammatory response to C. albicans corneal infection. PMID:20005222

  16. Inhibition of Epithelial CC-Family Chemokine Synthesis by the Synthetic Chalcone DMPF-1 via Disruption of NF-κB Nuclear Translocation and Suppression of Experimental Asthma in Mice

    PubMed Central

    Rajajendram, Revathee; Tham, Chau Ling; Akhtar, Mohamad Nadeem; Sulaiman, Mohd Roslan; Israf, Daud Ahmad

    2015-01-01

    Asthma is associated with increased pulmonary inflammation and airway hyperresponsiveness. The interaction between airway epithelium and inflammatory mediators plays a key role in the pathogenesis of asthma. In vitro studies evaluated the inhibitory effects of 3-(2,5-dimethoxyphenyl)-1-(5-methylfuran-2-yl)prop-2-en-1-one (DMPF-1), a synthetic chalcone analogue, upon inflammation in the A549 lung epithelial cell line. DMPF-1 selectively inhibited TNF-α-stimulated CC chemokine secretion (RANTES, eotaxin-1, and MCP-1) without any effect upon CXC chemokine (GRO-α and IL-8) secretion. Western blot analysis further demonstrated that the inhibitory activity resulted from disruption of p65NF-κB nuclear translocation without any effects on the mitogen-activated protein kinase (MAPK) pathway. Treatment of ovalbumin-sensitized and ovalbumin-challenged BALB/c mice with DMPF-1 (0.2–100 mg/kg) demonstrated significant reduction in the secretion and gene expression of CC chemokines (RANTES, eotaxin-1, and MCP-1) and Th2 cytokines (IL-4, IL-5, and IL-13). Furthermore, DMPF-1 treatment inhibited eosinophilia, goblet cell hyperplasia, peripheral blood total IgE, and airway hyperresponsiveness in ovalbumin-sensitized and ovalbumin-challenged mice. In conclusion, these findings demonstrate the potential of DMPF-1, a nonsteroidal compound, as an antiasthmatic agent for further pharmacological evaluation. PMID:26300589

  17. Chemokines and immunity

    PubMed Central

    Palomino, Diana Carolina Torres; Marti, Luciana Cavalheiro

    2015-01-01

    Chemokines are a large family of small cytokines and generally have low molecular weight ranging from 7 to 15kDa. Chemokines and their receptors are able to control the migration and residence of all immune cells. Some chemokines are considered pro-inflammatory, and their release can be induced during an immune response at a site of infection, while others are considered homeostatic and are involved in controlling of cells migration during tissue development or maintenance. The physiologic importance of this family of mediators is resulting from their specificity − members of the chemokine family induce recruitment of well-defined leukocyte subsets. There are two major chemokine sub-families based upon cysteine residues position: CXC and CC. As a general rule, members of the CXC chemokines are chemotactic for neutrophils, and CC chemokines are chemotactic for monocytes and sub-set of lymphocytes, although there are some exceptions. This review discusses the potential role of chemokines in inflammation focusing on the two best-characterized chemokines: monocyte chemoattractant protein-1, a CC chemokine, and interleukin-8, a member of the CXC chemokine sub-family. PMID:26466066

  18. Chemokines and chemokine receptors blockers as new drugs for the treatment of chronic obstructive pulmonary disease.

    PubMed

    Caramori, G; Di Stefano, A; Casolari, P; Kirkham, P A; Padovani, A; Chung, K F; Papi, A; Adcock, I M

    2013-01-01

    Chronic obstructive pulmonary disease (COPD) is characterised by an abnormal inflammatory response of the lung to noxious particles or gases. The cellular inflammatory response in COPD is characterised by an increased number of inflammatory cells in the lungs. Although the molecular and cellular mechanisms responsible for the development of COPD are not well understood; several mediators are assumed to regulate the activation and recruitment of these inflammatory cells into the lung of COPD patients particularly those belonging to the chemokine family. Inhibitors or blockers of chemokine and chemokine receptors are therefore of great interest as potential novel therapies for COPD and many are now in clinical development. A high degree of redundancy exists in the chemokine network and inhibition of a single chemokine or receptor may not be sufficient to block the inflammatory response. Despite this, animal studies suggest a strong rationale for inhibiting the chemokine network in COPD. As such, every leading pharmaceutical company maintains a significant interest in developing agents that regulate leukocyte navigation as potential anti-inflammatory drugs. Drugs and antibodies targeting chemokines and their receptors are generally still in early stages of development and the results of clinical trial are awaited with great interest. These agents may not only provide improved management of COPD but also, importantly, indicate proof-of-concept to further clarify the role of chemokines in the pathophysiology of COPD. PMID:24059236

  19. Touch of Chemokines

    PubMed Central

    Blanchet, Xavier; Langer, Marcella; Weber, Christian; Koenen, Rory R.; von Hundelshausen, Philipp

    2012-01-01

    Chemoattractant cytokines or chemokines constitute a family of structurally related proteins found in vertebrates, bacteria, or viruses. So far, 48 chemokine genes have been identified in humans, which bind to around 20 chemokine receptors. These receptors belong to the seven transmembrane G-protein-coupled receptor family. Chemokines and their receptors were originally studied for their role in cellular trafficking of leukocytes during inflammation and immune surveillance. It is now known that they exert different functions under physiological conditions such as homeostasis, development, tissue repair, and angiogenesis but also under pathological disorders including tumorigenesis, cancer metastasis, inflammatory, and autoimmune diseases. Physicochemical properties of chemokines and chemokine receptors confer the ability to homo- and hetero-oligomerize. Many efforts are currently performed in establishing new therapeutically compounds able to target the chemokine/chemokine receptor system. In this review, we are interested in the role of chemokines in inflammatory disease and leukocyte trafficking with a focus on vascular inflammatory diseases, the operating synergism, and the emerging therapeutic approaches of chemokines. PMID:22807925

  20. Profiling Heparin-Chemokine Interactions Using Synthetic Tools

    PubMed Central

    de Paz, Jose L.; Moseman, E. Ashley; Noti, Christian; Polito, Laura; von Andrian, Ulrich H.; Seeberger, Peter H.

    2009-01-01

    Glycosaminoglycans (GAGs), such as heparin or heparan sulfate, are required for the in vivo function of chemokines. Chemokines play a crucial role in the recruitment of leukocyte subsets to sites of inflammation and lymphocytes trafficking. GAG-chemokine interactions mediate cell migration and determine which leukocyte subsets enter tissues. Identifying the exact GAC sequences that bind to particular chemokines is key to understand chemokine function at the molecular level and develop strategies to interfere with chemokine-mediated processes. Here, we characterize the heparin binding profiles of eight chemokines (CCL21, IL-8, CXCL12, CXCL13, CCL19, CCL25, CCL28, and CXCL16) by employing heparin microarrays containing a small library of synthetic heparin oligosaccharides. The chemokines differ significantly in their interactions with heparin oligosaccharides: While some chemokines, (e.g., CCL21) strongly bind to a hexasaccharide containing the GlcNSO3(6-OSO3)-IdoA(2-OSO3) repeating unit, CCL19 does not bind and CXCL12 binds only weakly. The carbohydrate microarray binding results were validated by surface plasmon resonance experiments. In vitro chemotaxis assays revealed that dendrimers coated with the fully sulfated heparin hexasaccharide inhibit lymphocyte migration toward CCL21. Migration toward CXCL12 or CCL19 was not affected. These in vitro homing assays indicate that multivalent synthetic heparin dendrimers inhibit the migration of lymphocytes toward certain chemokine gradients by blocking the formation of a chemokine concentration gradient on GAG endothelial chains. These findings are in agreement with preliminary in vivo measurements of circulating lymphocytes. The results presented here contribute to the understanding of GAG-chemokine interactions, a first step toward the design of novel drugs that modulate chemokine activity. PMID:18030990

  1. Chemokines, chemokine receptors and the gastrointestinal system

    PubMed Central

    Miyazaki, Hiroshi; Takabe, Kazuaki; Yeudall, W Andrew

    2013-01-01

    The biological properties of tumor cells are known to be regulated by a multitude of cytokines and growth factors, which include epidermal growth factor receptor agonists and members of the transforming growth factor β family. Furthermore, the recent explosion of research in the field of chemokine function as mediators of tumor progression has led to the possibility that these small, immunomodulatory proteins also play key roles in carcinogenesis and may, therefore, be potential targets for novel therapeutic approaches. In this review, we will summarize recently reported findings in chemokine biology with a focus on the gastrointestinal tract. PMID:23704819

  2. Chemokines and tissue injury.

    PubMed Central

    Furie, M. B.; Randolph, G. J.

    1995-01-01

    Accumulation of leukocytes at sites of inflammation is essential for host defense, yet secretory products of the white cells may augment injury by damaging surrounding healthy tissues. Members of the chemokine family of chemotactic cytokines play a fundamental role in this process by attracting and stimulating specific subsets of leukocytes. In vitro studies suggest that chemokines participate in at least three phases of leukocyte recruitment. First, they foster tight adhesion of circulating leukocytes to the vascular endothelium by activating leukocytic integrins. Second, because of their chemoattractant properties, chemokines guide leukocytes through the endothelial junctions and underlying tissue to the inflammatory focus. Finally, chemokines activate effector functions of leukocytes, including production of reactive oxygen intermediates and exocytosis of degradative enzymes. Animal studies in which antibodies are used to neutralize the activity of individual members of the chemokine family confirm that these mediators contribute to the development of both acute and chronic inflammatory conditions. A number of mechanisms may operate in vivo to limit the proinflammatory properties of chemokines. Therapies that target chemokines directly or enhance the body's mechanisms for controlling their activity may prove to be reasonable approaches for treatment of inflammatory diseases. PMID:7778669

  3. Embelin Inhibits Invasion and Migration of MDA-MB-231 Breast Cancer Cells by Suppression of CXC Chemokine Receptor 4, Matrix Metalloproteinases-9/2, and Epithelial-Mesenchymal Transition.

    PubMed

    Lee, Hanwool; Ko, Jeong-Hyeon; Baek, Seung Ho; Nam, Dongwoo; Lee, Seok Geun; Lee, Junhee; Yang, Woong Mo; Um, Jae-Young; Kim, Sung-Hoon; Shim, Bum Sang; Ahn, Kwang Seok

    2016-06-01

    Embelin (EB) is a benzoquinone derivative isolated from Embelia ribes Burm plant. Recent scientific evidence shows that EB induces apoptosis and inhibits migration and invasion in highly metastatic human breast cancer cells. However, the exact mechanisms of EB in tumor metastasis and invasion have not been fully elucidated. Here, we investigated the underlying mechanisms of antimetastatic activities of EB in breast cancer cells. The EB downregulated the chemokine receptor 4 (CXCR4) as well as matrix metalloproteinase (MMP)-9/2 expression and upregulated the tissue inhibitor of metalloproteinase 1 expression in MDA-MB-231 cells under noncytotoxic concentrations but not in MCF-7 cells. Additionally, EB inhibited the CXC motif chemokine ligand 12 induced invasion and migration activities of MDA-MB-231 cells. A detailed study of underlying mechanisms revealed that the regulation of the downregulation of CXCR4 was at the transcriptional level, as indicated by the downregulation of mRNA expression and suppression of nuclear factor-kappa B (NF-κB) activation. It further reduced the binding of NF-κB to the CXCR4 promoter. Besides, EB downregulated mesenchymal marker proteins (neural cadherin and vimentin) and concurrently upregulated epithelial markers (epithelial cadherin and occludin). Overall, these findings suggest that EB can abrogate breast cancer cell invasion and metastasis by suppression of CXCR4, MMP-9/2 expressions, and inhibition of epithelial-mesenchymal transition and thus may have a great potential to suppress metastasis of breast cancer. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27030214

  4. Chemokines and skin diseases.

    PubMed

    Sugaya, Makoto

    2015-04-01

    Chemokines are small molecules that induce chemotaxis and activation of certain subsets of leukocytes. The expression patterns of chemokines and chemokine receptors are specific to certain organs and cells. Therefore, chemokines are important to elucidate the mechanism of organ-specific human diseases. CCL17 expressed by Langerhans cells, blood endothelial cells, and fibroblasts plays a key role in attracting Th2 cells and tumor cells of adult T-cell leukemia/lymphoma and mycosis fungoides/Sézary syndrome into the skin, developing various Th2-type inflammatory skin diseases as well as cutaneous lymphoma. CCL11 and CCL26 expressed by skin-resident cells, such as fibroblasts, blood endothelial cells, and keratinocytes, induce infiltration of CCR3-expressing cells such as Th2 cells and eosinophils. CCL11 may also serve as an autocrine as well as a paracrine in anaplastic large cell lymphoma. CX3CL1 expressed on blood endothelial cells leads to infiltration of CX3CR1(+) immune cells, such as mast cells, neutrophils, and macrophages, playing important roles in wound healing, tumor immunity, and vasculitis. Biologics targeting chemokines and their receptors are promising strategies for various skin diseases that are resistant to the current therapy. PMID:25182982

  5. Chemokines and Chemokine Receptors in the Development of Lupus Nephritis

    PubMed Central

    2016-01-01

    Lupus nephritis (LN) is a major cause of morbidity and mortality in the patients with systemic lupus erythematosus (SLE), an autoimmune disease with damage to multiple organs. Leukocyte recruitment into the inflamed kidney is a critical step to promote LN progression, and the chemokine/chemokine receptor system is necessary for leukocyte recruitment. In this review, we summarize recent studies on the roles of chemokines and chemokine receptors in the development of LN and discuss the potential and hurdles of developing novel, chemokine-based drugs to treat LN. PMID:27403037

  6. Chemokines and Chemokine Receptors in the Development of Lupus Nephritis.

    PubMed

    Liao, Xiaofeng; Pirapakaran, Tharshikha; Luo, Xin M

    2016-01-01

    Lupus nephritis (LN) is a major cause of morbidity and mortality in the patients with systemic lupus erythematosus (SLE), an autoimmune disease with damage to multiple organs. Leukocyte recruitment into the inflamed kidney is a critical step to promote LN progression, and the chemokine/chemokine receptor system is necessary for leukocyte recruitment. In this review, we summarize recent studies on the roles of chemokines and chemokine receptors in the development of LN and discuss the potential and hurdles of developing novel, chemokine-based drugs to treat LN. PMID:27403037

  7. 6-shogaol, an active constituent of dietary ginger, impairs cancer development and lung metastasis by inhibiting the secretion of CC-chemokine ligand 2 (CCL2) in tumor-associated dendritic cells.

    PubMed

    Hsu, Ya-Ling; Hung, Jen-Yu; Tsai, Ying-Ming; Tsai, Eing-Mei; Huang, Ming-Shyan; Hou, Ming-Feng; Kuo, Po-Lin

    2015-02-18

    This study has two novel findings: it is not only the first to demonstrate that tumor-associated dendritic cells (TADCs) facilitate lung and breast cancer metastasis in vitro and in vivo by secreting inflammatory mediator CC-chemokine ligand 2 (CCL2), but it is also the first to reveal that 6-shogaol can decrease cancer development and progression by inhibiting the production of TADC-derived CCL2. Human lung cancer A549 and breast cancer MDA-MB-231 cells increase TADCs to express high levels of CCL2, which increase cancer stem cell features, migration, and invasion, as well as immunosuppressive tumor-associated macrophage infiltration. 6-Shogaol decreases cancer-induced up-regulation of CCL2 in TADCs, preventing the enhancing effects of TADCs on tumorigenesis and metastatic properties in A549 and MDA-MB-231 cells. A549 and MDA-MB-231 cells enhance CCL2 expression by increasing the phosphorylation of signal transducer and activator of transcription 3 (STAT3), and the activation of STAT3 induced by A549 and MDA-MB-231 is completely inhibited by 6-shogaol. 6-Shogaol also decreases the metastasis of lung and breast cancers in mice. 6-Shogaol exerts significant anticancer effects on lung and breast cells in vitro and in vivo by targeting the CCL2 secreted by TADCs. Thus, 6-shogaol may have the potential of being an efficacious immunotherapeutic agent for cancers. PMID:25621970

  8. Mechanical stretch inhibits lipopolysaccharide-induced keratinocyte-derived chemokine and tissue factor expression while increasing procoagulant activity in murine lung epithelial cells.

    PubMed

    Sebag, Sara C; Bastarache, Julie A; Ware, Lorraine B

    2013-03-15

    Previous studies have shown that the innate immune stimulant LPS augments mechanical ventilation-induced pulmonary coagulation and inflammation. Whether these effects are mediated by alveolar epithelial cells is unclear. The alveolar epithelium is a key regulator of the innate immune reaction to pathogens and can modulate both intra-alveolar inflammation and coagulation through up-regulation of proinflammatory cytokines and tissue factor (TF), the principal initiator of the extrinsic coagulation pathway. We hypothesized that cyclic mechanical stretch (MS) potentiates LPS-mediated alveolar epithelial cell (MLE-12) expression of the chemokine keratinocyte-derived cytokine (KC) and TF. Contrary to our hypothesis, MS significantly decreased LPS-induced KC and TF mRNA and protein expression. Investigation into potential mechanisms showed that stretch significantly reduced LPS-induced surface expression of TLR4 that was not a result of increased degradation. Decreased cell surface TLR4 expression was concomitant with reduced LPS-mediated NF-κB activation. Immunofluorescence staining showed that cyclic MS markedly altered LPS-induced organization of actin filaments. In contrast to expression, MS significantly increased LPS-induced cell surface TF activity independent of calcium signaling. These findings suggest that cyclic MS of lung epithelial cells down-regulates LPS-mediated inflammatory and procoagulant expression by modulating actin organization and reducing cell surface TLR4 expression and signaling. However, because LPS-induced surface TF activity was enhanced by stretch, these data demonstrate differential pathways regulating TF expression and activity. Ultimately, loss of LPS responsiveness in the epithelium induced by MS could result in increased susceptibility of the lung to bacterial infections in the setting of mechanical ventilation. PMID:23362270

  9. Mechanical Stretch Inhibits Lipopolysaccharide-induced Keratinocyte-derived Chemokine and Tissue Factor Expression While Increasing Procoagulant Activity in Murine Lung Epithelial Cells*

    PubMed Central

    Sebag, Sara C.; Bastarache, Julie A.; Ware, Lorraine B.

    2013-01-01

    Previous studies have shown that the innate immune stimulant LPS augments mechanical ventilation-induced pulmonary coagulation and inflammation. Whether these effects are mediated by alveolar epithelial cells is unclear. The alveolar epithelium is a key regulator of the innate immune reaction to pathogens and can modulate both intra-alveolar inflammation and coagulation through up-regulation of proinflammatory cytokines and tissue factor (TF), the principal initiator of the extrinsic coagulation pathway. We hypothesized that cyclic mechanical stretch (MS) potentiates LPS-mediated alveolar epithelial cell (MLE-12) expression of the chemokine keratinocyte-derived cytokine (KC) and TF. Contrary to our hypothesis, MS significantly decreased LPS-induced KC and TF mRNA and protein expression. Investigation into potential mechanisms showed that stretch significantly reduced LPS-induced surface expression of TLR4 that was not a result of increased degradation. Decreased cell surface TLR4 expression was concomitant with reduced LPS-mediated NF-κB activation. Immunofluorescence staining showed that cyclic MS markedly altered LPS-induced organization of actin filaments. In contrast to expression, MS significantly increased LPS-induced cell surface TF activity independent of calcium signaling. These findings suggest that cyclic MS of lung epithelial cells down-regulates LPS-mediated inflammatory and procoagulant expression by modulating actin organization and reducing cell surface TLR4 expression and signaling. However, because LPS-induced surface TF activity was enhanced by stretch, these data demonstrate differential pathways regulating TF expression and activity. Ultimately, loss of LPS responsiveness in the epithelium induced by MS could result in increased susceptibility of the lung to bacterial infections in the setting of mechanical ventilation. PMID:23362270

  10. Chemokines in health and disease

    PubMed Central

    Raman, Dayanidhi; Sobolik-Delmaire, Tammy; Richmond, Ann

    2011-01-01

    Chemokines and their receptors play a key role in development and homeostasis as well as in the pathogenesis of tumors and autoimmune diseases. Chemokines are involved in the implantation of the early conceptus, the migration of subsets of cells during embryonic development, and the overall growth of the embryo. Chemokines also have an important role in the development and maintenance of innate and adaptive immunity. In addition, they play a significant role in wound healing and angiogenesis. When the physiological role of chemokines is subverted or chronically amplified, disease often follows. Chemokines are involved in the pathobiology of chronic inflammation, tumorigenesis and metastasis, as well as autoimmune diseases. This article reviews the role of chemokines and their receptors in normal and disease processes and the potential for using chemokine antagonists for appropriate targeted therapy. PMID:21223965

  11. Actions of Thyroid Hormone Analogues on Chemokines

    PubMed Central

    Glinsky, Gennadi V.

    2016-01-01

    The extracellular domain of plasma membrane integrin αvβ3 contains a receptor for thyroid hormone (L-thyroxine, T4; 3,5,3′-triiodo-L-thyronine, T3); this receptor also binds tetraiodothyroacetic acid (tetrac), a derivative of T4. Tetrac inhibits the binding of T4 and T3 to the integrin. Fractalkine (CX3CL1) is a chemokine relevant to inflammatory processes in the CNS that are microglia-dependent but also important to normal brain development. Expression of the CX3CL1 gene is downregulated by tetrac, suggesting that T4 and T3 may stimulate fractalkine expression. Independently of its specific receptor (CX3CR1), fractalkine binds to αvβ3 at a site proximal to the thyroid hormone-tetrac receptor and changes the physical state of the integrin. Tetrac also affects expression of the genes for other CNS-relevant chemokines, including CCL20, CCL26, CXCL2, CXCL3, and CXCL10. The chemokine products of these genes are important to vascularity of the brain, particularly of the choroid plexus, to inflammatory processes in the CNS and, in certain cases, to neuroprotection. Thyroid hormones are known to contribute to regulation of each of these CNS functions. We propose that actions of thyroid hormone and hormone analogues on chemokine gene expression contribute to regulation of inflammatory processes in brain and of brain blood vessel formation and maintenance. PMID:27493972

  12. Actions of Thyroid Hormone Analogues on Chemokines.

    PubMed

    Davis, Paul J; Glinsky, Gennadi V; Lin, Hung-Yun; Mousa, Shaker A

    2016-01-01

    The extracellular domain of plasma membrane integrin αvβ3 contains a receptor for thyroid hormone (L-thyroxine, T4; 3,5,3'-triiodo-L-thyronine, T3); this receptor also binds tetraiodothyroacetic acid (tetrac), a derivative of T4. Tetrac inhibits the binding of T4 and T3 to the integrin. Fractalkine (CX3CL1) is a chemokine relevant to inflammatory processes in the CNS that are microglia-dependent but also important to normal brain development. Expression of the CX3CL1 gene is downregulated by tetrac, suggesting that T4 and T3 may stimulate fractalkine expression. Independently of its specific receptor (CX3CR1), fractalkine binds to αvβ3 at a site proximal to the thyroid hormone-tetrac receptor and changes the physical state of the integrin. Tetrac also affects expression of the genes for other CNS-relevant chemokines, including CCL20, CCL26, CXCL2, CXCL3, and CXCL10. The chemokine products of these genes are important to vascularity of the brain, particularly of the choroid plexus, to inflammatory processes in the CNS and, in certain cases, to neuroprotection. Thyroid hormones are known to contribute to regulation of each of these CNS functions. We propose that actions of thyroid hormone and hormone analogues on chemokine gene expression contribute to regulation of inflammatory processes in brain and of brain blood vessel formation and maintenance. PMID:27493972

  13. Novel antiviral activity of chemokines

    SciTech Connect

    Nakayama, Takashi; Shirane, Jumi; Hieshima, Kunio; Shibano, Michiko; Watanabe, Masayasu; Jin, Zhe; Nagakubo, Daisuke; Saito, Takuya; Shimomura, Yoshikazu; Yoshie, Osamu . E-mail: o.yoshie@med.kindai.ac.jp

    2006-07-05

    Antimicrobial peptides are a diverse family of small, mostly cationic polypeptides that kill bacteria, fungi and even some enveloped viruses, while chemokines are a group of mostly cationic small proteins that induce directed migration of leukocytes through interactions with a group of seven transmembrane G protein-coupled receptors. Recent studies have shown that antimicrobial peptides and chemokines have substantially overlapping functions. Thus, while some antimicrobial peptides are chemotactic for leukocytes, some chemokines can kill a wide range of bacteria and fungi. Here, we examined a possible direct antiviral activity of chemokines against an enveloped virus HSV-1. Among 22 human chemokines examined, chemokines such as MIP-1{alpha}/CCL3, MIP-1{beta}/CCL4 and RANTES/CCL5 showed a significant direct antiviral activity against HSV-1. It is intriguing that these chemokines are mostly known to be highly expressed by effector CD8{sup +} T cells. The chemokines with a significant anti-HSV-1 activity commonly bound to HSV-1 virions via envelope glycoprotein gB. Electron microscopy revealed that the chemokines with a significant anti-HSV-1 activity were commonly capable of generating pores in the envelope of HSV-1. Thus, some chemokines have a significant direct antiviral activity against HSV-1 in vitro and may have a potential role in host defense against HSV-1 as a direct antiviral agent.

  14. Teleost Chemokines and Their Receptors

    PubMed Central

    Bird, Steve; Tafalla, Carolina

    2015-01-01

    Chemokines are a superfamily of cytokines that appeared about 650 million years ago, at the emergence of vertebrates, and are responsible for regulating cell migration under both inflammatory and physiological conditions. The first teleost chemokine gene was reported in rainbow trout in 1998. Since then, numerous chemokine genes have been identified in diverse fish species evidencing the great differences that exist among fish and mammalian chemokines, and within the different fish species, as a consequence of extensive intrachromosomal gene duplications and different infectious experiences. Subsequently, it has only been possible to establish clear homologies with mammalian chemokines in the case of some chemokines with well-conserved homeostatic roles, whereas the functionality of other chemokine genes will have to be independently addressed in each species. Despite this, functional studies have only been undertaken for a few of these chemokine genes. In this review, we describe the current state of knowledge of chemokine biology in teleost fish. We have mainly focused on those species for which more research efforts have been made in this subject, specifically zebrafish (Danio rerio), rainbow trout (Oncorhynchus mykiss) and catfish (Ictalurus punctatus), outlining which genes have been identified thus far, highlighting the most important aspects of their expression regulation and addressing any known aspects of their biological role in immunity. Finally, we summarise what is known about the chemokine receptors in teleosts and provide some analysis using recently available data to help characterise them more clearly. PMID:26569324

  15. Chemokines in cancer related inflammation

    SciTech Connect

    Allavena, Paola; Germano, Giovanni; Marchesi, Federica; Mantovani, Alberto

    2011-03-10

    Chemokines are key players of the cancer-related inflammation. Chemokine ligands and receptors are downstream of genetic events that cause neoplastic transformation and are abundantly expressed in chronic inflammatory conditions which predispose to cancer. Components of the chemokine system affect multiple pathways of tumor progression including: leukocyte recruitment, neo-angiogenesis, tumor cell proliferation and survival, invasion and metastasis. Evidence in pre-clinical and clinical settings suggests that the chemokine system represents a valuable target for the development of innovative therapeutic strategies.

  16. Association between preeclampsia and the CXC chemokine family (Review)

    PubMed Central

    LIU, XIJING; DAI, LI; ZHOU, RONG

    2015-01-01

    Preeclampsia is a major cause of maternal and perinatal mortality and morbidity, characterized by gestational hypertension, proteinuria, systemic endothelial cell activation and an exaggerated inflammatory response. The precise cause of preeclampsia is not currently known; however, it is widely accepted that the pathogenesis of preeclampsia involves inadequate trophoblast invasion, leading to generalized endothelial dysfunction and an exaggerated inflammatory response. Chemokines are a superfamily of structurally similar proteins that mediate cell recruitment, angiogenesis, immunity and stem cell trafficking. CXC chemokines are a family of cytokines, unique in their ability to behave in a disparate manner in the regulation of angiogenesis. The CXC chemokine family further divides into two subfamilies; CXC ELR+, which promotes angiogenesis, and CXC ELR-, which inhibits angiogenesis. Furthermore, CXC chemokines are involved in the pathogenesis of various conditions, including malignant tumors, wound repair, chronic inflammation, atherosclerosis and potentially preeclampsia. PMID:26136860

  17. NF-κB Repressing Factor Inhibits Chemokine Synthesis by Peripheral Blood Mononuclear Cells and Alveolar Macrophages in Active Pulmonary Tuberculosis

    PubMed Central

    Huang, Kuo-Hsiung; Wang, Chun-Hua; Lee, Kang-Yun; Lin, Shu-Min

    2013-01-01

    NF-κB repressing factor (NRF) is a transcriptional silencer implicated in the basal silencing of specific NF-κB targeting genes, including iNOS, IFN-β and IL-8/CXCL8. IP-10/CXCL10 and IL-8/CXCL8 are involved in neutrophil and lymphocyte recruitment against M. tuberculosis (MTb) and disease progression of pulmonary tuberculosis (TB). Alveolar macrophages (AM) and peripheral blood mononuclear cells (PBMC) were used to study the regulatory role of NRF in pulmonary TB. AM and PBMC were purified from 19 TB patients and 15 normal subjects. To study the underlying mechanism, PBMC were exposed to heated TB bacilli. The regulation role of NRF in IP-10/CXCL10 and IL-8/CXCL8 was determined by NRF knock-down or over-expression. NRF binding capabilities in promoter sites were measured by chromatin immunoprecipitation (ChIP) assay. The levels of IP-10/CXCL10, IL-8/CXCL8 and NRF were significantly higher in AM and PBMC in patients with active TB. NRF played an inhibitory role in IP-10/CXCL10 and IL-8/CXCL8 inductions. We delineate the role of NRF in pulmonary TB, which inhibits the expressions of IP-10/CXCL10 and IL-8/CXCL8 in AM and PBMC of patients with high bacterial load. NRF may serve as an endogenous repressor to prevent robust increase in IP-10/CXCL10 and IL-8/CXCL8 when TB bacterial load is high. PMID:24223729

  18. The Chemokine Platelet Factor-4 Variant (PF-4var)/CXCL4L1 Inhibits Diabetes-Induced Blood–Retinal Barrier Breakdown

    PubMed Central

    Abu El-Asrar, Ahmed M.; Mohammad, Ghulam; Nawaz, Mohd Imtiaz; Abdelsaid, Mohammed; Siddiquei, Mohammad Mairaj; Alam, Kaiser; Van den Eynde, Kathleen; De Hertogh, Gert; Opdenakker, Ghislain; Al-Shabrawey, Mohamed; Van Damme, Jo; Struyf, Sofie

    2015-01-01

    Purpose. To investigate the expression of platelet factor-4 variant (PF-4var/CXCL4L1) in epiretinal membranes from patients with proliferative diabetic retinopathy (PDR) and the role of PF-4var/CXCL4L1 in the regulation of blood–retinal barrier (BRB) breakdown in diabetic rat retinas and human retinal microvascular endothelial cells (HRMEC). Methods. Rats were treated intravitreally with PF-4var/CXCL4L1 or the anti-vascular endothelial growth factor (VEGF) agent bevacizumab on the first day after diabetes induction. Blood–retinal barrier breakdown was assessed in vivo with fluorescein isothiocyanate (FITC)-conjugated dextran and in vitro in HRMEC by transendothelial electrical resistance and FITC-conjugated dextran cell permeability assay. Occludin, vascular endothelial (VE)-cadherin, hypoxia-inducible factor (HIF)-1α, VEGF, tumor necrosis factor (TNF)-α, receptor for advanced glycation end products (RAGE), caspase-3 levels, and generation of reactive oxygen species (ROS) were assessed by Western blot, enzyme-linked immunosorbent assays, or spectrophotometry. Results. In epiretinal membranes, vascular endothelial cells and stromal cells expressed PF-4var/CXCL4L1. In vitro, HRMEC produced PF-4var/CXCL4L1 after stimulation with a combination of interleukin (IL)-1β and TNF-α, and PF-4var/CXCL4L1 inhibited VEGF-mediated hyperpermeability in HRMEC. In rats, PF-4var/CXCL4L1 was as potent as bevacizumab in attenuating diabetes-induced BRB breakdown. This effect was associated with upregulation of occludin and VE-cadherin and downregulation of HIF-1α, VEGF, TNF-α, RAGE, and caspase-3, whereas ROS generation was not altered. Conclusions. Our findings suggest that increasing the intraocular PF-4var/CXCL4L1 levels early after the onset of diabetes protects against diabetes-induced BRB breakdown. PMID:25711636

  19. A beginner's guide to chemokines.

    PubMed

    Vinader, Victoria; Afarinkia, Kamyar

    2012-05-01

    This review provides an overview of chemokines and their receptors, with an emphasis on general features and nomenclature along with a short summary of their properties and functions. It is intended as an introduction to the subject and a reference point for those wishing to learn key facts about chemokines and their role in biology. PMID:22571610

  20. Chemokines and diabetic wound healing.

    PubMed

    Ochoa, Oscar; Torres, Francis M; Shireman, Paula K

    2007-01-01

    Chemokines are critical for white blood cell recruitment to injured tissues and play an important role in normal wound healing processes. In contrast, impaired wound healing in diabetic patients is accompanied by decreased early inflammatory cell infiltration but persistence of neutrophils and macrophages in the chronic, nonhealing wounds. These changes in inflammatory cell recruitment occur in conjunction with alterations in chemokine and growth factor expression. In addition to leukocyte trafficking, many different cell types, including endothelial cells, fibroblasts, and keratinocytes, produce and respond to chemokines, and these interactions are altered in diabetic wounds. Thus, the chemokine system may have both direct and inflammatory-mediated effects on many different aspects of diabetic wound healing. The potential roles of chemokines and inflammatory or immune cells in nonhealing diabetic wounds, including impairments in growth factor expression, angiogenesis, extracellular matrix formation, and reepithelialization, are examined. PMID:18053419

  1. [Interceptors:--"silent" chemokine receptors].

    PubMed

    Grodecka, Magdalena; Waśniowska, Kazimiera

    2007-01-01

    The physiological effect caused by chemokines is regulated by interactions with a group of rodopsin-like G protein-coupled receptors (GPCRs). These receptors share a number of common features: the polypeptide chain is a 7-transmembrane ?-helix (7 TMD motif) and the region involved in G-protein interaction (the DRYLAIV sequence) is located in the second transmembrane loop. So far, 19 chemokine receptors have been identified. Three of them (Duffy glycoprotein, D6, and CCX-CKR proteins), although structurally related to other GPCRs, lack the ability of G-protein signal transduction. Instead, they efficiently internalize their cognate ligands, regulating chemokine levels in various body compartments. These three proteins are suggested to form a distinct chemokine receptor family, designated "interceptors" or "silent" chemokine receptors. PMID:17507871

  2. Chemokines and angiogenesis in rheumatoid arthritis

    PubMed Central

    Szekanecz, Zoltan; Pakozdi, Angela; Szentpetery, Agnes; Besenyei, Timea; Koch, Alisa E.

    2010-01-01

    In rheumatoid arthritis, chemokines mediate the migration of inflammatory leukocytes into the synovium. Among the four known chemokine families, CXC, CC chemokines and fractalkine seem to be of outstanding importance in this process. Angiogenesis, the formation of new vessels, is also important during the perpetuation of inflammation underlying rheumatoid arthritis. In this review, authors discuss the role of the most important chemokines and chemokine repetors in arthritis-associated neovascularization. The process and regulation of angiogenesis are described in this context as well. Apart from discussing the pathogenic role of chemokines and chemokine receptors in arthritic vessel formation, authors also review the important relevance of chemokines and angiogenesis for therapeutic intervention. PMID:19482623

  3. Targeting chemokine pathways in esophageal adenocarcinoma

    PubMed Central

    Shrivastava, Makardhwaj S; Hussain, Zulfiqar; Giricz, Orsolya; Shenoy, Niraj; Polineni, Rahul; Maitra, Anirban; Verma, Amit

    2014-01-01

    Esophageal adenocarcinoma (EAC) is one of the fastest growing malignancies in the US and needs newer therapeutic and diagnostic strategies. Chronic inflammation plays a role in the pathogenesis of EAC and contributes to the dysplastic conversion of normal esophageal epithelium to Barrett's esophagus and frank adenocarcinoma. Chemokines play important roles in mediating inflammation and recent evidence implicates these ligands and their receptors in the development and spread of various tumors. We demonstrated that the chemokines IL8, CXCL1 and CXCL3 are significantly overexpressed during esophageal carcinogenesis and accompanied by amplification and demethylation of the chr4q21 gene locus. We also demonstrated that IL8 levels can be detected in serum of patients with EAC and can serve as potential biomarkers. We now demonstrate that inhibition of IL8 receptor, CXCR2, leads to decreased invasiveness of esophageal adenocarcinoma derived cells without affecting cellular proliferation. Taken together, these studies reveal the important roles that chemokines play in development of esophageal cancer and demonstrate that these pathways can serve as potential therapeutic targets. PMID:25485576

  4. Chemokines as Cancer Vaccine Adjuvants

    PubMed Central

    Bobanga, Iuliana D.; Petrosiute, Agne; Huang, Alex Y.

    2013-01-01

    We are witnessing a new era of immune-mediated cancer therapies and vaccine development. As the field of cancer vaccines advances into clinical trials, overcoming low immunogenicity is a limiting step in achieving full success of this therapeutic approach. Recent discoveries in the many biological roles of chemokines in tumor immunology allow their exploitation in enhancing recruitment of antigen presenting cells (APCs) and effector cells to appropriate anatomical sites. This knowledge, combined with advances in gene therapy and virology, allows researchers to employ chemokines as potential vaccine adjuvants. This review will focus on recent murine and human studies that use chemokines as therapeutic anti-cancer vaccine adjuvants. PMID:24967094

  5. Discovery of indole inhibitors of chemokine receptor 9 (CCR9).

    PubMed

    Pandya, Bhaumik A; Baber, Christian; Chan, Audrey; Chamberlain, Brian; Chandonnet, Haoqun; Goss, Jennifer; Hopper, Timothy; Lippa, Blaise; Poutsiaka, Katherine; Romero, Jan; Stucka, Sabrina; Varoglu, Mustafa; Zhang, Jing; Zhang, Xin

    2016-07-15

    Irritable bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC) are serious chronic diseases affecting millions of patients worldwide. Studies of human chemokine biology has suggested C-C chemokine receptor 9 (CCR9) may be a key mediator of pro-inflammatory signaling. Discovery of agents that inhibit CCR9 may lead to new therapies for CD and UC patients. Herein we describe the evolution of a high content screening hit (1) into potent inhibitors of CCR9, such as azaindole 12. PMID:27256913

  6. Identification and profiling of CXCR3–CXCR4 chemokine receptor heteromer complexes

    PubMed Central

    Watts, AO; van Lipzig, MMH; Jaeger, WC; Seeber, RM; van Zwam, M; Vinet, J; van der Lee, MMC; Siderius, M; Zaman, GJR; Boddeke, HWGM; Smit, MJ; Pfleger, KDG; Leurs, R; Vischer, HF

    2013-01-01

    Background and Purpose The C-X-C chemokine receptors 3 (CXCR3) and C-X-C chemokine receptors 4 (CXCR4) are involved in various autoimmune diseases and cancers. Small antagonists have previously been shown to cross-inhibit chemokine binding to CXCR4, CC chemokine receptors 2 (CCR2) and 5 (CCR5) heteromers. We investigated whether CXCR3 and CXCR4 can form heteromeric complexes and the binding characteristics of chemokines and small ligand compounds to these chemokine receptor heteromers. Experimental Approach CXCR3–CXCR4 heteromers were identified in HEK293T cells using co-immunoprecipitation, time-resolved fluorescence resonance energy transfer, saturation BRET and the GPCR-heteromer identification technology (HIT) approach. Equilibrium competition binding and dissociation experiments were performed to detect negative binding cooperativity. Key Results We provide evidence that chemokine receptors CXCR3 and CXCR4 form heteromeric complexes in HEK293T cells. Chemokine binding was mutually exclusive on membranes co-expressing CXCR3 and CXCR4 as revealed by equilibrium competition binding and dissociation experiments. The small CXCR3 agonist VUF10661 impaired binding of CXCL12 to CXCR4, whereas small antagonists were unable to cross-inhibit chemokine binding to the other chemokine receptor. In contrast, negative binding cooperativity between CXCR3 and CXCR4 chemokines was not observed in intact cells. However, using the GPCR-HIT approach, we have evidence for specific β-arrestin2 recruitment to CXCR3-CXCR4 heteromers in response to agonist stimulation. Conclusions and Implications This study indicates that heteromeric CXCR3–CXCR4 complexes may act as functional units in living cells, which potentially open up novel therapeutic opportunities. PMID:23170857

  7. The chemokine system: novel broad-spectrum therapeutic targets.

    PubMed

    Power, C A; Proudfoot, A E

    2001-08-01

    Chemokines are cytokines that specifically direct the trafficking of immune cells in the body. They offer a novel point of therapeutic intervention, as inhibiting specific chemokines and receptors could prevent the excessive recruitment of leukocytes to sites of inflammation. This approach could be considered to act upstream of the therapies used today which, for the most part, act on the cells already at the site of inflammation. The receptors for chemokines are G-protein-coupled seven-transmembrane receptors, which are particularly tractable for the pharmaceutical industry. The search for small-molecule inhibitors of these receptors has been fruitful and the numbers of patents and, more recently, peer-reviewed publications are growing rapidly. The first clinical trial was initiated this year, so although it is too soon to be able to report these results we hope to see the outcome of this research in the near future. PMID:11710742

  8. Rodent herpesvirus Peru encodes a secreted chemokine decoy receptor.

    PubMed

    Lubman, Olga Y; Cella, Marina; Wang, Xinxin; Monte, Kristen; Lenschow, Deborah J; Huang, Yina H; Fremont, Daved H

    2014-01-01

    Viruses have long been studied not only for their pathology and associated disease but also as model systems for understanding cellular and immunological processes. Rodent herpesvirus Peru (RHVP) is a recently characterized rhadinovirus related to murine gammaherpesvirus 68 (MHV68) and Kaposi's sarcoma-associated herpesvirus (KSHV) that establishes acute and latent infection in laboratory mice. RHVP encodes numerous unique proteins that we hypothesize might facilitate host immune evasion during infection. We report here that open reading frame (ORF) R17 encodes a high-affinity chemokine binding protein that broadly recognizes human and murine CC and C chemokines. The interaction of R17 with chemokines is generally characterized by rapid association kinetics, and in the case of CCL3, CCL4, CCL5, CCL24, and XCL1, extremely stable complexes are formed. Functionally, R17 potently inhibited CCL2-driven chemotaxis of the human monocytic cell line THP-1, CCL3-driven chemotaxis of peripheral blood mononuclear cells, and CCL2-mediated calcium flux. Our studies also reveal that R17 binds to glycosaminoglycans (GAGs) in a process dependent upon two BBXB motifs and that chemokine and GAG binding can occur simultaneously at distinct sites. Collectively, these studies suggest that R17 may play a role in RHVP immune evasion through the targeted sabotage of chemokine-mediated immune surveillance. PMID:24173234

  9. Chemokines and Chemokine Receptors in Lymphoid Tissue Dynamics.

    PubMed

    Schulz, Olga; Hammerschmidt, Swantje I; Moschovakis, G Leandros; Förster, Reinhold

    2016-05-20

    The continuous migration of immune cells between lymphoid and nonlymphoid organs is a key feature of the immune system, facilitating the distribution of effector cells within nearly all compartments of the body. Furthermore, reaching their correct position within primary, secondary, or tertiary lymphoid organs is a prerequisite to ensure immune cells' unimpaired differentiation, maturation, and selection, as well as their activation or functional silencing. The superfamilies of chemokines and chemokine receptors are of major importance in guiding immune cells to and within lymphoid and nonlymphoid tissues. In this review we focus on the role of the chemokine system in the migration dynamics of immune cells within lymphoid organs at the steady state and on how these dynamics are affected by infectious and inflammatory processes. PMID:26907216

  10. Chemokine receptor internalization and intracellular trafficking.

    PubMed

    Neel, Nicole F; Schutyser, Evemie; Sai, Jiqing; Fan, Guo-Huang; Richmond, Ann

    2005-12-01

    The internalization and intracellular trafficking of chemokine receptors have important implications for the cellular responses elicited by chemokine receptors. The major pathway by which chemokine receptors internalize is the clathrin-mediated pathway, but some receptors may utilize lipid rafts/caveolae-dependent internalization routes. This review discusses the current knowledge and controversies regarding these two different routes of endocytosis. The functional consequences of internalization and the regulation of chemokine receptor recycling will also be addressed. Modifications of chemokine receptors, such as palmitoylation, ubiquitination, glycosylation, and sulfation, may also impact trafficking, chemotaxis and signaling. Finally, this review will cover the internalization and trafficking of viral and decoy chemokine receptors. PMID:15998596

  11. Semi-synthesis of chemokines.

    PubMed

    Beck-Sickinger, Annette G; Panitz, Nydia

    2014-10-01

    Protein ligation allows the introduction of a wide range of modifications into proteins that are not accessible by mutagenesis. This includes non-proteinogenic amino acids and even backbone modification. This review summarizes recent reports on modified chemokine variants by ligation technologies and includes the development of the first protein with a full secondary structure motif exchanged by a helix that exclusively consists of β-amino acids. Furthermore the first protein activatable by light by rearrangement of a depsi-peptide bond is described. Combining different ligation methods, immobilization and specific release of chemokines were achieved, which is of major importance for the gradient forming activity of chemokines. Examples are shown for CXCL8 (interleukin 8, IL-8) and CXCL12 (stromal derived factor 1, SDF 1) including their chemical and structural characterization as well as the most frequently used assays. PMID:25299571

  12. Structure and Function of A41, a Vaccinia Virus Chemokine Binding Protein

    PubMed Central

    Abrescia, Nicola G. A; Pease, James E; Wise, Emma L; Stuart, David I; Smith, Geoffrey L; Grimes, Jonathan M

    2008-01-01

    The vaccinia virus (VACV) A41L gene encodes a secreted 30 kDa glycoprotein that is nonessential for virus replication but affects the host response to infection. The A41 protein shares sequence similarity with another VACV protein that binds CC chemokines (called vCKBP, or viral CC chemokine inhibitor, vCCI), and strains of VACV lacking the A41L gene induced stronger CD8+ T-cell responses than control viruses expressing A41. Using surface plasmon resonance, we screened 39 human and murine chemokines and identified CCL21, CCL25, CCL26 and CCL28 as A41 ligands, with Kds of between 8 nM and 118 nM. Nonetheless, A41 was ineffective at inhibiting chemotaxis induced by these chemokines, indicating it did not block the interaction of these chemokines with their receptors. However the interaction of A41 and chemokines was inhibited in a dose-dependent manner by heparin, suggesting that A41 and heparin bind to overlapping sites on these chemokines. To better understand the mechanism of action of A41 its crystal structure was solved to 1.9 Å resolution. The protein has a globular β sandwich structure similar to that of the poxvirus vCCI family of proteins, but there are notable structural differences, particularly in surface loops and electrostatic charge distribution. Structural modelling suggests that the binding paradigm as defined for the vCCI–chemokine interaction is likely to be conserved between A41 and its chemokine partners. Additionally, sequence analysis of chemokines binding to A41 identified a signature for A41 binding. The biological and structural data suggest that A41 functions by forming moderately strong (nM) interactions with certain chemokines, sufficient to interfere with chemokine-glycosaminoglycan interactions at the cell surface (μM–nM) and thereby to destroy the chemokine concentration gradient, but not strong enough to disrupt the (pM) chemokine–chemokine receptor interactions. PMID:18208323

  13. Suppression of T-Cell Chemokines by Porphyromonas gingivalis

    PubMed Central

    Jauregui, Catherine E.; Wang, Qian; Wright, Christopher J.; Takeuchi, Hiroki; Uriarte, Silvia M.

    2013-01-01

    Porphyromonas gingivalis is a major pathogen in periodontal disease and is associated with immune dysbiosis. In this study, we found that P. gingivalis did not induce the expression of the T-cell chemokine IP-10 (CXCL10) from neutrophils, peripheral blood mononuclear cells (PBMCs), or gingival epithelial cells. Furthermore, P. gingivalis suppressed gamma interferon (IFN-γ)-stimulated release of IP-10, ITAC (CXCL11), and Mig (CXCL9) from epithelial cells and inhibited IP-10 secretion in a mixed infection with the otherwise stimulatory Fusobacterium nucleatum. Inhibition of chemokine expression occurred at the level of gene transcription and was associated with downregulation of interferon regulatory factor 1 (IRF-1) and decreased levels of Stat1. Ectopic expression of IRF-1 in epithelial cells relieved P. gingivalis-induced inhibition of IP-10 release. Direct contact between P. gingivalis and epithelial cells was not required for IP-10 inhibition. These results highlight the immune-disruptive potential of P. gingivalis. Suppression of IP-10 and other Th1-biasing chemokines by P. gingivalis may perturb the balance of protective and destructive immunity in the periodontal tissues and facilitate the pathogenicity of oral microbial communities. PMID:23589576

  14. Chemokines in tumor progression and metastasis.

    PubMed

    Sarvaiya, Purvaba J; Guo, Donna; Ulasov, Ilya; Gabikian, Patrik; Lesniak, Maciej S

    2013-12-01

    Chemokines play a vital role in tumor progression and metastasis. Chemokines are involved in the growth of many cancers including breast cancer, ovarian cancer, pancreatic cancer, melanoma, lung cancer, gastric cancer, acute lymphoblastic leukemia, colon cancer, non-small lung cancer, non-hodgkin's lymphoma, etc. The expression of chemokines and their receptors is altered in many malignancies and leads to aberrant chemokine receptor signaling. This review focuses on the role of chemokines in key processes that facilitate tumor progression including proliferation, senescence, angiogenesis, epithelial mesenchymal transition, immune evasion and metastasis. PMID:24259307

  15. Chemokines in tumor development and progression

    SciTech Connect

    Mukaida, Naofumi; Baba, Tomohisa

    2012-01-15

    Chemokines were originally identified as mediators of the inflammatory process and regulators of leukocyte trafficking. Subsequent studies revealed their essential roles in leukocyte physiology and pathology. Moreover, chemokines have profound effects on other types of cells associated with the inflammatory response, such as endothelial cells and fibroblasts. Thus, chemokines are crucial for cancer-related inflammation, which can promote tumor development and progression. Increasing evidence points to the vital effects of several chemokines on the proliferative and invasive properties of tumor cells. The wide range of activities of chemokines in tumorigenesis highlights their roles in tumor development and progression.

  16. Chemokines in tumor progression and metastasis

    PubMed Central

    Sarvaiya, Purvaba J.; Guo, Donna; Ulasov, Ilya; Gabikian, Patrik; Lesniak, Maciej S.

    2013-01-01

    Chemokines play a vital role in tumor progression and metastasis. Chemokines are involved in the growth of many cancers including breast cancer, ovarian cancer, pancreatic cancer, melanoma, lung cancer, gastric cancer, acute lymphoblastic leukemia, colon cancer, non-small lung cancer and non-hodgkin's lymphoma among many others. The expression of chemokines and their receptors is altered in many malignancies and leads to aberrant chemokine receptor signaling. This review focuses on the role of chemokines in key processes that facilitate tumor progression including proliferation, senescence, angiogenesis, epithelial mesenchymal transition, immune evasion and metastasis. PMID:24259307

  17. Chemokine receptor CXCR3 agonist prevents human T-cell migration in a humanized model of arthritic inflammation.

    PubMed

    O'Boyle, Graeme; Fox, Christopher R J; Walden, Hannah R; Willet, Joseph D P; Mavin, Emily R; Hine, Dominic W; Palmer, Jeremy M; Barker, Catriona E; Lamb, Christopher A; Ali, Simi; Kirby, John A

    2012-03-20

    The recruitment of T lymphocytes during diseases such as rheumatoid arthritis is regulated by stimulation of the chemokine receptors expressed by these cells. This study was designed to assess the potential of a CXCR3-specific small-molecule agonist to inhibit the migration of activated human T cells toward multiple chemokines. Further experiments defined the molecular mechanism for this anti-inflammatory activity. Analysis in vitro demonstrated agonist induced internalization of both CXCR3 and other chemokine receptors coexpressed by CXCR3(+) T cells. Unlike chemokine receptor-specific antagonists, the CXCR3 agonist inhibited migration of activated T cells toward the chemokine mixture in synovial fluid from patients with active rheumatoid arthritis. A humanized mouse air-pouch model showed that intravenous treatment with the CXCR3 agonist prevented inflammatory migration of activated human T cells toward this synovial fluid. A potential mechanism for this action was defined by demonstration that the CXCR3 agonist induces receptor cross-phosphorylation within CXCR3-CCR5 heterodimers on the surface of activated T cells. This study shows that generalized chemokine receptor desensitization can be induced by specific stimulation of a single chemokine receptor on the surface of activated human T cells. A humanized mouse model was used to demonstrate that this receptor desensitization inhibits the inflammatory response that is normally produced by the chemokines present in synovial fluid from patients with active rheumatoid arthritis. PMID:22392992

  18. Enhancement of Chemokine Function as an Immunomodulatory Strategy Employed by Human Herpesviruses

    PubMed Central

    Viejo-Borbolla, Abel; Martinez-Martín, Nadia; Nel, Hendrik J.; Rueda, Patricia; Martín, Rocío; Blanco, Soledad; Arenzana-Seisdedos, Fernando; Thelen, Marcus; Fallon, Padraic G.; Alcamí, Antonio

    2012-01-01

    Herpes simplex virus (HSV) types 1 and 2 are highly prevalent human neurotropic pathogens that cause a variety of diseases, including lethal encephalitis. The relationship between HSV and the host immune system is one of the main determinants of the infection outcome. Chemokines play relevant roles in antiviral response and immunopathology, but the modulation of chemokine function by HSV is not well understood. We have addressed the modulation of chemokine function mediated by HSV. By using surface plasmon resonance and crosslinking assays we show that secreted glycoprotein G (SgG) from both HSV-1 and HSV-2 binds chemokines with high affinity. Chemokine binding activity was also observed in the supernatant of HSV-2 infected cells and in the plasma membrane of cells infected with HSV-1 wild type but not with a gG deficient HSV-1 mutant. Cell-binding and competition experiments indicate that the interaction takes place through the glycosaminoglycan-binding domain of the chemokine. The functional relevance of the interaction was determined both in vitro, by performing transwell assays, time-lapse microscopy, and signal transduction experiments; and in vivo, using the air pouch model of inflammation. Interestingly, and in contrast to what has been observed for previously described viral chemokine binding proteins, HSV SgGs do not inhibit chemokine function. On the contrary, HSV SgGs enhance chemotaxis both in vitro and in vivo through increasing directionality, potency and receptor signaling. This is the first report, to our knowledge, of a viral chemokine binding protein from a human pathogen that increases chemokine function and points towards a previously undescribed strategy of immune modulation mediated by viruses. PMID:22319442

  19. Chemokine gene variants in schizophrenia.

    PubMed

    Dasdemir, Selcuk; Kucukali, Cem Ismail; Bireller, Elif Sinem; Tuzun, Erdem; Cakmakoglu, Bedia

    2016-08-01

    Background Chemokines are known to play a major role in driving inflammation and immune responses in several neuroinflammatory diseases, including multiple sclerosis, Alzheimer's disease and Parkinson's disease. Inflammation has also been implicated in the pathogenesis of schizophrenia. Aim We aimed to investigate a potential link between chemokines and schizophrenia and analyze the role of MCP-1-A2518G, SDF-1-3'A, CCR5-delta32, CCR5-A55029G, CXCR4-C138T and CCR2-V64I gene polymorphisms in the Turkish population. Methods Genotyping was conducted by PCR-RFLP based on 140 patients and 123 unrelated healthy controls to show the relation between chemokine gene variants and schizophrenia risk. Results Frequencies of CCR5-A55029G A genotypes and CCR5-A55029G AG genotypes were found higher in patients than the controls and even also CCR2-V64I WT: CCR5-A55029G A and CCR2-V64I 64I: CCR5-A55029G A haplotypes significantly associated according to Bonferroni correction. However, no significant association was found for any of the other polymorphisms with the risk of schizophrenia. Conclusions Our findings suggest that CCR5-A55029G polymorphisms and CCR2-V64I WT: CCR5-A55029G A and CCR2-V64I 64I: CCR5-A55029G A haplotypes might have association with schizophrenia pathogenesis. PMID:26906930

  20. Chemokines and the pathophysiology of neuropathic pain

    PubMed Central

    White, Fletcher A.; Jung, Hosung; Miller, Richard J.

    2007-01-01

    Chemokines and chemokine receptors are widely expressed by cells of the immune and nervous systems. This review focuses on our current knowledge concerning the role of chemokines in the pathophysiology of chronic pain syndromes. Injury- or disease-induced changes in the expression of diverse chemokines and their receptors have been demonstrated in the neural and nonneural elements of pain pathways. Under these circumstances, chemokines have been shown to modulate the electrical activity of neurons by multiple regulatory pathways including increases in neurotransmitter release through Ca-dependent mechanisms and transactivation of transient receptor channels. Either of these mechanisms alone, or in combination, may contribute to sustained excitability of primary afferent and secondary neurons within spinal pain pathways. Another manner in which chemokines may influence sustained neuronal excitability may be their ability to function as excitatory neurotransmitters within the peripheral and central nervous system. As is the case for traditional neurotransmitters, injury-induced up-regulated chemokines are found within synaptic vesicles. Chemokines released after depolarization of the cell membrane can then act on other chemokine receptor-bearing neurons, glia, or immune cells. Because up-regulation of chemokines and their receptors may be one of the mechanisms that directly or indirectly contribute to the development and maintenance of chronic pain, these molecules may then represent novel targets for therapeutic intervention in chronic pain states. PMID:18083844

  1. A Subset of Patients with Acute Myeloid Leukemia Has Leukemia Cells Characterized by Chemokine Responsiveness and Altered Expression of Transcriptional as well as Angiogenic Regulators

    PubMed Central

    Brenner, Annette K.; Reikvam, Håkon; Bruserud, Øystein

    2016-01-01

    Acute myeloid leukemia (AML) is an aggressive and heterogeneous bone marrow malignancy, the only curative treatment being intensive chemotherapy eventually in combination with allogeneic stem cell transplantation. Both the AML and their neighboring stromal cells show constitutive chemokine release, but chemokines seem to function as regulators of AML cell proliferation only for a subset of patients. Chemokine targeting is therefore considered not only for immunosuppression in allotransplanted patients but also as a possible antileukemic strategy in combination with intensive chemotherapy or as part of disease-stabilizing treatment at least for the subset of patients with chemokine-responsive AML cells. In this study, we characterized more in detail the leukemia cell phenotype of the chemokine-responsive patients. We investigated primary AML cells derived from 79 unselected patients. Standardized in vitro suspension cultures were used to investigate AML cell proliferation, and global gene expression profiles were compared for chemokine responders and non-responders identified through the proliferation assays. CCL28-induced growth modulation was used as marker of chemokine responsiveness, and 38 patients were then classified as chemokine-responsive. The effects of exogenous CCL28 (growth inhibition/enhancement/no effect) thus differed among patients and was also dependent on the presence of exogenous hematopoietic growth factors as well as constitutive AML cell cytokine release. The effect of CCR1 inhibition in the presence of chemokine-secreting mesenchymal stem cells also differed among patients. Chemokine-responsive AML cells showed altered expression of genes important for (i) epigenetic transcriptional regulation, particularly lysine acetylation; (ii) helicase activity, especially DExD/H RNA helicases; and (iii) angioregulatory proteins important for integrin binding. Thus, chemokine responsiveness is part of a complex AML cell phenotype with regard to

  2. Local Chemokine Paralysis, a Novel Pathogenic Mechanism for Porphyromonas gingivalis

    PubMed Central

    Darveau, Richard P.; Belton, Carol M.; Reife, Robert A.; Lamont, Richard J.

    1998-01-01

    Periodontitis, which is widespread in the adult population, is a persistent bacterial infection associated with Porphyromonas gingivalis. Gingival epithelial cells are among the first cells encountered by both P. gingivalis and commensal oral bacteria. The chemokine interleukin 8 (IL-8), a potent chemoattractant and activator of polymorphonuclear leukocytes, was secreted by gingival epithelial cells in response to components of the normal oral flora. In contrast, P. gingivalis was found to strongly inhibit IL-8 accumulation from gingival epithelial cells. Inhibition was associated with a decrease in mRNA for IL-8. Antagonism of IL-8 accumulation did not occur in KB cells, an epithelial cell line that does not support high levels of intracellular invasion by P. gingivalis. Furthermore, a noninvasive mutant of P. gingivalis was unable to antagonize IL-8 accumulation. Invasion-dependent destruction of the gingival IL-8 chemokine gradient at sites of P. gingivalis colonization (local chemokine paralysis) will severely impair mucosal defense and represents a novel mechanism for bacterial colonization of host tissue. PMID:9529095

  3. ROLE OF CHEMOKINES IN TUMOR GROWTH

    PubMed Central

    Raman, Dayanidhi; Baugher, Paige J.; Thu, Yee Mon; Richmond, Ann

    2007-01-01

    Chemokines play a paramount role in the tumor progression. Chronic inflammation promotes tumor formation. Both tumor cells and stromal cells elaborate chemokines and cytokines. These act either by autocrine or paracrine mechanisms to sustain tumor cell growth, induce angiogenesis and facilitate evasion of immune surveillance through immunoediting. The chemokine receptor CXCR2 and its ligands promote tumor angiogenesis and leukocyte infiltration into the tumor microenvironment. In harsh acidic and hypoxic microenvironmental conditions tumor cells up-regulate their expression of CXCR4, which equips them to migrate up a gradient of CXCL12 elaborated by carcinoma associated fibroblasts (CAFs) to a normoxic microenvironment. The CXCL12-CXCR4 axis facilitates metastasis to distant organs and the CCL21-CCR7 chemokine ligand-receptor pair favors metastasis to lymph nodes. These two chemokine ligand-receptor systems are common key mediators of tumor cell metastasis for several malignancies and as such provide key targets for chemotherapy. In this paper, the role of specific chemokines/chemokine receptor interactions in tumor progression, growth and metastasis and the role of chemokine/chemokine receptor interactions in the stromal compartment as related to angiogenesis, metastasis, and immune response to the tumor are reviewed. PMID:17629396

  4. Increased expression of chemokines in patients with Wegener's granulomatosis – modulating effects of methylprednisolone in vitro

    PubMed Central

    Torheim, E A; Yndestad, A; Bjerkeli, V; Halvorsen, B; Aukrust, P; Frøland, S S

    2005-01-01

    Chemokines, a group of cytokines that attracts and activates leucocyte subpopulations in inflamed tissue, have been associated with the pathogenesis of a number of inflammatory diseases, and some recent reports have suggested their involvement in Wegener's granulomatosis (WG). To elucidate further the possible role of chemokines in WG we examined serum levels of several CC- and CXC-chemokines in WG patients and assessed the ability of corticosteroids to modulate the expression of these mediators in vitro. Our main findings were: (i) WG patients (n = 14) had elevated serum levels of several inflammatory chemokines [i.e. regulated upon activation normal T cell expressed and secreted (RANTES), monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-8] compared to healthy controls (n = 9), as assessed by enzyme immunoassays (EIAs); (ii) by using EIAs and real-time reverse transcription-polymerase chain reaction (RT-PCR), we demonstrated the ability of methylprednisolone (MP) to down-regulate both the spontaneous and the staphylococcal enterotoxin B (SEB)-induced release of chemokines from peripheral blood mononuclear cells (PBMC) in vitro in both WG patients and controls, possibly involving both transcriptional and post-transcriptional mechanisms; and (iii) the ability of MP to attenuate chemokine secretion was less pronounced in WG patients than in controls, particularly with regard to inhibition of spontaneous release. Our findings suggest a role for chemokines in the pathogenesis of WG. The diminished MP-mediated suppression of chemokines in PBMC from WG patients suggests that more specific modulators of chemokine levels should be investigated in this disorder. PMID:15807865

  5. CD26/dipeptidylpeptidase IV-chemokine interactions: double-edged regulation of inflammation and tumor biology.

    PubMed

    Mortier, Anneleen; Gouwy, Mieke; Van Damme, Jo; Proost, Paul; Struyf, Sofie

    2016-06-01

    Post-translational modification of chemokines is an essential regulatory mechanism to enhance or dampen the inflammatory response. CD26/dipeptidylpeptidase IV, ubiquitously expressed in tissues and blood, removes NH2-terminal dipeptides from proteins with a penultimate Pro or Ala. A large number of human chemokines, including CXCL2, CXCL6, CXCL9, CXCL10, CXCL11, CXCL12, CCL3L1, CCL4, CCL5, CCL11, CCL14, and CCL22, are cleaved by CD26; however, the efficiency is clearly influenced by the amino acids surrounding the cleavage site and although not yet proven, potentially affected by the chemokine concentration and interactions with third molecules. NH2-terminal cleavage of chemokines by CD26 has prominent effects on their receptor binding, signaling, and hence, in vitro and in vivo biologic activities. However, rather than having a similar result, the outcome of NH2-terminal truncation is highly diverse. Either no difference in activity or drastic alterations in receptor recognition/specificity and hence, chemotactic activity are observed. Analogously, chemokine-dependent inhibition of HIV infection is enhanced (for CCL3L1 and CCL5) or decreased (for CXCL12) by CD26 cleavage. The occurrence of CD26-processed chemokine isoforms in plasma underscores the importance of the in vitro-observed CD26 cleavages. Through modulation of chemokine activity, CD26 regulates leukocyte/tumor cell migration and progenitor cell release from the bone marrow, as shown by use of mice treated with CD26 inhibitors or CD26 knockout mice. As chemokine processing by CD26 has a significant impact on physiologic and pathologic processes, application of CD26 inhibitors to affect chemokine function is currently explored, e.g., as add-on therapy in viral infection and cancer. PMID:26744452

  6. Ozone Exposure of Macrophages Induces an Alveolar Epithelial Chemokine Response through IL-1α

    PubMed Central

    Manzer, Rizwan; Dinarello, Charles A.; McConville, Glen; Mason, Robert J.

    2008-01-01

    Ozone is known to produce an acute influx of neutrophils, and alveolar epithelial cells can secrete chemokines and modulate inflammatory processes. However, direct exposure of alveolar epithelial cells and macrophages to ozone (O3) produces little chemokine response. To determine if cell–cell interactions might be responsible, we investigated the effect of alveolar macrophage–conditioned media after ozone exposure (MO3CM) on alveolar epithelial cell chemokine production. Serum-free media were conditioned by exposing a rat alveolar macrophage cell line NR8383 to ozone for 1 hour. Ozone stimulated secretion of IL-1α, IL-1β, and IL-18 from NR8383 cells, but there was no secretion of chemokines or TNF-α. Freshly isolated type II cells were cultured, so as to express the biological markers of type I cells, and these cells are referred to as type I–like cells. Type I–like cells were exposed to diluted MO3CM for 24 hours, and this conditioned medium stimulated secretion of cytokine-induced neutrophil chemattractant-1 (CXCL1) and monocyte chemoattractant protein-1 (CCL2). Secretion of these chemokines was inhibited by the IL-1 receptor antagonist. Although both recombinant IL-1α and IL-1β stimulated alveolar epithelial cells to secrete chemokines, recombinant IL-1α was 100-fold more potent than IL-1β. Furthermore, neutralizing anti-rat IL-1α antibodies inhibited the secretion of chemokines by alveolar epithelial cells, whereas neutralizing anti-rat IL-1β antibodies had no effect. These observations indicate that secretion of IL-1α from macrophages stimulates alveolar epithelial cells to secrete chemokines that can elicit an inflammatory response. PMID:17901407

  7. Ras regulates alveolar macrophage formation of CXC chemokines and neutrophil activation in streptococcal M1 protein-induced lung injury.

    PubMed

    Zhang, Songen; Hwaiz, Rundk; Rahman, Milladur; Herwald, Heiko; Thorlacius, Henrik

    2014-06-15

    Streptococcal toxic shock syndrome (STSS) is associated with a high mortality rate. The M1 serotype of Streptococcus pyogenes is most frequently associated with STSS. Herein, we examined the role of Ras signaling in M1 protein-induced lung injury. Male C57BL/6 mice received the Ras inhibitor (farnesylthiosalicylic acid, FTS) prior to M1 protein challenge. Bronchoalveolar fluid and lung tissue were harvested for quantification of neutrophil recruitment, edema and CXC chemokine formation. Neutrophil expression of Mac-1 was quantified by use of flow cytometry. Quantitative RT-PCR was used to determine gene expression of CXC chemokines in alveolar macrophages. Administration of FTS reduced M1 protein-induced neutrophil recruitment, edema formation and tissue damage in the lung. M1 protein challenge increased Mac-1 expression on neutrophils and CXC chemokine levels in the lung. Inhibition of Ras activity decreased M1 protein-induced expression of Mac-1 on neutrophils and secretion of CXC chemokines in the lung. Moreover, FTS abolished M1 protein-provoked gene expression of CXC chemokines in alveolar macrophages. Ras inhibition decreased chemokine-mediated neutrophil migration in vitro. Taken together, our novel findings indicate that Ras signaling is a potent regulator of CXC chemokine formation and neutrophil infiltration in the lung. Thus, inhibition of Ras activity might be a useful way to antagonize streptococcal M1 protein-triggered acute lung injury. PMID:24704370

  8. The cyclophilin-binding agent Sanglifehrin A is a dendritic cell chemokine and migration inhibitor.

    PubMed

    Immecke, Sabrina N; Baal, Nelli; Wilhelm, Jochen; Bechtel, Juliane; Knoche, Angela; Bein, Gregor; Hackstein, Holger

    2011-01-01

    Sanglifehrin A (SFA) is a cyclophilin-binding immunosuppressant but the immunobiology of action is poorly understood. We and others have reported that SFA inhibits IL-12 production and antigen uptake in dendritic cells (DC) and exhibits lower activity against lymphocytes. Here we show that SFA suppresses DC chemokine production and migration. Gene expression analysis and subsequent protein level confirmation revealed that SFA suppressed CCL5, CCL17, CCL19, CXCL9 and CXCL10 expression in human monocyte-derived DC (moDC). A systems biology analysis, Onto Express, confirmed that SFA interferes with chemokine-chemokine receptor gene expression with the highest impact. Direct comparison with the related agent cyclosporine A (CsA) and dexamethasone indicated that SFA uniquely suppresses moDC chemokine expression. Competitive experiments with a 100-fold molar excess of CsA and with N-Methyl-Val-4-cyclosporin, representing a nonimmunosuppressive derivative of CsA indicated chemokine suppression through a cyclophilin-A independent pathway. Functional assays confirmed reduced migration of CD4+ Tcells and moDCs to supernatant of SFA-exposed moDCs. Vice versa, SFA-exposed moDC exhibited reduced migration against CCL19. Moreover, SFA suppressed expression of the ectoenzyme CD38 that was reported to regulate DC migration and cytokine production. These results identify SFA as a DC chemokine and migration inhibitor and provide novel insight into the immunobiology of SFA. PMID:21483789

  9. The Cyclophilin-Binding Agent Sanglifehrin A Is a Dendritic Cell Chemokine and Migration Inhibitor

    PubMed Central

    Immecke, Sabrina N.; Baal, Nelli; Wilhelm, Jochen; Bechtel, Juliane; Knoche, Angela; Bein, Gregor; Hackstein, Holger

    2011-01-01

    Sanglifehrin A (SFA) is a cyclophilin-binding immunosuppressant but the immunobiology of action is poorly understood. We and others have reported that SFA inhibits IL-12 production and antigen uptake in dendritic cells (DC) and exhibits lower activity against lymphocytes. Here we show that SFA suppresses DC chemokine production and migration. Gene expression analysis and subsequent protein level confirmation revealed that SFA suppressed CCL5, CCL17, CCL19, CXCL9 and CXCL10 expression in human monocyte-derived DC (moDC). A systems biology analysis, Onto Express, confirmed that SFA interferes with chemokine-chemokine receptor gene expression with the highest impact. Direct comparison with the related agent cyclosporine A (CsA) and dexamethasone indicated that SFA uniquely suppresses moDC chemokine expression. Competitive experiments with a 100-fold molar excess of CsA and with N-Methyl-Val-4-cyclosporin, representing a nonimmunosuppressive derivative of CsA indicated chemokine suppression through a cyclophilin-A independent pathway. Functional assays confirmed reduced migration of CD4+ Tcells and moDCs to supernatant of SFA-exposed moDCs. Vice versa, SFA-exposed moDC exhibited reduced migration against CCL19. Moreover, SFA suppressed expression of the ectoenzyme CD38 that was reported to regulate DC migration and cytokine production. These results identify SFA as a DC chemokine and migration inhibitor and provide novel insight into the immunobiology of SFA. PMID:21483789

  10. Chemokine Expression in Melanoma Metastases Associated with CD8+ T-Cell Recruitment

    PubMed Central

    Harlin, Helena; Meng, Yuru; Peterson, Amy C.; Zha, Yuanyuan; Tretiakova, Maria; Slingluff, Craig; McKee, Mark; Gajewski, Thomas F.

    2013-01-01

    Despite the frequent detection of circulating tumor antigen–specific T cells, either spontaneously or following active immunization or adoptive transfer, immune-mediated cancer regression occurs only in the minority of patients. One theoretical rate-limiting step is whether effector T cells successfully migrate into metastatic tumor sites. Affymetrix gene expression profiling done on a series of metastatic melanoma biopsies revealed a major segregation of samples based on the presence or absence of T-cell-associated transcripts. The presence of lymphocytes correlated with the expression of defined chemokine genes. A subset of six chemokines (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10) was confirmed by protein array and/or quantitative reverse transcription-PCR to be preferentially expressed in tumors that contained T cells. Corresponding chemokine receptors were found to be up-regulated on human CD8+ effector T cells, and transwell migration assays confirmed the ability of each of these chemokines to promote migration of CD8+ effector cells in vitro. Screening by chemokine protein array identified a subset of melanoma cell lines that produced a similar broad array of chemokines. These melanoma cells more effectively recruited human CD8+ effector T cells when implanted as xenografts in nonobese diabetic/severe combined immunodeficient mice in vivo. Chemokine blockade with specific antibodies inhibited migration of CD8+ T cells. Our results suggest that lack of critical chemokines in a subset of melanoma metastases may limit the migration of activated T cells, which in turn could limit the effectiveness of antitumor immunity. PMID:19293190

  11. Chemokines and their receptors in Atherosclerosis.

    PubMed

    van der Vorst, Emiel P C; Döring, Yvonne; Weber, Christian

    2015-09-01

    Atherosclerosis, a chronic inflammatory disease of the medium- and large-sized arteries, is the main underlying cause of cardiovascular diseases (CVDs) most often leading to a myocardial infarction or stroke. However, atherosclerosis can also develop without this clinical manifestation. The pathophysiology of atherosclerosis is very complex and consists of many cells and molecules interacting with each other. Over the last years, chemokines (small 8-12 kDa cytokines with chemotactic properties) have been identified as key players in atherogenesis. However, this remains a very active and dynamic field of research. Here, we will give an overview of the current knowledge about the involvement of chemokines in all phases of atherosclerotic lesion development. Furthermore, we will focus on two chemokines that recently have been associated with atherogenesis, CXCL12, and macrophage migration inhibitory factor (MIF). Both chemokines play a crucial role in leukocyte recruitment and arrest, a critical step in atherosclerosis development. MIF has shown to be a more pro-inflammatory and thus pro-atherogenic chemokine, instead CXCL12 seems to have a more protective function. However, results about this protective role are still quite debatable. Future research will further elucidate the precise role of these chemokines in atherosclerosis and determine the potential of chemokine-based therapies. PMID:26175090

  12. A strategy to discover decoy chemokine ligands with an anti-inflammatory activity

    PubMed Central

    Abboud, Dayana; Daubeuf, François; Do, Quoc Tuan; Utard, Valérie; Villa, Pascal; Haiech, Jacques; Bonnet, Dominique; Hibert, Marcel; Bernard, Philippe; Galzi, Jean-Luc; Frossard, Nelly

    2015-01-01

    Excessive signaling by chemokines has been associated with chronic inflammation or cancer, thus attracting substantial attention as promising therapeutic targets. Inspired by chemokine-clearing molecules shaped by pathogens to escape the immune system, we designed a generic screening assay to discover chemokine neutralizing molecules (neutraligands) and unambiguously distinguish them from molecules that block the receptor (receptor antagonists). This assay, called TRIC-r, combines time-resolved intracellular calcium recordings with pre-incubation of bioactive compounds either with the chemokine or the receptor-expressing cells. We describe here the identification of high affinity neutraligands of CCL17 and CCL22, two chemokines involved in the Th2-type of lung inflammation. The decoy molecules inhibit in vitro CCL17- or CCL22-induced intracellular calcium responses, CCR4 endocytosis and human T cell migration. In vivo, they inhibit inflammation in a murine model of asthma, in particular the recruitment of eosinophils, dendritic cells and CD4+T cells. Altogether, we developed a successful strategy to discover as new class of pharmacological tools to potently control cell chemotaxis in vitro and in vivo. PMID:26442456

  13. Anti-metastatic effect of supercritical extracts from the Citrus hassaku pericarp via inhibition of C-X-C chemokine receptor type 4 (CXCR4) and matrix metalloproteinase-9 (MMP-9).

    PubMed

    Kim, Chulwon; Kim, Dongmin; Nam, Dongwoo; Chung, Won-Seok; Ahn, Kyoo Seok; Kim, Sung-Hoon; Choi, Seung-Hoon; Shim, Bum Sang; Cho, Somi K; Ahn, Kwang Seok

    2014-09-01

    The fruit of hassaku (Citrus hassaku Hort. ex Tanaka) is locally known as phalsak in Korea. Recently, the fruit extract has been known to exhibit in vivo preventive effects against UVB-induced pigmentation, antiallergic activity, and enhancement of blood fluidity. However, the exact mechanisms of how supercritical extracts of phalsak peel (SEPS) inhibits tumor metastasis and invasion are still not fully understood. We found that SEPS could downregulate the constitutive expression of both CXCR4 and HER2 in human breast cancer MDA-MB-231 cells as compared with other cells. SEPS also suppressed matrix metalloproteinase-9 (MMP-9) expression and its enzymatic activity under non-cytotoxic concentrations. Neither proteasome inhibition nor lysosomal stabilization had any effect on the SEPS-induced decrease in CXCR4 expression. A detailed study of the underlying molecular mechanisms revealed that the regulation of the downregulation of CXCR4 was at the transcriptional level, as indicated by downregulation of mRNA expression, suppression of NF-κB activity, and inhibition of chromatin immunoprecipitation activity. Suppression of CXCR4 expression by SEPS correlated with the inhibition of CXCL12-stimulated invasion of MDA-MB-231 cells. Overall, our results indicate, for the first time, that SEPS can suppress CXCR4 and MMP-9 expressions through blockade of NF-κB activation and thus has the potential to suppress metastasis of breast cancer. PMID:24638915

  14. Chemokine receptors in cancer metastasis and cancer cell-derived chemokines in host immune response.

    PubMed

    Koizumi, Keiichi; Hojo, Shozo; Akashi, Takuya; Yasumoto, Kazuo; Saiki, Ikuo

    2007-11-01

    The chemotactic cytokines called chemokines are a superfamily of small secreted cytokines that were initially characterized through their ability to prompt the migration of leukocytes. Attention has been focused on the chemokine receptors expressed on cancer cells because cancer cell migration and metastasis show similarities to leukocyte trafficking. CXC chemokine receptor 4 (CXCR4) was first investigated as a chemokine receptor that is associated with lung metastasis of breast cancers. Recently, CXCR4 was reported to be a key molecule in the formation of peritoneal carcinomatosis in gastric cancer. In the present review, we highlight current knowledge about the role of CXCR4 in cancer metastases. In contrast to chemokine receptors expressed on cancer cells, little is known about the roles of cancer cell-derived chemokines. Cancer tissue consists of both cancer cells and various stromal cells, and leukocytes that infiltrate into cancer are of particular importance in cancer progression. Although colorectal cancer invasion is regulated by the chemokine CCL9-induced infiltration of immature myeloid cells into cancer, high-level expression of cancer cell-derived chemokine CXCL16 increases infiltrating CD8(+) and CD4(+) T cells into cancer tissues, and correlates with a good prognosis. We discuss the conflicting biological effects of cancer cell-derived chemokines on cancer progression, using CCL9 and CXCL16 as examples. PMID:17894551

  15. Chemokines and chemokine receptors in mucosal homeostasis at the intestinal epithelial barrier in inflammatory bowel disease.

    PubMed

    Zimmerman, Noah P; Vongsa, Rebecca A; Wendt, Michael K; Dwinell, Michael B

    2008-07-01

    Chemokines, a large family of small chemoattractive cytokines, and their receptors play an integral role in the regulation of the immune response and homeostasis. The ability of chemokines to attract specific populations of immune cells sets them apart from other chemoattractants. Chemokines produced within the gastrointestinal mucosa are critical players in directing the balance between physiological and pathophysiological inflammation in health, inflammatory bowel disease (IBD), and the progression to colon cancer. In addition to the well-characterized role of chemokines in directed trafficking of immune cells to the gut mucosa, the expression of chemokine receptors on the cells of the epithelium makes them active participants in the chemokine signaling network. Recent findings demonstrate an important role for chemokines and chemokine receptors in epithelial barrier repair and maintenance as well as an intricate involvement in limiting metastasis of colonic carcinoma. Increased recognition of the association between barrier defects and inflammation and the subsequent progression to cancer in IBD thus implicates chemokines as key regulators of mucosal homeostasis and disease pathogenesis. PMID:18452220

  16. The anti-inflammatory compound curcumin inhibits Neisseria gonorrhoeae-induced NF-kappaB signaling, release of pro-inflammatory cytokines/chemokines and attenuates adhesion in late infection.

    PubMed

    Wessler, Silja; Muenzner, Petra; Meyer, Thomas F; Naumann, Michael

    2005-05-01

    Neisseria gonorrhoeae (Ngo) is a Gram-negative pathogenic bacterium responsible for an array of diseases ranging from urethritis to disseminated gonococcal infections. Early events in the establishment of infection involve interactions between Ngo and the mucosal epithelium, which induce a local inflammatory response. Here we analyzed the molecular mechanism involved in the Ngo-induced induction of the proinflammatory cytokines tumor necrosis factor alpha (TNFalpha), interleukin-6 (IL-6), and IL-8. We identified the immediate early response transcription factor nuclear factor kappaB (NF-kappaB) as a key molecule for the induction of cytokine release. Ngo-induced activation of direct upstream signaling molecules was demonstrated for IkappaB kinase alpha and beta (IKKalpha and IKKbeta) by phosphorylation of IkappaBalpha as a substrate and IKK autophosphorylation. Using dominant negative cDNAs encoding kinase-dead IKKalpha, IKKbeta, and NF-kappaB-inducing kinase (NIK), Ngo-induced NF-kappaB activity was significantly inhibited. Curcumin, the yellow pigment derived from Curcuma longa, inhibited IKKalpha, IKKbeta and NIK, indicating its strong potential to block NF-kappaB-mediated cytokine release and the innate immune response. In addition to the inhibition of Ngo-induced signaling, curcumin treatment of cells completely abolished the adherence of bacteria to cells in late infection, underlining the high potential of curcumin as an anti-microbial compound without cytotoxic side effects. PMID:15927892

  17. Acoustic sensing of the initial adhesion of chemokine-stimulated cancer cells.

    PubMed

    Wei, Xiao-Lan; Zhang, Jing; Zhao, Na

    2013-11-01

    Chemokines together with their receptors play important roles in tumor metastasis. Intracellular signals stimulated by chemokines regulate the initial adhesion of cancer cells, which controls the subsequent cell spreading and migration. Until now, the nature of initial cell adhesion has been understood very poorly, since conventional assays are static and could not provide dynamic information. In order to address this issue, we adopt an acoustic sensor, quartz crystal microbalance (QCM), to monitor the attachment of chemokine-stimulated cancer cells in real-time. As a model, the chemokine CXCL12 was used to stimulate three human breast cancer cell lines expressing different levels of its receptor CXCR4, which triggers intracellular signaling pathways that activate integrins across cell membrane. Interaction between cellular integrins and adhesion molecules (CAMs) pre-coated on sensor surfaces were in situ monitored by QCM of which the frequency was sensitive to the mechanical connection of cells to the sensor surface. The ratio of frequency shift under stimulation to that without stimulation indicated the number and strength of integrin-CAM binding stimulated by the chemokine. The cell-surface binding was found to be enhanced by CXCL12, which depends on the CAM type and levels of chemokine and receptor, and was significantly inhibited by a blocker of the chemokine pathway. The binding of integrin with intercellular adhesion molecule was also found to be strong and in good correlated with the chemotactic indexes obtained by the classical Boyden chamber assay. This research suggests that acoustic sensing of initial cell adhesion could provide a dynamic insight into cell interfacial phenomena. PMID:23911626

  18. Structure of the CCR5 Chemokine Receptor-HIV Entry Inhibitor Maraviroc Complex

    SciTech Connect

    Tan, Qiuxiang; Zhu, Ya; Li, Jian; Chen, Zhuxi; Han, Gye Won; Kufareva, Irina; Li, Tingting; Ma, Limin; Fenalti, Gustavo; Li, Jing; Zhang, Wenru; Xie, Xin; Yang, Huaiyu; Jiang, Hualiang; Cherezov, Vadim; Liu, Hong; Stevens, Raymond C.; Zhao, Qiang; Wu, Beili

    2013-10-21

    The CCR5 chemokine receptor acts as a co-receptor for HIV-1 viral entry. Here we report the 2.7 angstrom–resolution crystal structure of human CCR5 bound to the marketed HIV drug maraviroc. The structure reveals a ligand-binding site that is distinct from the proposed major recognition sites for chemokines and the viral glycoprotein gp120, providing insights into the mechanism of allosteric inhibition of chemokine signaling and viral entry. A comparison between CCR5 and CXCR4 crystal structures, along with models of co-receptor–gp120-V3 complexes, suggests that different charge distributions and steric hindrances caused by residue substitutions may be major determinants of HIV-1 co-receptor selectivity. These high-resolution insights into CCR5 can enable structure-based drug discovery for the treatment of HIV-1 infection.

  19. C-C chemokine receptor type 4 antagonist Compound 22 ameliorates experimental autoimmune encephalomyelitis.

    PubMed

    Moriguchi, Kota; Miyamoto, Katsuichi; Tanaka, Noriko; Ueno, Rino; Nakayama, Takashi; Yoshie, Osamu; Kusunoki, Susumu

    2016-02-15

    Chemokines and chemokine receptors play important roles in the immune response. We previously reported the pathogenic role of C-C chemokine receptor type 4 (CCR4) in experimental autoimmune encephalomyelitis (EAE). Here, we examined whether CCR4 antagonism modulates the disease course of EAE. Wild-type and CCR4-knockout mice were induced EAE and were administered Compound 22, an antagonist of CCR4. Compound 22 significantly ameliorated the severity of EAE in wild-type mice, but not in the CCR4-knockout mice. Compound 22 inhibited Th1 and Th17 polarization of antigen-induced T-cell responses. Therefore, CCR4 antagonists might be potential therapeutic agents for multiple sclerosis. PMID:26857495

  20. Pharmacological modulation of chemokine receptor function

    PubMed Central

    Scholten, DJ; Canals, M; Maussang, D; Roumen, L; Smit, MJ; Wijtmans, M; de Graaf, C; Vischer, HF; Leurs, R

    2012-01-01

    G protein-coupled chemokine receptors and their peptidergic ligands are interesting therapeutic targets due to their involvement in various immune-related diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease, HIV-1 infection and cancer. To tackle these diseases, a lot of effort has been focused on discovery and development of small-molecule chemokine receptor antagonists. This has been rewarded by the market approval of two novel chemokine receptor inhibitors, AMD3100 (CXCR4) and Maraviroc (CCR5) for stem cell mobilization and treatment of HIV-1 infection respectively. The recent GPCR crystal structures together with mutagenesis and pharmacological studies have aided in understanding how small-molecule ligands interact with chemokine receptors. Many of these ligands display behaviour deviating from simple competition and do not interact with the chemokine binding site, providing evidence for an allosteric mode of action. This review aims to give an overview of the evidence supporting modulation of this intriguing receptor family by a range of ligands, including small molecules, peptides and antibodies. Moreover, the computer-assisted modelling of chemokine receptor–ligand interactions is discussed in view of GPCR crystal structures. Finally, the implications of concepts such as functional selectivity and chemokine receptor dimerization are considered. LINKED ARTICLES This article is part of a themed section on the Molecular Pharmacology of G Protein-Coupled Receptors (GPCRs). To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-6. To view the 2010 themed section on the same topic visit http://onlinelibrary.wiley.com/doi/10.1111/bph.2010.159.issue-5/issuetoc PMID:21699506

  1. Significance of chemokine and chemokine receptors in head and neck squamous cell carcinoma: A critical review.

    PubMed

    da Silva, Janine Mayra; Soave, Danilo Figueiredo; Moreira Dos Santos, Tálita Pollyanna; Batista, Aline Carvalho; Russo, Remo Castro; Teixeira, Mauro Martins; Silva, Tarcília Aparecida da

    2016-05-01

    Chemokines are small chemotactic proteins that coordinate circulation of immune/inflammatory cells throughout body compartments. Because of this property chemokines and their cell surface receptors are implicated in several physiological and pathological conditions, including cancer. These molecules are expressed by neoplastic or stromal cells and have effects at tumor primary site (e.g. stimulating angiogenesis and tumor cells motility) and lymph nodes (creating a gradient to direct migration of neoplastic cells). In this article we review the current knowledge about the function(s) of chemokines and receptors in squamous cell carcinoma from the oral cavity and head and neck region. Accumulating evidence suggests some chemokine(s) and receptor(s) as potential targets in adjuvant therapies for these malignancies. PMID:27086481

  2. Structural biology. Crystal structure of the chemokine receptor CXCR4 in complex with a viral chemokine.

    PubMed

    Qin, Ling; Kufareva, Irina; Holden, Lauren G; Wang, Chong; Zheng, Yi; Zhao, Chunxia; Fenalti, Gustavo; Wu, Huixian; Han, Gye Won; Cherezov, Vadim; Abagyan, Ruben; Stevens, Raymond C; Handel, Tracy M

    2015-03-01

    Chemokines and their receptors control cell migration during development, immune system responses, and in numerous diseases, including inflammation and cancer. The structural basis of receptor:chemokine recognition has been a long-standing unanswered question due to the challenges of structure determination for membrane protein complexes. Here, we report the crystal structure of the chemokine receptor CXCR4 in complex with the viral chemokine antagonist vMIP-II at 3.1 angstrom resolution. The structure revealed a 1:1 stoichiometry and a more extensive binding interface than anticipated from the paradigmatic two-site model. The structure helped rationalize a large body of mutagenesis data and together with modeling provided insights into CXCR4 interactions with its endogenous ligand CXCL12, its ability to recognize diverse ligands, and the specificity of CC and CXC receptors for their respective chemokines. PMID:25612609

  3. Chemokines and the microenvironment in neuroectodermal tumor-host interaction

    PubMed Central

    Somasundaram, Rajasekharan; Herlyn, Dorothee

    2009-01-01

    Chemokines and chemokine receptors play an important role in immune homeostasis and surveillance. Altered or defective expression of chemokines and/or chemokine receptors could lead to a disease state including autoimmune disorder or cancer. Tumors from glioblastoma, melanoma, and neuroblastoma secrete high levels of chemokines that can promote tumor growth and progression or induce stromal cells present in the tumor microenvironment to produce cytokines or chemokines which, in turn, can regulate angiogenesis, tumor growth, and metastasis. On the other hand, chemokines secreted by tumor or stromal cells can also attract leukocytes such as dendritic cells, macrophages, neutrophils, and lymphocytes which may downmodulate tumor growth. New therapies that are aimed at limiting tumor growth and progression by attracting immune effector cells to the tumor site with chemokines may hold the key to the successful treatment of cancer, although this approach may be hampered by possible tumor growth-stimulating effects of chemokines. PMID:19049876

  4. Berberine suppresses migration of MCF-7 breast cancer cells through down-regulation of chemokine receptors

    PubMed Central

    Ahmadiankia, Naghmeh; Moghaddam, Hamid Kalalian; Mishan, Mohammad Amir; Bahrami, Ahmad Reza; Naderi-Meshkin, Hojjat; Bidkhori, Hamid Reza; Moghaddam, Maryam; Mirfeyzi, Seyed Jamal Aldin

    2016-01-01

    Objective(s): Berberine is one of the main alkaloids and it has been proven to have different pharmacological effects including inhibition of cell cycle and progression of apoptosis in various cancerous cells; however, its effects on cancer metastasis are not well known. Cancer cells obtain the ability to change their chemokine system and convert into metastatic cells. In this study, we examined the effect of berberine on breast cancer cell migration and its probable interaction with the chemokine system in cancer cells. Materials and Methods: The MCF-7 breast cancer cell line was cultured, and then, treated with berberine (10, 20, 40 and 80 μg/ml) for 24 hr. MTT assay was used in order to determine the cytotoxic effect of berberine on MCF-7 breast cancer cells. Wound healing assay was applied to determine the inhibitory effect of berberine on cell migration. Moreover, real-time quantitative PCR analysis of selected chemokine receptors was performed to determine the probable molecular mechanism underlying the effect of berberine on breast cancer cell migration. Results: The results of wound healing assay revealed that berberine decreases cell migration. Moreover, we found that the mRNA levels of some chemokine receptors were reduced after berberine treatment, and this may be the underlying mechanism for decreased cell migration. Conclusion: Our results indicate that berberine might be a potential preventive biofactor for human breast cancer metastasis by targeting chemokine receptor genes. PMID:27081456

  5. Chemokine Receptor-Specific Antibodies in Cancer Immunotherapy: Achievements and Challenges

    PubMed Central

    Vela, Maria; Aris, Mariana; Llorente, Mercedes; Garcia-Sanz, Jose A.; Kremer, Leonor

    2015-01-01

    The 1990s brought a burst of information regarding the structure, expression pattern, and role in leukocyte migration and adhesion of chemokines and their receptors. At that time, the FDA approved the first therapeutic antibodies for cancer treatment. A few years later, it was reported that the chemokine receptors CXCR4 and CCR7 were involved on directing metastases to liver, lung, bone marrow, or lymph nodes, and the over-expression of CCR4, CCR6, and CCR9 by certain tumors. The possibility of inhibiting the interaction of chemokine receptors present on the surface of tumor cells with their ligands emerged as a new therapeutic approach. Therefore, many research groups and companies began to develop small molecule antagonists and specific antibodies, aiming to neutralize signaling from these receptors. Despite great expectations, so far, only one anti-chemokine receptor antibody has been approved for its clinical use, mogamulizumab, an anti-CCR4 antibody, granted in Japan to treat refractory adult T-cell leukemia and lymphoma. Here, we review the main achievements obtained with anti-chemokine receptor antibodies for cancer immunotherapy, including discovery and clinical studies, proposed mechanisms of action, and therapeutic applications. PMID:25688243

  6. Immunohistochemical Analysis of Paraoxonases and Chemokines in Arteries of Patients with Peripheral Artery Disease

    PubMed Central

    Hernández-Aguilera, Anna; Sepúlveda, Julio; Rodríguez-Gallego, Esther; Guirro, Maria; García-Heredia, Anabel; Cabré, Noemí; Luciano-Mateo, Fedra; Fort-Gallifa, Isabel; Martín-Paredero, Vicente; Joven, Jorge; Camps, Jordi

    2015-01-01

    Oxidative damage to lipids and lipoproteins is implicated in the development of atherosclerotic vascular diseases, including peripheral artery disease (PAD). The paraoxonases (PON) are a group of antioxidant enzymes, termed PON1, PON2, and PON3 that protect lipoproteins and cells from peroxidation and, as such, may be involved in protection against the atherosclerosis process. PON1 inhibits the production of chemokine (C–C motif) ligand 2 (CCL2) in endothelial cells incubated with oxidized lipoproteins. PON1 and CCL2 are ubiquitously distributed in tissues, and this suggests a joint localization and combined systemic effect. The aim of the present study has been to analyze the quantitative immunohistochemical localization of PON1, PON3, CCL2 and CCL2 receptors in a series of patients with severe PAD. Portions of femoral and/or popliteal arteries from 66 patients with PAD were obtained during surgical procedures for infra-inguinal limb revascularization. We used eight normal arteries from donors as controls. PON1 and PON3, CCL2 and the chemokine-binding protein 2, and Duffy antigen/chemokine receptor, were increased in PAD patients. There were no significant changes in C–C chemokine receptor type 2. Our findings suggest that paraoxonases and chemokines play an important role in the development and progression of atherosclerosis in peripheral artery disease. PMID:25993297

  7. Chemokines and chemokine receptors as novel therapeutic targets in rheumatoid arthritis (RA): inhibitory effects of traditional Chinese medicinal components.

    PubMed

    Chen, Xin; Oppenheim, Joost J; Howard, O M Zack

    2004-10-01

    Chemokines belong to a large family of inflammatory cytokines responsible for migration and accumulation of leukocytes at inflammatory sites. Over the past decade, accumulating evidence indicated a crucial role for chemokines and chemokine receptors in the pathophysiology of rheumatoid arthritis (RA). RA is a chronic autoimmune disease in which the synovial tissue is heavily infiltrated by leukocytes. Chemokines play an important role in the infiltration, localization, retention of infiltrating leukocytes and generation of ectopic germinal centers in the inflamed synovium. Recent evidence also suggests that identification of inhibitors directly targeting chemokines or their receptors may provide a novel therapeutic strategy in RA. Traditional Chinese medicines (TCMs) have a long history in the treatment of inflammatory joint disease. The basis for the clinical benefits of TCM remains largely unclear. Our studies have led to the identification of numerous novel chemokine/chemokine receptor inhibitors present in anti-inflammatory TCMs. All of these inhibitors were previously reported by other researchers to have anti-arthritic effect, which may be attributable, at least in part, to their inhibitory effect on chemokine and/or chemokine receptor. Therefore, identification of agents capable of targeting chemokine/chemokine receptor interactions has suggested a mechanism of action for several TCM components and provided a means of identifying additional anti-RA TCM. Thus, this approach may lead to the discovery of new inhibitors of chemokines or chemokine receptors that can be used to treat diseases associated with inappropriately overactive chemokine mediated inflammatory reactions. PMID:16285892

  8. CXC-type chemokines promote myofibroblast phenoconversion and prostatic fibrosis.

    PubMed

    Gharaee-Kermani, Mehrnaz; Kasina, Sathish; Moore, Bethany B; Thomas, Dafydd; Mehra, Rohit; Macoska, Jill A

    2012-01-01

    Recent studies from our group suggest that extracellular matrix (ECM) deposition and fibrosis characterize the peri-urethral prostate tissues of some men suffering from Lower Urinary Tract Symptoms (LUTS) and that fibrosis may be a contributing factor to the etiology of LUTS. Fibrosis can generally be regarded as an errant wound-healing process in response to chronic inflammation, and several studies have shown that the aging prostate tissue microenvironment is rich with inflammatory cells and proteins. However, it is unclear whether these same inflammatory proteins, particularly CXC-type chemokines, can mediate myofibroblast phenoconversion and the ECM deposition necessary for the development of prostatic tissue fibrosis. To examine this, immortalized and primary prostate stromal fibroblasts treated with TGF-β1, CXCL5, CXCL8, or CXCL12 were evaluated morphologically by microscopy, by immunofluorescence and qRT-PCR for αSMA, collagen 1, vimentin, calponin, and tenascin protein and transcript expression, and by gel contraction assays for functional myofibroblast phenoconversion. The results of these studies showed that that immortalized and primary prostate stromal fibroblasts are induced to express collagen 1 and 3 and αSMA gene transcripts and proteins and to undergo complete and functional myofibroblast phenoconversion in response to CXC-type chemokines, even in the absence of exogenous TGF-β1. Moreover, CXCL12-mediated myofibroblast phenoconversion can be completely abrogated by inhibition of the CXCL12 receptor, CXCR4. These findings suggest that CXC-type chemokines, which comprise inflammatory proteins known to be highly expressed in the aging prostate, can efficiently and completely mediate myofibroblast phenoconversion and may thereby promote fibrotic changes in prostate tissue architecture associated with the development and progression of male lower urinary tract dysfunction. PMID:23173053

  9. Decidual Cell Regulation of Natural Killer Cell–Recruiting Chemokines

    PubMed Central

    Lockwood, Charles J.; Huang, S. Joseph; Chen, Chie-Pein; Huang, Yingqun; Xu, Jie; Faramarzi, Saeed; Kayisli, Ozlem; Kayisli, Umit; Koopman, Louise; Smedts, Dineke; Buchwalder, Lynn F.; Schatz, Frederick

    2014-01-01

    First trimester human decidua is composed of decidual cells, CD56brightCD16− decidual natural killer (dNK) cells, and macrophages. Decidual cells incubated with NK cell–derived IFN-γ and either macrophage-derived TNF-α or IL-1β synergistically enhanced mRNA and protein expression of IP-10 and I-TAC. Both chemokines recruit CXCR3-expressing NK cells. This synergy required IFN-γ receptor 1 and 2 mediation via JAK/STAT and NFκB signaling pathways. However, synergy was not observed on neutrophil, monocyte, and NK cell–recruiting chemokines. Immunostaining of first trimester decidua localized IP-10, I-TAC, IFN-γR1, and -R2 to vimentin-positive decidual cells versus cytokeratin-positive interstitial trophoblasts. Flow cytometry identified high CXCR3 levels on dNK cells and minority peripheral CD56brightCD16− pNK cells and intermediate CXCR3 levels on the majority of CD56dimCD16+ pNK cells. Incubation of pNK cells with either IP-10 or I-TAC elicited concentration-dependent enhanced CXCR3 levels and migration of both pNK cell subsets that peaked at 10 ng/mL, whereas each chemokine at a concentration of 50 ng/mL inhibited CXCR3 expression and pNK cell migration. Deciduae from women with preeclampsia, a leading cause of maternal and fetal morbidity and mortality, displayed significantly lower dNK cell numbers and higher IP-10 and I-TAC levels versus gestational age–matched controls. Significantly elevated IP-10 levels in first trimester sera from women eventually developing preeclampsia compared with controls, identifying IP-10 as a novel, robust early predictor of preeclampsia. PMID:23973270

  10. Chemokines, costimulatory molecules and fusion proteins for the immunotherapy of solid tumors

    PubMed Central

    Lechner, Melissa G; Russell, Sarah M; Bass, Rikki S; Epstein, Alan L

    2011-01-01

    In this article, the role of chemokines and costimulatory molecules in the immunotherapy of experimental murine solid tumors and immunotherapy used in ongoing clinical trials are presented. Chemokine networks regulate physiologic cell migration that may be disrupted to inhibit antitumor immune responses or coopted to promote tumor growth and metastasis in cancer. Recent studies highlight the potential use of chemokines in cancer immunotherapy to improve innate and adaptive cell interactions and to recruit immune effector cells into the tumor microenvironment. Another critical component of antitumor immune responses is antigen priming and activation of effector cells. Reciprocal expression and binding of costimulatory molecules and their ligands by antigen-presenting cells and naive lymphocytes ensures robust expansion, activity and survival of tumor-specific effector cells in vivo. Immunotherapy approaches using agonist antibodies or fusion proteins of immunomodulatory molecules significantly inhibit tumor growth and boost cell-mediated immunity. To localize immune stimulation to the tumor site, a series of fusion proteins consisting of a tumor-targeting monoclonal antibody directed against tumor necrosis and chemokines or costimulatory molecules were generated and tested in tumor-bearing mice. While several of these reagents were initially shown to have therapeutic value, combination therapies with methods to delete suppressor cells had the greatest effect on tumor growth. In conclusion, a key conclusion that has emerged from these studies is that successful immunotherapy will require both advanced methods of immunostimulation and the removal of immunosuppression in the host. PMID:22053884

  11. Chemokine Signaling Specificity: Essential Role for the N-Terminal Domain of Chemokine Receptors†

    PubMed Central

    N. Prado, Gregory; Suetomi, Katsutoshi; Shumate, David; Maxwell, Carrie; Ravindran, Aishwarya; Rajarathnam, Krishna; Navarro, Javier

    2009-01-01

    Chemokine IL-8 (CXCL8) binds to its cognate receptors CXCR1 and CXCR2 to induce inflammatory responses, wound healing, tumorogenesis, and neuronal survival. Here we identify the N-loop residues in IL-8 (H18 and F21) and the receptor N-termini as the major structural determinants regulating the rate of receptor internalization, which in turn controlled the activation profile of ERK1/2, a central component of the receptor/ERK signaling pathway that dictates signal specificity. Our data further support the idea that the chemokine receptor core acts as a plastic scaffold. Thus, the diversity and intensity of inflammatory and noninflammatory responses mediated by chemokine receptors appear to be primarily determined by the initial interaction between the receptor N-terminus and the N-loop of chemokines. PMID:17630697

  12. Role of chemokine pathways in hepatobiliary cancer.

    PubMed

    Ehling, Josef; Tacke, Frank

    2016-09-01

    Persistent hepatic inflammation resulting from hepatitis B or C virus infections (HBV or HCV, respectively), obesity-associated non-alcoholic steatohepatitis (NASH) or alcohol abuse is a hallmark feature of chronic liver diseases and appears to be an essential prerequisite of hepatocarcinogenesis. The inflammatory processes in the liver are regulated by various chemokines, which orchestrate the interaction between parenchymal liver cells, Kupffer cells (resident macrophages), hepatic stellate cells (HSC), endothelial cells, and infiltrating immune cells. In consequence, these cellular interactions result in the re-modeling of the hepatic microenvironment toward a pro-inflammatory, pro-fibrotic, pro-angiogenic and thus pre-neoplastic milieu. Once developed, liver neoplasms provoke pro- and anti-tumor immune responses that are also critically regulated through differential activation of chemokine pathways. With respect to hepatobiliary cancers, including hepatocellular carcinoma (HCC), gallbladder cancer and cholangiocellular carcinoma (cholangiocarcinoma), together belonging to the highest causes of cancer-related deaths worldwide, this review article will give an overview of chemokine pathways involved in both the establishment of a pro-tumorigenic microenvironment as well as the development and progression of hepatobiliary cancer. Pharmaceutical targeting of chemokine pathways is a promising approach to treat or even prevent hepatobiliary cancer. PMID:26123664

  13. Chemokine/chemokine receptor pair CCL20/CCR6 in human colorectal malignancy: An overview

    PubMed Central

    Frick, Vilma Oliveira; Rubie, Claudia; Keilholz, Ulrich; Ghadjar, Pirus

    2016-01-01

    Chemokines belong to a superfamily of small, cytokine-like proteins, which induce multiple physiological functions, particularly cytoskeletal rearrangement and compartment-specific migration through their interaction with G-protein-coupled receptors. Chemokines and their receptors have been widely acknowledged as essential and selective mediators in leukocyte migration in inflammatory response. It is now established that the chemokine/chemokine receptor system is also used by cancer cells to direct lymphatic and haematogenous spreading and additionally has an impact on the site of metastatic growth of different tumours. In recent years an increasing number of studies have drawn attention to CC-chemokine cysteine motif chemokine ligand 20 (CCL20) and its physiological sole receptor CCR6 to play a role in the onset, development and metastatic spread of various gastrointestinal cancer entities. Among various cancer types CCR6 was also demonstrated to be significantly overexpressed in colorectal cancer (CRC) and stimulation by its physiological ligand CCL20 has been reported to promote CRC cell proliferation and migration in vitro. Further, the CCL20/CCR6 system apparently plays a role in the organ-selective liver metastasis of CRC. Here we review the literature on expression patterns of CCL20 and CCR6 and their physiological interactions as well as the currently presumed role of CCL20 and CCR6 in the formation of CRC and the development of liver metastasis, providing a potential basis for novel treatment strategies. PMID:26811629

  14. The atypical chemokine receptor CCX-CKR regulates metastasis of mammary carcinoma via an effect on EMT.

    PubMed

    Harata-Lee, Yuka; Turvey, Michelle E; Brazzatti, Julie A; Gregor, Carly E; Brown, Michael P; Smyth, Mark J; Comerford, Iain; McColl, Shaun R

    2014-11-01

    Over the last decade, the significance of the homeostatic CC chemokine receptor-7 and its ligands CC chemokine ligand-19 (CCL19) and CCL21, in various types of cancer, particularly mammary carcinoma, has been highlighted. The chemokine receptor CCX-CKR is a high-affinity receptor for these chemokine ligands but rather than inducing classical downstream signalling events promoting migration, it instead sequesters and targets its ligands for degradation, and appears to function as a regulator of the bioavailability of these chemokines in vivo. Therefore, in this study, we tested the hypothesis that local regulation of chemokine levels by CCX-CKR expressed on tumours alters tumour growth and metastasis in vivo. Expression of CCX-CKR on 4T1.2 mouse mammary carcinoma cells inhibited orthotopic tumour growth. However, this effect could not be correlated with chemokine scavenging in vivo and was not mediated by host adaptive immunity. Conversely, expression of CCX-CKR on 4T1.2 cells resulted in enhanced spontaneous metastasis and haematogenous metastasis in vivo. In vitro characterisation of the tumourigenicity of CCX-CKR-expressing 4T1.2 cells suggested accelerated epithelial-mesenchymal transition (EMT) revealed by their more invasive and motile character, lower adherence to the extracellular matrix and to each other, and greater resistance to anoikis. Further analysis of CCX-CKR-expressing 4T1.2 cells also revealed that transforming growth factor (TGF)-β1 expression was increased both at mRNA and protein levels leading to enhanced autocrine phosphorylation of Smad 2/3 in these cells. Together, our data show a novel function for the chemokine receptor CCX-CKR as a regulator of TGF-β1 expression and the EMT in breast cancer cells. PMID:25027038

  15. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells

    PubMed Central

    Ugel, Stefano; Del Pozzo, Federica; Soldani, Cristiana; Zilio, Serena; Avella, Debora; De Palma, Antonella; Mauri, PierLuigi; Monegal, Ana; Rescigno, Maria; Savino, Benedetta; Colombo, Piergiuseppe; Jonjic, Nives; Pecanic, Sanja; Lazzarato, Loretta; Fruttero, Roberta; Gasco, Alberto; Bronte, Vincenzo; Viola, Antonella

    2011-01-01

    Tumor-promoted constraints negatively affect cytotoxic T lymphocyte (CTL) trafficking to the tumor core and, as a result, inhibit tumor killing. The production of reactive nitrogen species (RNS) within the tumor microenvironment has been reported in mouse and human cancers. We describe a novel RNS-dependent posttranslational modification of chemokines that has a profound impact on leukocyte recruitment to mouse and human tumors. Intratumoral RNS production induces CCL2 chemokine nitration and hinders T cell infiltration, resulting in the trapping of tumor-specific T cells in the stroma that surrounds cancer cells. Preconditioning of the tumor microenvironment with novel drugs that inhibit CCL2 modification facilitates CTL invasion of the tumor, suggesting that these drugs may be effective in cancer immunotherapy. Our results unveil an unexpected mechanism of tumor evasion and introduce new avenues for cancer immunotherapy. PMID:21930770

  16. Extensive expansion and diversification of the chemokine gene family in zebrafish: Identification of a novel chemokine subfamily CX

    PubMed Central

    Nomiyama, Hisayuki; Hieshima, Kunio; Osada, Naoki; Kato-Unoki, Yoko; Otsuka-Ono, Kaori; Takegawa, Sumio; Izawa, Toshiaki; Yoshizawa, Akio; Kikuchi, Yutaka; Tanase, Sumio; Miura, Retsu; Kusuda, Jun; Nakao, Miki; Yoshie, Osamu

    2008-01-01

    Background The chemokine family plays important roles in cell migration and activation. In humans, at least 44 members are known. Based on the arrangement of the four conserved cysteine residues, chemokines are now classified into four subfamilies, CXC, CC, XC and CX3C. Given that zebrafish is an important experimental model and teleost fishes constitute an evolutionarily diverse group that forms half the vertebrate species, it would be useful to compare the zebrafish chemokine system with those of mammals. Prior to this study, however, only incomplete lists of the zebrafish chemokine genes were reported. Results We systematically searched chemokine genes in the zebrafish genome and EST databases, and identified more than 100 chemokine genes. These genes were CXC, CC and XC subfamily members, while no CX3C gene was identified. We also searched chemokine genes in pufferfish fugu and Tetraodon, and found only 18 chemokine genes in each species. The majority of the identified chemokine genes are unique to zebrafish or teleost fishes. However, several groups of chemokines are moderately similar to human chemokines, and some chemokines are orthologous to human homeostatic chemokines CXCL12 and CXCL14. Zebrafish also possesses a novel species-specific subfamily consisting of five members, which we term the CX subfamily. The CX chemokines lack one of the two N-terminus conserved cysteine residues but retain the third and the fourth ones. (Note that the XC subfamily only retains the second and fourth of the signature cysteines residues.) Phylogenetic analysis and genome organization of the chemokine genes showed that successive tandem duplication events generated the CX genes from the CC subfamily. Recombinant CXL-chr24a, one of the CX subfamily members on chromosome 24, showed marked chemotactic activity for carp leukocytes. The mRNA was expressed mainly during a certain period of the embryogenesis, suggesting its role in the zebrafish development. Conclusion The

  17. The Role of Chemokines in Acute Liver Injury

    PubMed Central

    Saiman, Yedidya; Friedman, Scott L.

    2012-01-01

    Chemokines are small molecular weight proteins primarily known to drive migration of immune cell populations. In both acute and chronic liver injury, hepatic chemokine expression is induced resulting in inflammatory cell infiltration, angiogenesis, and cell activation and survival. During acute injury, massive parenchymal cell death due to apoptosis and/or necrosis leads to chemokine production by hepatocytes, cholangiocytes, Kupffer cells, hepatic stellate cells, and sinusoidal endothelial cells. The specific chemokine profile expressed during injury is dependent on both the type and course of injury. Hepatotoxicity by acetaminophen for example leads to cellular necrosis and activation of Toll-like receptors while the inciting insult in ischemia reperfusion injury produces reactive oxygen species and subsequent production of pro-inflammatory chemokines. Chemokine expression by these cells generates a chemoattractant gradient promoting infiltration by monocytes/macrophages, NK cells, NKT cells, neutrophils, B cells, and T cells whose activity are highly regulated by the specific chemokine profiles within the liver. Additionally, resident hepatic cells express chemokine receptors both in the normal and injured liver. While the role of these receptors in normal liver has not been well described, during injury, receptor up-regulation, and chemokine engagement leads to cellular survival, proliferation, apoptosis, fibrogenesis, and expression of additional chemokines and growth factors. Hepatic-derived chemokines can therefore function in both paracrine and autocrine fashions further expanding their role in liver disease. More recently it has been appreciated that chemokines can have diverging effects depending on their temporal expression pattern and the type of injury. A better understanding of chemokine/chemokine receptor axes will therefore pave the way for development of novel targeted therapies for the treatment of liver disease. PMID:22723782

  18. Detection and Quantification of Citrullinated Chemokines

    PubMed Central

    Moelants, Eva A. V.; Van Damme, Jo; Proost, Paul

    2011-01-01

    Background Posttranslational deimination or citrullination by peptidylarginine deiminases (PAD) regulates the biological function of proteins and may be involved in the development of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. This posttranslational modification of arginine was recently discovered on inflammatory chemokines including CXCL8 and CXCL10, and significantly reduced their biological activity. To evaluate the importance of these modified chemokines in patients, methods for the detection and quantification of citrullinated chemokines are needed. Since citrullination only results in an increase of the protein mass with one mass unit and the loss of one positive charge, selective biochemical detection is difficult. Therefore, we developed an antibody-based method to specifically detect and quantify citrullination on a protein of interest. Methodology/Principal Findings First, the citrullinated proteins were chemically modified with antipyrine and 2,3-butanedione at low pH. Such selectively modified citrullines were subsequently detected and quantified by specific antibodies raised against a modified citrulline-containing peptide. The specificity of this two-step procedure was validated for citrullinated CXCL8 ([Cit5]CXCL8). Specific detection of [Cit5]CXCL8 concentrations between 1 and 50 ng/ml was possible, also in complex samples containing an excess of contaminating proteins. This novel detection method was used to evaluate the effect of lipopolysaccharide (LPS) on the citrullination of inflammatory chemokines induced in peripheral blood mononuclear cells (PBMCs) and granulocytes. LPS had no significant effect on the induction of CXCL8 citrullination in human PBMCs and granulocytes. However, granulocytes, known to contain PAD, were essential for the production of significant amounts of [Cit5]CXCL8. Conclusion/Significance The newly developed antibody-based method to specifically detect and quantify chemically modified

  19. Role of chemokines and chemokine receptors in shaping the effector phase of the antitumor immune response.

    PubMed

    Franciszkiewicz, Katarzyna; Boissonnas, Alexandre; Boutet, Marie; Combadière, Christophe; Mami-Chouaib, Fathia

    2012-12-15

    Immune system-mediated eradication of neoplastic cells requires induction of a strong long-lasting antitumor T-cell response. However, generation of tumor-specific effector T cells does not necessarily result in tumor clearance. CTL must first be able to migrate to the tumor site, infiltrate the tumor tissue, and interact with the target to finally trigger effector functions indispensable for tumor destruction. Chemokines are involved in circulation, homing, retention, and activation of immunocompetent cells. Although some of them are known to contribute to tumor growth and metastasis, others are responsible for changes in the tumor microenvironment that lead to extensive infiltration of lymphocytes, resulting in tumor eradication. Given their chemoattractive and activating properties, a role for chemokines in the development of the effector phase of the antitumor immune response has been suggested. Here, we emphasize the role of the chemokine-chemokine receptor network at multiple levels of the T-cell-mediated antitumor immune response. The identification of chemokine-dependent molecular mechanisms implicated in tumor-specific CTL trafficking, retention, and regulation of their in situ effector functions may offer new perspectives for development of innovative immunotherapeutic approaches to cancer treatment. PMID:23222302

  20. Mechanisms and implications of air pollution particle associations with chemokines

    SciTech Connect

    Seagrave, JeanClare

    2008-11-01

    Inflammation induced by inhalation of air pollutant particles has been implicated as a mechanism for the adverse health effects associated with exposure to air pollution. The inflammatory response is associated with upregulation of various pro-inflammatory cytokines and chemokines. We have previously shown that diesel exhaust particles (DEP), a significant constituent of air pollution particulate matter in many urban areas, bind and concentrate IL-8, an important human neutrophil-attracting chemokine, and that the chemokine remains biologically active. In this report, we examine possible mechanisms of this association and the effects on clearance of the chemokine. The binding appears to be the result of ionic interactions between negatively charged particles and positively charged chemokine molecules, possibly combined with intercalation into small pores in the particles. The association is not limited to diesel exhaust particles and IL-8: several other particle types also adsorb the chemokine and several other cytokines are adsorbed onto the diesel particles. However, there are wide ranges in the effectiveness of various particle types and various cytokines. Finally, male Fisher 344 rats were intratracheally instilled with chemokine alone or combined with diesel exhaust or silica particles under isofluorane anesthesia. In contrast to silica particles, which do not bind the chemokine, the presence of diesel exhaust particles, which bind the chemokine, prolonged the retention of the chemokine.

  1. Chemokine Regulation of Neutrophil Infiltration of Skin Wounds

    PubMed Central

    Su, Yingjun; Richmond, Ann

    2015-01-01

    Significance: Efficient recruitment of neutrophils to an injured skin lesion is an important innate immune response for wound repair. Defects in neutrophil recruitment lead to impaired wound healing. Recent Advances: Chemokines and chemokine receptors are known to regulate neutrophil recruitment. Recent research advances reveal more mechanistic details about the regulation of chemokines and chemokine receptors on neutrophil egress from bone marrow, transmigration into the wound site, spatial navigation toward the necrotic skin tissue, and apoptosis-induced clearance by efferocytosis. Critical Issues: Skin injury triggers local and systemic alterations in the expression of multiple chemotactic molecules and the magnitude of chemokine receptor-mediated signaling. The responses of a number of CXC and CX3C chemokines and their receptors closely associate with the temporal and spatial recruitment of neutrophils to wound sites during the inflammatory phase and promote the clearance of necrotic neutrophils during the transition into the proliferative phase. Functional aberrancy in these chemokines and chemokine receptor systems is recognized as one of the important mechanisms underlying the pathology of impaired wound healing. Future Directions: Future research should aim to investigate the therapeutic modulation of neutrophil activity through the targeting of specific chemokines or chemokine receptors in the early inflammatory phase to improve clinical management of wound healing. PMID:26543677

  2. Expression Profiles of Circulating Cytokines, Chemokines and Immune Cells in Patients With Hepatitis B Virus Infection

    PubMed Central

    Lian, Jian-Qi; Yang, Xiao-Fei; Zhao, Rong-Rong; Zhao, Yan-Yan; Li, Yu; Zhang, Ye; Huang, Chang-Xing

    2014-01-01

    Background: Immune cells and molecules play a vital role in initiating, maintaining, regulating immunological homeostasis and inflammation in many pathological and physiological processes; however, the changes on expressions and functions of these cells and molecules in hepatitis B virus (HBV) infection have not been elucidated well. Objectives: The current study aimed to determine the expression pattern of different cytokines, chemokines, immune cells in HBV infection and their association with disease progression. Patients and Methods: Sixty-nine patients with chronic HBV infection were enrolled. Five immune cell subsets and 46 cytokines and chemokines were analyzed by flow cytometry and Luminex 200. Results: In comparison to healthy individuals and asymptomatic HBV carriers, expression of CXCL9, CXCL10, CXCL11, and IL-10 were elevated in patients with chronic active HBV and had positive correlation with ALT levels. In contrast, G-CSF, MCP-3, and IFN-γ levels were significantly decreased in patients with chronic active HBV infection in contrast to carriers and healthy individuals; however, these down regulations did not show any correlation with either virological findings or liver inflammation. Although the proportion of CD4+ CD25 high regulatory T cells (Tregs) was higher in patients with HBV infection than in healthy controls, no correlations were found between Tregs and other cytokines or chemokines. Conclusions: CXCR3-associated chemokines might contribute to liver inflammation in chronic hepatitis B, while MCP-3 and G-CSF were inhibited by HBV infection. Host immune response was suppressed as manifested by an increase in CD4+ CD25high Tregs and IL-10 as well as a decrease in IFN-γ. Exploiting the expression pattern of cytokine and chemokine may help to develop a better understanding of chronic HBV infection pathogenesis. PMID:24976843

  3. The biochemistry and biology of the atypical chemokine receptors.

    PubMed

    Graham, G J; Locati, M; Mantovani, A; Rot, A; Thelen, M

    2012-07-30

    A subset of chemokine receptors, initially called "silent" on the basis of their apparent failure to activate conventional signalling events, has recently attracted growing interest due to their ability to internalize, degrade, or transport ligands and thus modify gradients and create functional chemokine patterns in tissues. These receptors recognize distinct and complementary sets of ligands with high affinity, are strategically expressed in different cellular contexts, and lack structural determinants supporting Gα(i) activation, a key signalling event in cell migration. This is in keeping with the hypothesis that they have evolved to fulfil fundamentally different functions to the classical signalling chemokine receptors. Based on these considerations, these receptors (D6, Duffy antigen receptor for chemokines (DARC), CCX-CKR1 and CXCR7) are now collectively considered as an emerging class of 'atypical' chemokine receptors. In this article, we review the biochemistry and biology of this emerging chemokine receptor subfamily. PMID:22698181

  4. Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation.

    PubMed

    Pan, Y; Lloyd, C; Zhou, H; Dolich, S; Deeds, J; Gonzalo, J A; Vath, J; Gosselin, M; Ma, J; Dussault, B; Woolf, E; Alperin, G; Culpepper, J; Gutierrez-Ramos, J C; Gearing, D

    1997-06-01

    Chemokines are small secreted proteins that stimulate the directional migration of leukocytes and mediate inflammation. During screening of a murine choroid plexus complementary DNA library, we identified a new chemokine, designated neurotactin. Unlike other chemokines, neurotactin has a unique cysteine pattern, Cys-X-X-X-Cys, and is predicted to be a type 1 membrane protein. Full-length recombinant neurotactin is localized on the surface of transfected 293 cells. Recombinant neurotactin containing the chemokine domain is chemotactic for neutrophils both in vitro and in vivo. Neurotactin messenger RNA is predominantly expressed in normal murine brain and its protein expression in activated brain microglia is upregulated in mice with experimental autoimmune encephalomyelitis, as well as in mice treated with lipopolysaccharide. Distinct from all other chemokine genes, the neurotactin gene is localized to human chromosome 16q. Consequently we propose that neurotactin represents a new delta-chemokine family and that it may play a role in brain inflammation processes. PMID:9177350

  5. Chemokine binding proteins: An immunomodulatory strategy going viral.

    PubMed

    González-Motos, Víctor; Kropp, Kai A; Viejo-Borbolla, Abel

    2016-08-01

    Chemokines are chemotactic cytokines whose main function is to direct cell migration. The chemokine network is highly complex and its deregulation is linked to several diseases including immunopathology, cancer and chronic pain. Chemokines also play essential roles in the antiviral immune response. Viruses have therefore developed several counter strategies to modulate chemokine activity. One of these is the expression of type I transmembrane or secreted proteins with the ability to bind chemokines and modulate their activity. These proteins, termed viral chemokine binding proteins (vCKBP), do not share sequence homology with host proteins and are immunomodulatory in vivo. In this review we describe the discovery and characterization of vCKBP, explain their role in the context of infection in vivo and discuss relevant novel findings. PMID:26987612

  6. Vascular Stem/Progenitor Cell Migration Induced by Smooth Muscle Cell-Derived Chemokine (C-C Motif) Ligand 2 and Chemokine (C-X-C motif) Ligand 1 Contributes to Neointima Formation.

    PubMed

    Yu, Baoqi; Wong, Mei Mei; Potter, Claire M F; Simpson, Russell M L; Karamariti, Eirini; Zhang, Zhongyi; Zeng, Lingfang; Warren, Derek; Hu, Yanhua; Wang, Wen; Xu, Qingbo

    2016-09-01

    Recent studies have shown that Sca-1(+) (stem cell antigen-1) stem/progenitor cells within blood vessel walls may contribute to neointima formation, but the mechanism behind their recruitment has not been explored. In this work Sca-1(+) progenitor cells were cultivated from mouse vein graft tissue and found to exhibit increased migration when cocultured with smooth muscle cells (SMCs) or when treated with SMC-derived conditioned medium. This migration was associated with elevated levels of chemokines, CCL2 (chemokine (C-C motif) ligand 2) and CXCL1 (chemokine (C-X-C motif) ligand 1), and their corresponding receptors on Sca-1(+) progenitors, CCR2 (chemokine (C-C motif) receptor 2) and CXCR2 (chemokine (C-X-C motif) receptor 2), which were also upregulated following SMC conditioned medium treatment. Knockdown of either receptor in Sca-1(+) progenitors significantly inhibited cell migration. The GTPases Cdc42 and Rac1 were activated by both CCL2 and CXCL1 stimulation and p38 phosphorylation was increased. However, only Rac1 inhibition significantly reduced migration and p38 phosphorylation. After Sca-1(+) progenitors labeled with green fluorescent protein (GFP) were applied to the adventitial side of wire-injured mouse femoral arteries, a large proportion of GFP-Sca-1(+) -cells were observed in neointimal lesions, and a marked increase in neointimal lesion formation was seen 1 week post-operation. Interestingly, Sca-1(+) progenitor migration from the adventitia to the neointima was abrogated and neointima formation diminished in a wire injury model using CCL2(-/-) mice. These findings suggest vascular stem/progenitor cell migration from the adventitia to the neointima can be induced by SMC release of chemokines which act via CCR2/Rac1/p38 and CXCR2/Rac1/p38 signaling pathways. Stem Cells 2016;34:2368-2380. PMID:27300479

  7. CXC and CC Chemokines as Angiogenic Modulators in Nonhaematological Tumors

    PubMed Central

    Bracarda, Sergio; Nabissi, Massimo; Massari, Francesco; Bria, Emilio; Tortora, Giampaolo; Santoni, Giorgio; Cascinu, Stefano

    2014-01-01

    Chemokines are a superfamily of structurally homologous heparin-binding proteins that includes potent inducers and inhibitors of angiogenesis. The imbalance between angiogenic and angiostatic chemokine activities can lead to abnormalities, such as chronic inflammation, dysplastic transformation, and even tumor development and spreading. In this review, we summarize the current literature regarding the role of chemokines as modulators of tumor angiogenesis and their potential role as therapeutic targets in patients with nonhaematological tumors. PMID:24971349

  8. Chemokine-like receptor 1 (CMKLR1) and chemokine (C-C motif) receptor-like 2 (CCRL2); two multifunctional receptors with unusual properties.

    PubMed

    Yoshimura, Teizo; Oppenheim, Joost J

    2011-03-10

    Chemokine-like receptor 1 (CMKLR1), also known as ChemR23, and chemokine (C-C motif) receptor-like 2 (CCRL2) are 7-transmembrane receptors that were cloned in the late 1990s based on their homology to known G-protein-coupled receptors. They were previously orphan receptors without any known biological roles; however, recent studies identified ligands for these receptors and their functions have begun to be unveiled. The plasma protein-derived chemoattractant chemerin is a ligand for CMKLR1 and activation of CMKLR1 with chemerin induces the migration of macrophages and dendritic cells (DCs) in vitro, suggesting a proinflammatory role. However, in vivo studies using CMKLR-deficient mice suggest an anti-inflammatory role for this receptor, possibly due to the recruitment of tolerogenic plasmacytoid DCs. Chemerin/CMKLR1 interaction also promotes adipogenesis and angiogenesis. The anti-inflammatory lipid mediator, resolving E1, is another CMKLR1 ligand and it inhibits leukocyte infiltration and proinflammatory gene expression. These divergent results suggest that CMKLR1 is a multifunctional receptor. The chemokine CCL5 and CCL19 are reported to bind to CCRL2. Like Duffy antigen for chemokine receptor (DARC), D6 and CCX-CKR, CCRL2 does not signal, but it constitutively recycles, potentially reducing local concentration of CCL5 and CCL19 and subsequent immune responses. Surprisingly, chemerin, a ligand for CMKLR1, is a ligand for CCRL2. CCRL2 binds chemerin and increases local chemerin concentration to efficiently present it to CMKLR1 on nearby cells, providing a link between CCRL2 and CMKLR1. Although these findings suggest an anti-inflammatory role, a recent study using CCRL2-deficient mice indicates a proinflammatory role; thus, CCRL2 may also be multifunctional. Further studies using CMKLR1- or CCRL2-deficient mice are needed to further define the role of these receptors in immune responses and other cellular processes. PMID:21056554

  9. Transient expression of recombinant ACKR4 (CCRL1) gene, an atypical chemokine receptor in human embryonic kidney (HEK 293) cells.

    PubMed

    Parsi, Bahareh; Esmaeili, Abolghasem; Hashemi, Mohammad; Behjati, Mohaddeseh

    2016-07-01

    ACKR4 also called CCX-CKR, CCRL1 as a member of atypical chemokine receptors, regulates the biological responses by clearance or transporting homeostatic chemokines such as CCL19, CCL21, CCL25, and CXCL13. Since these chemokines are involved in cancer development and metastasis, ACKR4 could have inhibition roles in cancer cell proliferation and invasion. Forming complexes with chemokine receptors by ACKR4 as in the case of hCXCR3 which lead to chemotaxis prevention is the other function of this protein is. However, as an atypical chemokine receptor, ACKR4 is less well-characterized compared to other members. Here, as the first step in understanding the molecular mechanisms of ACKR4 action, transfectants in HEK293T cell, was generated. In this study, ACKR4 coding sequence was cloned and human embryonic kidney 293T cells were used for recombinant production of ACKR4 protein. The liposome-mediated transfection with ACKR4 CDs, were detected in ACKR4 positive cells as early as 48 h post-transfection. The production of ACKR4 protein was confirmed using RT-PCR, dot blot, western blot, and flow cytometry. ACKR4 may represent a novel molecular target in cancer therapy, which might provide a chance for new therapeutic strategy. Therefore, the first step in the understanding of the molecular mechanisms of ACKR4 action is generation ACKR4-HEK293T recombinant cells. PMID:27168154

  10. The N-terminal Region of the Atypical Chemokine Receptor ACKR2 Is a Key Determinant of Ligand Binding*

    PubMed Central

    Hewit, Kay D.; Fraser, Alasdair; Nibbs, Robert J. B.; Graham, Gerard J.

    2014-01-01

    The atypical chemokine receptor, ACKR2 is a pivotal regulator of chemokine-driven inflammatory responses and works by binding, internalizing, and degrading inflammatory CC-chemokines. ACKR2 displays promiscuity of ligand binding and is capable of interacting with up to 14 different inflammatory CC-chemokines. Despite its prominent biological role, little is known about the structure/function relationship within ACKR2, which regulates ligand binding. Here we demonstrate that a conserved tyrosine motif at the N terminus of ACKR2 is essential for ligand binding, internalization, and scavenging. In addition we demonstrate that sulfation of this motif contributes to ligand internalization. Furthermore, a peptide derived from this region is capable of binding inflammatory chemokines and inhibits their interaction with their cognate signaling receptors. Importantly, the peptide is only active in the sulfated form, further confirming the importance of the sulfated tyrosines for function. Finally, we demonstrate that the bacterial protease, staphopain A, can cleave the N terminus of ACKR2 and suppress its ligand internalization activity. Overall, these results shed new light on the nature of the structural motifs in ACKR2 that are responsible for ligand binding. The study also highlights ACKR2-derived N-terminal peptides as being of potential therapeutic significance. PMID:24644289

  11. Antimicrobial Activities of Chemokines: Not Just a Side-Effect?

    PubMed Central

    Wolf, Marlene; Moser, Bernhard

    2012-01-01

    The large family of chemoattractant cytokines (chemokines) embraces multiple, in part unrelated functions that go well beyond chemotaxis. Undoubtedly, the control of immune cell migration (chemotaxis) is the single, unifying response mediated by all chemokines, which involves the sequential engagement of chemokine receptors on migrating target cells. However, numerous additional cellular responses are mediated by some (but not all) chemokines, including angiogenesis, tumor cell growth, T-cell co-stimulation, and control of HIV-1 infection. The recently described antimicrobial activity of several chemokines is of particular interest because antimicrobial peptides are thought to provide an essential first-line defense against invading microbes at the extremely large body surfaces of the skin, lungs, and gastrointestinal-urinary tract. Here we summarize the current knowledge about chemokines with antimicrobial activity and discuss their potential contribution to the control of bacterial infections that may take place at the earliest stage of antimicrobial immunity. In the case of homeostatic chemokines with antimicrobial function, such as CXCL14, we propose an immune surveillance function in healthy epithelial tissues characterized by low-level exposure to environmental microbes. Inflammatory chemokines, i.e., chemokines that are produced in tissue cells in response to microbial antigens (such as pathogen-associated molecular patterns) may be more important in orchestrating the cellular arm in antimicrobial immunity. PMID:22837760

  12. Transcriptional regulation of chemokine expression in ovarian cancer.

    PubMed

    Singha, Bipradeb; Gatla, Himavanth R; Vancurova, Ivana

    2015-01-01

    The increased expression of pro-inflammatory and pro-angiogenic chemokines contributes to ovarian cancer progression through the induction of tumor cell proliferation, survival, angiogenesis, and metastasis. The substantial potential of these chemokines to facilitate the progression and metastasis of ovarian cancer underscores the need for their stringent transcriptional regulation. In this Review, we highlight the key mechanisms that regulate the transcription of pro-inflammatory chemokines in ovarian cancer cells, and that have important roles in controlling ovarian cancer progression. We further discuss the potential mechanisms underlying the increased chemokine expression in drug resistance, along with our perspective for future studies. PMID:25790431

  13. Chemokines: key players in cancer progression and metastasis

    PubMed Central

    Singh, Rajesh; Lilladr, James W.; Singh, Shailesh

    2013-01-01

    Instructed cell migration is a fundamental component of various biological systems and is critical to the pathogenesis of many diseases including cancer. Role of chemokines in providing navigational cues to migrating cancer cells bearing specific receptors is well established. However, functional mechanisms of chemokine are not well implicit, which is crucial for designing new therapeutics to control tumor growth and metastasis. Multiple functions and mode of actions have been advocated for chemokines and their receptors in the progression of primary and secondary tumors. In this review, we have discussed current advances in understanding the role of the chemokines and their corresponding receptor in tumor progression and metastasis. PMID:21622291

  14. Negative feedback between prostaglandin and alpha- and beta-chemokine synthesis in human microglial cells and astrocytes.

    PubMed

    Janabi, N; Hau, I; Tardieu, M

    1999-02-01

    The understanding of immune surveillance and inflammation regulation in cerebral tissue is essential in the therapy of neuroimmunological disorders. We demonstrate here that primary human glial cells were able to produce alpha- and beta-chemokines (IL-8 > growth related protein alpha (GROalpha) > RANTES > microphage inflammatory protein (MIP)-1alpha and MIP-1beta) in parallel to PGs (PGE2 and PGF2alpha) after proinflammatory cytokine stimulation: TNF-alpha + IL-1beta induced all except RANTES, which was induced by TNF-alpha + IFN-gamma. Purified cultures of astrocytes and microglia were also induced by the same combination of cytokines, to produce all these mediators except MIP-1alpha and MIP-1beta, which were produced predominantly by astrocytes. The inhibition of PG production by indomethacin led to a 37-60% increase in RANTES, MIP-1alpha, and MIP-1beta but not in GROalpha and IL-8 secretion. In contrast, inhibition of IL-8 and GRO activities using neutralizing Abs resulted in a specific 6-fold increase in PGE2 but not in PGF2alpha production by stimulated microglial cells and astrocytes, whereas Abs to beta-chemokines had no effect. Thus, the production of PGs in human glial cells down-regulates their beta-chemokine secretion, whereas alpha-chemokine production in these cells controls PG secretion level. These data suggest that under inflammatory conditions, the intraparenchymal production of PGs could control chemotactic gradient of beta-chemokines for an appropriate effector cell recruitment or activation. Conversely, the elevated intracerebral alpha-chemokine levels could reduce PG secretion, preventing the exacerbation of inflammation and neurotoxicity. PMID:9973432

  15. Evasins: Therapeutic Potential of a New Family of Chemokine-Binding Proteins from Ticks

    PubMed Central

    Bonvin, Pauline; Power, Christine A.; Proudfoot, Amanda E. I.

    2016-01-01

    Blood-sucking parasites, such as ticks, remain attached to their hosts for relatively long periods of time in order to obtain their blood meal without eliciting an immune response. One mechanism used to avoid rejection is the inhibition of the recruitment of immune cells, which can be achieved by a class of chemokine-binding proteins (CKBPs) known as Evasins. We have identified three distinct Evasins produced by the salivary glands of the common brown dog tick, Rhipicephalus sanguineus. They display different selectivities for chemokines, the first two identified show a narrow selectivity profile, while the third has a broader binding spectrum. The Evasins showed efficacy in animal models of inflammatory disease. Here, we will discuss the potential of their development for therapeutic use, addressing both the advantages and disadvantages that this entails. PMID:27375615

  16. Upregulation of chemokine receptor CCR10 is essential for glioma proliferation, invasion and patient survival

    PubMed Central

    Chen, Lingchao; Liu, Xing; Zhang, Hai-Yan; Du, Wenzong; Qin, Zhiyong; Yao, Yu; Mao, Ying; Zhou, Liangfu

    2014-01-01

    Human gliomas are characterized by their invasion of normal brain structures irrespective of their grade of malignancy. Tumor cell invasion share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. Here we report that the chemokine receptor CCR10 is highly expressed in human glioblastoma compared with control brain tissue. In vitro, signaling through CCL27-CCR10 mediates activation of p-Akt, and subsequently induces proliferation and invasive responses. Cell proliferation and invasion promoted by CCL27 were blocked by inhibition of p-Akt or CCR10. In vivo, down-regulation of CCR10 significantly impairs growth of glioma. Clinically, High CCR10 expression in GBM correlated with p-Akt, shorter overall survival and progression-free survival (P < 0.05). Together, these findings suggest that elevated CCR10 is a critical molecular event associated with gliomagenesis. PMID:25149529

  17. Roles of Chemokines and Chemokine Receptors in Obesity-Associated Insulin Resistance and Nonalcoholic Fatty Liver Disease

    PubMed Central

    Xu, Liang; Kitade, Hironori; Ni, Yinhua; Ota, Tsuguhito

    2015-01-01

    Abundant evidence has demonstrated that obesity is a state of low-grade chronic inflammation that triggers the release of lipids, aberrant adipokines, pro-inflammatory cytokines, and several chemokines from adipose tissue. This low-grade inflammation underlies the development of insulin resistance and associated metabolic comorbidities such as type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). During this development, adipose tissue macrophages accumulate through chemokine (C-C motif) receptor 2 and the ligand for this receptor, monocyte chemoattractant protein-1 (MCP-1), is considered to be pivotal for the development of insulin resistance. To date, the chemokine system is known to be comprised of approximately 40 chemokines and 20 chemokine receptors that belong to the seven-transmembrane G protein-coupled receptor family and, as a result, chemokines appear to exhibit a high degree of functional redundancy. Over the past two decades, the physiological and pathological properties of many of these chemokines and their receptors have been elucidated. The present review highlights chemokines and chemokine receptors as key contributing factors that link obesity to insulin resistance, T2DM, and NAFLD. PMID:26197341

  18. Structure of mouse IP-10, a chemokine.

    PubMed

    Jabeen, Talat; Leonard, Philip; Jamaluddin, Haryati; Acharya, K Ravi

    2008-06-01

    Interferon-gamma-inducible protein (IP-10) belongs to the CXC class of chemokines and plays a significant role in the pathophysiology of various immune and inflammatory responses. It is also a potent angiostatic factor with antifibrotic properties. The biological activities of IP-10 are exerted by interactions with the G-protein-coupled receptor CXCR3 expressed on Th1 lymphocytes. IP-10 thus forms an attractive target for structure-based rational drug design of anti-inflammatory molecules. The crystal structure of mouse IP-10 has been determined and reveals a novel tetrameric association. In the tetramer, two conventional CXC chemokine dimers are associated through their N-terminal regions to form a 12-stranded elongated beta-sheet of approximately 90 A in length. This association differs significantly from the previously studied tetramers of human IP-10, platelet factor 4 and neutrophil-activating peptide-2. In addition, heparin- and receptor-binding residues were mapped on the surface of IP-10 tetramer. Two heparin-binding sites were observed on the surface and were present at the interface of each of the two beta-sheet dimers. The structure supports the formation of higher order oligomers of IP-10, as observed in recent in vivo studies with mouse IP-10, which will have functional relevance. PMID:18560148

  19. Structure of mouse IP-10, a chemokine

    SciTech Connect

    Jabeen, Talat; Leonard, Philip; Jamaluddin, Haryati; Acharya, K. Ravi

    2008-06-01

    The structure of mouse IP-10 shows a novel tetrameric association. Interferon-γ-inducible protein (IP-10) belongs to the CXC class of chemokines and plays a significant role in the pathophysiology of various immune and inflammatory responses. It is also a potent angiostatic factor with antifibrotic properties. The biological activities of IP-10 are exerted by interactions with the G-protein-coupled receptor CXCR3 expressed on Th1 lymphocytes. IP-10 thus forms an attractive target for structure-based rational drug design of anti-inflammatory molecules. The crystal structure of mouse IP-10 has been determined and reveals a novel tetrameric association. In the tetramer, two conventional CXC chemokine dimers are associated through their N-terminal regions to form a 12-stranded elongated β-sheet of ∼90 Å in length. This association differs significantly from the previously studied tetramers of human IP-10, platelet factor 4 and neutrophil-activating peptide-2. In addition, heparin- and receptor-binding residues were mapped on the surface of IP-10 tetramer. Two heparin-binding sites were observed on the surface and were present at the interface of each of the two β-sheet dimers. The structure supports the formation of higher order oligomers of IP-10, as observed in recent in vivo studies with mouse IP-10, which will have functional relevance.

  20. Soluble M3 proteins of murine gammaherpesviruses 68 and 72 expressed in Escherichia coli: analysis of chemokine-binding properties.

    PubMed

    Matúšková, R; Pančík, P; Štibrániová, I; Belvončíková, P; Režuchová, I; Kúdelová, M

    2015-12-01

    M3 protein of murine gammaherpesvirus 68 (MHV-68) was identified as a viral chemokine-binding protein 3 (vCKBP-3) capable to bind a broad spectrum of chemokines and their receptors. During both acute and latent infection MHV-68 M3 protein provides a selective advantage for the virus by inhibiting the antiviral and inflammatory response. A unique mutation Asp307Gly was identified in the M3 protein of murine gammaherpesvirus 72 (MHV-72), localized near chemokine-binding domain. Study on chemokine-binding properties of MHV-72 M3 protein purified from medium of infected cells implied reduced binding to some chemokines when compared to MHV-68 M3 protein. It was suggested that the mutation in the M3 protein might be involved in the attenuation of immune response to infection with MHV-72. Recently, Escherichia coli cells were used to prepare native recombinant M3 proteins of murine gammaherpesviruses 68 and 72 (Pančík et al., 2013). In this study, we assessed the chemokine-binding properties of three M3 proteins prepared in E. coli Rosetta-gami 2 (DE3) cells, the full length M3 protein of both MHV-68 and MHV-72 and MHV-68 M3 protein truncated in the signal sequence (the first 24 aa). They all displayed binding activity to human chemokines CCL5 (RANTES), CXCL8 (IL-8), and CCL3 (MIP-1α). The truncated MHV-68 M3 protein had more than twenty times reduced binding activity to CCL5, but only about five and three times reduced binding to CXCL8 and CCL3 when compared to its full length counterpart. Binding of the full length MHV-72 M3 protein to all chemokines was reduced when compared to MHV-68 M3 protein. Its binding to CCL5 and CCL3 was reduced over ten and seven times. However, its binding to CXCL8 was only slightly reduced (64.8 vs 91.8%). These data implied the significance of the signal sequence and also of a single mutation (at aa 307) for efficient M3 protein binding to some chemokines. PMID:26666184

  1. Chemokine Involvement in Fetal and Adult Wound Healing

    PubMed Central

    Balaji, Swathi; Watson, Carey L.; Ranjan, Rajeev; King, Alice; Bollyky, Paul L.; Keswani, Sundeep G.

    2015-01-01

    Significance: Fetal wounds heal with a regenerative phenotype that is indistinguishable from surrounding skin with restored skin integrity. Compared to this benchmark, all postnatal wound healing is impaired and characterized by scar formation. The biologic basis of the fetal regenerative phenotype can serve as a roadmap to recapitulating regenerative repair in adult wounds. Reduced leukocyte infiltration, likely mediated, in part, through changes in the chemokine milieu, is a fundamental feature of fetal wound healing. Recent Advances: The contributions of chemokines to wound healing are a topic of active investigation. Recent discoveries have opened the possibility of targeting chemokines therapeutically to treat disease processes and improve healing capability, including the possibility of achieving a scarless phenotype in postnatal wounds. Critical Issues: Successful wound healing is a complex process, in which there is a significant interplay between multiple cell types, signaling molecules, growth factors, and extracellular matrix. Chemokines play a crucial role in this interplay and have been shown to have different effects in various stages of the healing process. Understanding how these chemokines are locally produced and regulated during wound healing and how the chemokine milieu differs in fetal versus postnatal wounds may help us identify ways in which we can target chemokine pathways. Future Directions: Further studies on the role of chemokines and their role in the healing process will greatly advance the potential for using these molecules as therapeutic targets. PMID:26543680

  2. Chemokine-Derived Peptides: Novel Antimicrobial and Antineoplasic Agents.

    PubMed

    Valdivia-Silva, Julio; Medina-Tamayo, Jaciel; Garcia-Zepeda, Eduardo A

    2015-01-01

    Chemokines are a burgeoning family of chemotactic cytokines displaying a broad array of functions such as regulation of homeostatic leukocyte traffic and development, as well as activating the innate immune system. Their role in controlling early and late inflammatory stages is now well recognized. An improper balance either in chemokine synthesis or chemokine receptor expression contributes to various pathological disorders making chemokines and their receptors a useful therapeutic target. Research in this area is progressing rapidly, and development of novel agents based on chemokine/ chemokine receptors antagonist functions are emerging as attractive alternative drugs. Some of these novel agents include generation of chemokine-derived peptides (CDP) with potential agonist and antagonist effects on inflammation, cancer and against bacterial infections. CDP have been generated mainly from N- and C-terminus chemokine sequences with subsequent modifications such as truncations or elongations. In this review, we present a glimpse of the different pharmacological actions reported for CDP and our current understanding regarding the potential use of CDP alone or as part of the novel therapies proposed in the treatment of microbial infections and cancer. PMID:26062132

  3. Chemokine-Derived Peptides: Novel Antimicrobial and Antineoplasic Agents

    PubMed Central

    Valdivia-Silva, Julio; Medina-Tamayo, Jaciel; Garcia-Zepeda, Eduardo A.

    2015-01-01

    Chemokines are a burgeoning family of chemotactic cytokines displaying a broad array of functions such as regulation of homeostatic leukocyte traffic and development, as well as activating the innate immune system. Their role in controlling early and late inflammatory stages is now well recognized. An improper balance either in chemokine synthesis or chemokine receptor expression contributes to various pathological disorders making chemokines and their receptors a useful therapeutic target. Research in this area is progressing rapidly, and development of novel agents based on chemokine/chemokine receptors antagonist functions are emerging as attractive alternative drugs. Some of these novel agents include generation of chemokine-derived peptides (CDP) with potential agonist and antagonist effects on inflammation, cancer and against bacterial infections. CDP have been generated mainly from N- and C-terminus chemokine sequences with subsequent modifications such as truncations or elongations. In this review, we present a glimpse of the different pharmacological actions reported for CDP and our current understanding regarding the potential use of CDP alone or as part of the novel therapies proposed in the treatment of microbial infections and cancer. PMID:26062132

  4. Chemokine-guided cell migration and motility in zebrafish development

    PubMed Central

    Bussmann, Jeroen; Raz, Erez

    2015-01-01

    Chemokines are vertebrate-specific, structurally related proteins that function primarily in controlling cell movements by activating specific 7-transmembrane receptors. Chemokines play critical roles in a large number of biological processes and are also involved in a range of pathological conditions. For these reasons, chemokines are at the focus of studies in developmental biology and of clinically oriented research aimed at controlling cancer, inflammation, and immunological diseases. The small size of the zebrafish embryos, their rapid external development, and optical properties as well as the large number of eggs and the fast expansion in genetic tools available make this model an extremely useful one for studying the function of chemokines and chemokine receptors in an in vivo setting. Here, we review the findings relevant to the role that chemokines play in the context of directed single-cell migration, primarily in neutrophils and germ cells, and compare it to the collective cell migration of the zebrafish lateral line. We present the current knowledge concerning the formation of the chemokine gradient, its interpretation within the cell, and the molecular mechanisms underlying the cellular response to chemokine signals during directed migration. PMID:25762592

  5. Chemokine Detection Using Receptors Immobilized on an SPR Sensor Surface.

    PubMed

    Rodríguez-Frade, José Miguel; Martínez-Muñoz, Laura; Villares, Ricardo; Cascio, Graciela; Lucas, Pilar; Gomariz, Rosa P; Mellado, Mario

    2016-01-01

    Chemokines and their receptors take part in many physiological and pathological processes, and their dysregulated expression is linked to chronic inflammatory and autoimmune diseases, immunodeficiencies, and cancer. The chemokine receptors, members of the G protein-coupled receptor family, are integral membrane proteins, with seven-transmembrane domains that bind the chemokines and transmit signals through GTP-binding proteins. Many assays used to study the structure, conformation, or activation mechanism of these receptors are based on ligand-binding measurement, as are techniques to detect new agonists and antagonists that modulate chemokine function. Such methods require labeling of the chemokine and/or its receptor, which can alter their binding characteristics. Surface plasmon resonance (SPR) is a powerful technique for analysis of the interaction between immobilized receptors and ligands in solution, in real time, and without labeling. SPR measurements nonetheless require expression and purification steps that can alter the conformation, stability, and function of the chemokine and/or the chemokine receptor. In this review, we focus on distinct methods to immobilize chemokine receptors on the surface of an optical biosensor. We expose the advantages and disadvantages of different protocols used and describe in detail the method to retain viral particles as receptor carriers that can be used for SPR determinations. PMID:26921939

  6. Chemokine decoy receptors: new players in reproductive immunology.

    PubMed

    Borroni, Elena Monica; Bonecchi, Raffaella; Buracchi, Chiara; Savino, Benedetta; Mantovani, Alberto; Locati, Massimo

    2008-01-01

    Chemokines are multifunctional molecules with roles in leukocyte trafficking and developmental processes. Both fetal and maternal components of the placenta produce chemokines, which control leukocyte trafficking observed in the placenta. Thus, chemokines play roles in the balance between protection of the developing embryo/fetus and tolerance of its hemiallogeneic tissues. Recently, a group of chemokine receptors, which include D6, DARC, and CCX-CKR, have been described as "silent" receptors by virtue of their inability to activate signal transduction events leading to cell chemoattraction. Here we review in vitro and in vivo evidence indicating that chemokine "silent" receptors regulate innate and adaptive immunity behaving as decoy receptors that support internalization and degradation of chemotactic factors, and discuss available information on their potential role in reproductive immunology. PMID:18716935

  7. Production of Recombinant Chemokines and Validation of Refolding.

    PubMed

    Veldkamp, Christopher T; Koplinski, Chad A; Jensen, Davin R; Peterson, Francis C; Smits, Kaitlin M; Smith, Brittney L; Johnson, Scott K; Lettieri, Christina; Buchholz, Wallace G; Solheim, Joyce C; Volkman, Brian F

    2016-01-01

    The diverse roles of chemokines in normal immune function and many human diseases have motivated numerous investigations into the structure and function of this family of proteins. Recombinant chemokines are often used to study how chemokines coordinate the trafficking of immune cells in various biological contexts. A reliable source of biologically active protein is vital for any in vitro or in vivo functional analysis. In this chapter, we describe a general method for the production of recombinant chemokines and robust techniques for efficient refolding that ensure consistently high biological activity. Considerations for initiating development of protocols consistent with Current Good Manufacturing Practices (cGMPs) to produce biologically active chemokines suitable for use in clinical trials are also discussed. PMID:26921961

  8. The expression and role of CXC chemokines in colorectal cancer.

    PubMed

    Verbeke, Hannelien; Struyf, Sofie; Laureys, Geneviève; Van Damme, Jo

    2011-01-01

    Cancer is a life-threatening disease world-wide and colorectal cancer is the second common cause of cancer mortality. The interaction between tumor cells and stromal cells plays a crucial role in tumor initiation and progression and is partially mediated by chemokines. Chemokines predominantly participate in the chemoattraction of leukocytes to inflammatory sites. Nowadays, it is clear that CXC chemokines and their receptors (CXCR) may also modulate tumor behavior by several important mechanisms: regulation of angiogenesis, activation of a tumor-specific immune response by attracting leukocytes, stimulation of tumor cell proliferation and metastasis. Here, we review the expression and complex roles of CXC chemokines (CXCL1 to CXCL16) and their receptors (CXCR1 to CXCR6) in colorectal cancer. Overall, increased expression levels of CXC chemokines correlate with poor prognosis. PMID:22000992

  9. Differential Chemokine Signature between Human Preadipocytes and Adipocytes

    PubMed Central

    Ignacio, Rosa Mistica C.; Gibbs, Carla R.; Lee, Eun-Sook

    2016-01-01

    Obesity is characterized as an accumulation of adipose tissue mass represented by chronic, low-grade inflammation. Obesity-derived inflammation involves chemokines as important regulators contributing to the pathophysiology of obesity-related diseases such as cardiovascular disease, diabetes and some cancers. The obesity-driven chemokine network is poorly understood. Here, we identified the profiles of chemokine signature between human preadipocytes and adipocytes, using PCR arrays and qRT-PCR. Both preadipocytes and adipocytes showed absent or low levels in chemokine receptors in spite of some changes. On the other hand, the chemokine levels of CCL2, CCL7-8, CCL11, CXCL1-3, CXCL6 and CXCL10-11 were dominantly expressed in preadipocytes compared to adipocytes. Interestingly, CXCL14 was the most dominant chemokine expressed in adipocytes compared to preadipocytes. Moreover, there is significantly higher protein level of CXCL14 in conditioned media from adipocytes. In addition, we analyzed the data of the chemokine signatures in adipocytes obtained from healthy lean and obese postmenopausal women based on Gene Expression Omnibus (GEO) dataset. Adipocytes from obese individuals had significantly higher levels in chemokine signature as follows: CCL2, CCL13, CCL18-19, CCL23, CCL26, CXCL1, CXCL3 and CXCL14, as compared to those from lean ones. Also, among the chemokine networks, CXCL14 appeared to be the highest levels in adipocytes from both lean and obese women. Taken together, these results identify CXCL14 as an important chemokine induced during adipogenesis, requiring further research elucidating its potential therapeutic benefits in obesity. PMID:27340388

  10. Atlantic cod (Gadus morhua) CC chemokines: Diversity and expression analysis.

    PubMed

    Borza, Tudor; Stone, Cynthia; Rise, Matthew L; Bowman, Sharen; Johnson, Stewart C

    2010-08-01

    Chemokines are a large, diverse group of small cytokines that can be classified into several families, including the CC chemokines that are characterized by two adjacent cysteines near their amino terminus. CC chemokines play a pivotal role in host defense mechanisms by inducing leukocyte chemotaxis under physiological and inflammatory conditions. Analysis of CC chemokines from teleost fishes indicates that the number of CC chemokine genes and their tissue expression patterns vary largely in this group of vertebrates. Here we describe 32 distinct CC chemokine sequences from Atlantic cod (Gadus morhua) identified by analysis of approximately 206,000 ESTs. Phylogenetic analysis of Atlantic cod CC chemokines placed these sequences in seven clusters, most likely resulting from species-specific gene duplications, and two unique sequences; 12 of these CC chemokines, including at least one member of each cluster, were analyzed by QPCR using four immune-related tissues (head kidney, liver, spleen and blood) obtained from unstimulated, polyriboinosinic polyribocytidylic acid (pIC)-stimulated and formalin-killed atypical Aeromonas salmonicida-stimulated individuals. EST abundance and QPCR analysis indicate that the expression of closely related CC chemokines GmSCYA101 and GmSCYA102, GmSCYA108 and GmSCYA109 or GmSCYA122 and GmSCYA124 can be highly tissue-specific despite substantial sequence identity. Stimulation with the viral mimic pIC or formalin-killed atypical A. salmonicida resulted in increased expression of most of the CC chemokines, indicating that they can be regarded as either inducible (inflammatory) or dual-function rather than constitutive (homeostatic). Tissue specificity, and the level of induction, varied broadly; for example, GmSCYA123 was at least 4-fold up-regulated by both inducers in all tissues analyzed, whereas pIC increased the expression of GmSCYA124 in liver over 1500 times. PMID:20381521

  11. Differential Chemokine Signature between Human Preadipocytes and Adipocytes.

    PubMed

    Ignacio, Rosa Mistica C; Gibbs, Carla R; Lee, Eun-Sook; Son, Deok-Soo

    2016-06-01

    Obesity is characterized as an accumulation of adipose tissue mass represented by chronic, low-grade inflammation. Obesity-derived inflammation involves chemokines as important regulators contributing to the pathophysiology of obesity-related diseases such as cardiovascular disease, diabetes and some cancers. The obesity-driven chemokine network is poorly understood. Here, we identified the profiles of chemokine signature between human preadipocytes and adipocytes, using PCR arrays and qRT-PCR. Both preadipocytes and adipocytes showed absent or low levels in chemokine receptors in spite of some changes. On the other hand, the chemokine levels of CCL2, CCL7-8, CCL11, CXCL1-3, CXCL6 and CXCL10-11 were dominantly expressed in preadipocytes compared to adipocytes. Interestingly, CXCL14 was the most dominant chemokine expressed in adipocytes compared to preadipocytes. Moreover, there is significantly higher protein level of CXCL14 in conditioned media from adipocytes. In addition, we analyzed the data of the chemokine signatures in adipocytes obtained from healthy lean and obese postmenopausal women based on Gene Expression Omnibus (GEO) dataset. Adipocytes from obese individuals had significantly higher levels in chemokine signature as follows: CCL2, CCL13, CCL18-19, CCL23, CCL26, CXCL1, CXCL3 and CXCL14, as compared to those from lean ones. Also, among the chemokine networks, CXCL14 appeared to be the highest levels in adipocytes from both lean and obese women. Taken together, these results identify CXCL14 as an important chemokine induced during adipogenesis, requiring further research elucidating its potential therapeutic benefits in obesity. PMID:27340388

  12. Ionizing radiation increases adhesiveness of human aortic endothelial cells via a chemokine-dependent mechanism.

    PubMed

    Khaled, Saman; Gupta, Kiran B; Kucik, Dennis F

    2012-05-01

    Exposure to radiation from a variety of sources is associated with increased risk of heart disease and stroke. Since radiation also induces inflammation, a possible mechanism is a change in the adhesiveness of vascular endothelial cells, triggering pro-atherogenic accumulation of leukocytes. To investigate this mechanism at the cellular level, the effect of X rays on adhesiveness of cultured human aortic endothelial cells (HAECs) was determined. HAECs were grown as monolayers and exposed to 0 to 30 Gy X rays, followed by measurement of adhesiveness under physiological shear stress using a flow chamber adhesion assay. Twenty-four hours after irradiation, HAEC adhesiveness was increased, with a peak effect at 15 Gy. Radiation had no significant effect on surface expression of the endothelial adhesion molecules ICAM-1 and VCAM-1. Antibody blockade of the leukocyte integrin receptors for ICAM-1 and VCAM-1, however, abolished the radiation-induced adhesiveness. Since these leukocyte integrins can be activated by chemokines presented on the endothelial cell surface, the effect of pertussis toxin (PTX), an inhibitor of chemokine-mediated integrin activation, was tested. PTX specifically inhibited radiation-induced adhesiveness, with no significant effect on nonirradiated cells. Therefore, radiation induces increased adhesiveness of aortic endothelial cells through chemokine-dependent signaling from endothelial cells to leukocytes, even in the absence of increased expression of the adhesion molecules involved. PMID:22087741

  13. The Chemokine MIP-1α/CCL3 impairs mouse hippocampal synaptic transmission, plasticity and memory

    PubMed Central

    Marciniak, Elodie; Faivre, Emilie; Dutar, Patrick; Alves Pires, Claire; Demeyer, Dominique; Caillierez, Raphaëlle; Laloux, Charlotte; Buée, Luc; Blum, David; Humez, Sandrine

    2015-01-01

    Chemokines are signaling molecules playing an important role in immune regulations. They are also thought to regulate brain development, neurogenesis and neuroendocrine functions. While chemokine upsurge has been associated with conditions characterized with cognitive impairments, their ability to modulate synaptic plasticity remains ill-defined. In the present study, we specifically evaluated the effects of MIP1-α/CCL3 towards hippocampal synaptic transmission, plasticity and spatial memory. We found that CCL3 (50 ng/ml) significantly reduced basal synaptic transmission at the Schaffer collateral-CA1 synapse without affecting NMDAR-mediated field potentials. This effect was ascribed to post-synaptic regulations, as CCL3 did not impact paired-pulse facilitation. While CCL3 did not modulate long-term depression (LTD), it significantly impaired long-term potentiation (LTP), an effect abolished by Maraviroc, a CCR5 specific antagonist. In addition, sub-chronic intracerebroventricular (icv) injections of CCL3 also impair LTP. In accordance with these electrophysiological findings, we demonstrated that the icv injection of CCL3 in mouse significantly impaired spatial memory abilities and long-term memory measured using the two-step Y-maze and passive avoidance tasks. These effects of CCL3 on memory were inhibited by Maraviroc. Altogether, these data suggest that the chemokine CCL3 is an hippocampal neuromodulator able to regulate synaptic plasticity mechanisms involved in learning and memory functions. PMID:26511387

  14. Nitric Oxide Donors Suppress Chemokine Production by Keratinocytes in Vitro and in Vivo

    PubMed Central

    Giustizieri, Maria Laura; Albanesi, Cristina; Scarponi, Claudia; De Pità, Ornella; Girolomoni, Giampiero

    2002-01-01

    Nitric oxide (NO) is involved in the modulation of inflammatory responses. In psoriatic skin, NO is highly produced by epidermal keratinocytes in response to interferon-γ and tumor necrosis factor-α. In this study, we investigated whether the NO donors, S-nitrosoglutathione (GS-NO) and NOR-1, could regulate chemokine production by human keratinocytes activated with interferon-γ and tumor necrosis factor-α. In addition, we studied the effects of the topical application of a GS-NO ointment on chemokine expression in lesional psoriatic skin. NO donors diminished in a dose-dependent manner and at both mRNA and protein levels the IP-10, RANTES, and MCP-1 expression in keratinocytes cultured from healthy patients and psoriatic patients. In contrast, constitutive and induced interleukin-8 production was unchanged. GS-NO-treated psoriatic skin showed reduction of IP-10, RANTES, and MCP-1, but not interleukin-8 expression by keratinocytes. Moreover, the number of CD14+ and CD3+ cells infiltrating the epidermis and papillary dermis diminished significantly. NO donors also down-regulated ICAM-1 protein expression without affecting mRNA accumulation in vitro, and suppressed keratinocyte ICAM-1 in vivo. Finally, NO donors inhibited nuclear factor-κB and STAT-1, but not AP-1 activities in transiently transfected keratinocytes. These results define NO donors as negative regulators of chemokine production by keratinocytes. PMID:12368213

  15. Overexpression of GAB2 in ovarian cancer cells promotes tumor growth and angiogenesis by upregulating chemokine expression

    PubMed Central

    Duckworth, C; Zhang, L; Carroll, S L; Ethier, S P; Cheung, H W

    2016-01-01

    We previously found that the scaffold adapter GRB2-associated binding protein 2 (GAB2) is amplified and overexpressed in a subset of primary high-grade serous ovarian cancers and cell lines. Ovarian cancer cells overexpressing GAB2 are dependent on GAB2 for activation of the phosphatidylinositol 3-kinase (PI3K) pathway and are sensitive to PI3K inhibition. In this study, we show an important role of GAB2 overexpression in promoting tumor angiogenesis by upregulating expression of multiple chemokines. Specifically, we found that suppression of GAB2 by inducible small hairpin RNA in ovarian cancer cells inhibited tumor cell proliferation, angiogenesis and peritoneal tumor growth in immunodeficient mice. Overexpression of GAB2 upregulated the secretion of several chemokines from ovarian cancer cells, including CXCL1, CXCL2 and CXCL8. The secreted chemokines not only signal through endothelial CXCR2 receptor in a paracrine manner to promote endothelial tube formation, but also act as autocrine growth factors for GAB2-induced transformation of fallopian tube secretory epithelial cells and clonogenic growth of ovarian cancer cells overexpressing GAB2. Pharmacological inhibition of inhibitor of nuclear factor kappa-B kinase subunit β (IKKβ), but not PI3K, mechanistic target of rapamycin (mTOR) or mitogen-activated protein kinase (MEK), could effectively suppress GAB2-induced chemokine expression. Inhibition of IKKβ augmented the efficacy of PI3K/mTOR inhibition in suppressing clonogenic growth of ovarian cancer cells with GAB2 overexpression. Taken together, these findings suggest that overexpression of GAB2 in ovarian cancer cells promotes tumor growth and angiogenesis by upregulating expression of CXCL1, CXCL2 and CXCL8 that is IKKβ-dependent. Co-targeting IKKβ and PI3K pathways downstream of GAB2 might be a promising therapeutic strategy for ovarian cancer that overexpresses GAB2. PMID:26657155

  16. Overexpression of GAB2 in ovarian cancer cells promotes tumor growth and angiogenesis by upregulating chemokine expression.

    PubMed

    Duckworth, C; Zhang, L; Carroll, S L; Ethier, S P; Cheung, H W

    2016-08-01

    We previously found that the scaffold adapter GRB2-associated binding protein 2 (GAB2) is amplified and overexpressed in a subset of primary high-grade serous ovarian cancers and cell lines. Ovarian cancer cells overexpressing GAB2 are dependent on GAB2 for activation of the phosphatidylinositol 3-kinase (PI3K) pathway and are sensitive to PI3K inhibition. In this study, we show an important role of GAB2 overexpression in promoting tumor angiogenesis by upregulating expression of multiple chemokines. Specifically, we found that suppression of GAB2 by inducible small hairpin RNA in ovarian cancer cells inhibited tumor cell proliferation, angiogenesis and peritoneal tumor growth in immunodeficient mice. Overexpression of GAB2 upregulated the secretion of several chemokines from ovarian cancer cells, including CXCL1, CXCL2 and CXCL8. The secreted chemokines not only signal through endothelial CXCR2 receptor in a paracrine manner to promote endothelial tube formation, but also act as autocrine growth factors for GAB2-induced transformation of fallopian tube secretory epithelial cells and clonogenic growth of ovarian cancer cells overexpressing GAB2. Pharmacological inhibition of inhibitor of nuclear factor kappa-B kinase subunit β (IKKβ), but not PI3K, mechanistic target of rapamycin (mTOR) or mitogen-activated protein kinase (MEK), could effectively suppress GAB2-induced chemokine expression. Inhibition of IKKβ augmented the efficacy of PI3K/mTOR inhibition in suppressing clonogenic growth of ovarian cancer cells with GAB2 overexpression. Taken together, these findings suggest that overexpression of GAB2 in ovarian cancer cells promotes tumor growth and angiogenesis by upregulating expression of CXCL1, CXCL2 and CXCL8 that is IKKβ-dependent. Co-targeting IKKβ and PI3K pathways downstream of GAB2 might be a promising therapeutic strategy for ovarian cancer that overexpresses GAB2. PMID:26657155

  17. Differential expression of chemokines, chemokine receptors and proteinases by foreign body giant cells (FBGCs) and osteoclasts.

    PubMed

    Khan, Usman A; Hashimi, Saeed M; Khan, Shershah; Quan, Jingjing; Bakr, Mahmoud M; Forwood, Mark R; Morrison, Nigel M

    2014-07-01

    Osteoclasts and foreign body giant cells (FBGCs) are both derived from the fusion of macropahges. These cells are seen in close proximity during foreign body reactions, therefore it was assumed that they might interact with each other. The aim was to identify important genes that are expressed by osteoclasts and FBGCs which can be used to understand peri-implantitis and predict the relationship of these cells during foreign body reactions. Bone marrow macrophages (BMM) were treated with receptor activator of nuclear factor kappa B ligand (RANKL) to produce osteoclasts. Quantitative PCR (qPCR) was used to identify the genes that were expressed by osteoclasts and FBGCs compared to macrophage controls. TRAP staining was used to visualise the cells while gelatine zymography and western blots were used for protein expression. Tartrate-resistant acid phosphatase (TRAP), matrix metallo proteinase 9 (MMP9), nuclear factor of activated T cells 1 (NFATc1), cathepsin K (CTSK) and RANK were significantly lower in FBGCs compared to osteoclasts. Inflammation specific chemokines such as monocyte chemotactic protein (MCP1 also called CCL2), macrophage inflammatory protein 1 alpha (MIP1α), MIP1β and MIP1γ, and their receptors CCR1, CCR3 and CCR5, were highly expressed by FBGCs. FBGCs were negative for osteoclast specific markers (RANK, NFATc1, CTSK). FBGCs expressed chemokines such as CCL2, 3, 5 and 9 while osteoclasts expressed the receptors for these chemokines i.e. CCR1, 2 and 3. Our findings show that osteoclast specific genes are not expressed by FBGCs and that FBGCs interact with osteoclasts during foreign body reaction through chemokines. PMID:24500983

  18. The Role of Chemokines in Breast Cancer Pathology and Its Possible Use as Therapeutic Targets

    PubMed Central

    Palacios-Arreola, M. Isabel; Nava-Castro, Karen E.; Castro, Julieta I.; García-Zepeda, Eduardo; Carrero, Julio C.; Morales-Montor, Jorge

    2014-01-01

    Chemokines are small proteins that primarily regulate the traffic of leukocytes under homeostatic conditions and during specific immune responses. The chemokine-chemokine receptor system comprises almost 50 chemokines and approximately 20 chemokine receptors; thus, there is no unique ligand for each receptor and the binding of different chemokines to the same receptor might have disparate effects. Complicating the system further, these effects depend on the cellular milieu. In cancer, although chemokines are associated primarily with the generation of a protumoral microenvironment and organ-directed metastasis, they also mediate other phenomena related to disease progression, such as angiogenesis and even chemoresistance. Therefore, the chemokine system is becoming a target in cancer therapeutics. We review the emerging data and correlations between chemokines/chemokine receptors and breast cancer, their implications in cancer progression, and possible therapeutic strategies that exploit the chemokine system. PMID:25165728

  19. TLR3 activation increases chemokine expression in human fetal airway smooth muscle cells.

    PubMed

    Faksh, Arij; Britt, Rodney D; Vogel, Elizabeth R; Thompson, Michael A; Pandya, Hitesh C; Martin, Richard J; Pabelick, Christina M; Prakash, Y S

    2016-01-15

    Viral infections, such as respiratory syncytial virus and rhinovirus, adversely affect neonatal and pediatric populations, resulting in significant lung morbidity, including acute asthma exacerbation. Studies in adults have demonstrated that human airway smooth muscle (ASM) cells modulate inflammation through their ability to secrete inflammatory cytokines and chemokines. The role of ASM in the developing airway during infection remains undefined. In our study, we used human fetal ASM cells as an in vitro model to examine the effect of Toll-like receptor (TLR) agonists on chemokine secretion. We found that fetal ASM express multiple TLRs, including TLR3 and TLR4, which are implicated in the pathogenesis of respiratory syncytial virus and rhinovirus infection. Cells were treated with TLR agonists, polyinosinic-polycytidylic acid [poly(I:C)] (TLR3 agonist), lipopolysaccharide (TLR4 agonist), or R848 (TLR7/8 agonist), and IL-8 and chemokine (C-C motif) ligand 5 (CCL5) secretion were evaluated. Interestingly, poly(I:C), but neither lipopolysaccharide nor R848, increased IL-8 and chemokine (C-C motif) ligand 5 secretion. Examination of signaling pathways suggested that the poly(I:C) effects in fetal ASM involve TLR and ERK signaling, in addition to another major inflammatory pathway, NF-κB. Moreover, there are variations between fetal and adult ASM with respect to poly(I:C) effects on signaling pathways. Pharmacological inhibition suggested that ERK pathways mediate poly(I:C) effects. Overall, our data show that poly(I:C) initiates activation of proinflammatory pathways in developing ASM, which may contribute to immune responses to infection and exacerbation of asthma. PMID:26589477

  20. Chemokine genetic polymorphism in human health and disease.

    PubMed

    Qidwai, Tabish

    2016-08-01

    Chemokine receptor-ligand interaction regulates transmigration of lymphocytes and monocytes from circulation to the inflammatory sites. CC chemokine receptors, chemokine receptor 2(CCR2) and 5 (CCR5) are important in recruitment of immune cells as well as non-immune cells under pathological condition. CCR2, CCR5 and their ligands (CCL2 and CCL5) are major contributor to the autoimmune and inflammatory diseases and cancer. Currently studies are being done to explore genetic variations in chemokine genes and their involvement in diseases that could make clear disease severity and deaths. Conflicting results of studies in different populations and diseases promoted to investigate chemokines genetic polymorphisms in miscellaneous diseases. This study is aimed to evaluate the influence of chemokines genetic polymorphisms in pathogenesis and outcome of prevalent non infectious diseases. Present study demonstrates the likely role played by genetic variations in drug response and evolution. Moreover this study highlights chemokine as therapeutic target and diagnostic biomarker in pathological condition. PMID:27262929

  1. The protein phosphatase inhibitor calyculin A stimulates chemokine production by human synovial cells.

    PubMed Central

    Jordan, N J; Watson, M L; Westwick, J

    1995-01-01

    Cultured human synovial fibroblasts express mRNA for the chemotactic cytokines (chemokines) interleukin-8 (IL-8), monocyte chemotactic protein 1 (MCP-1) and regulated upon activation normal T-cell expressed and presumably secreted (RANTES), when stimulated with IL-1 or tumour necrosis factor alpha (TNF alpha). Calyculin A, a potent type 1/2A protein serine/threonine phosphatase inhibitor, was used to examine the role of protein phosphatases in the regulation of chemokine gene expression. Calyculin A (1 nM) mimicked IL-1 by inducing IL-8 and MCP-1 mRNA expression in synovial cells. IL-8 mRNA was induced over a similar time period (1-6 h) in response to IL-1 or calyculin A, whereas MCP-1 mRNA was induced more rapidly (1-2 h) by calyculin A than by IL-1 (4-6 h). Expression of RANTES mRNA occurred in response to TNF alpha, but could not be induced by stimulation with calyculin A alone. These results suggest that inhibition of protein phosphatase type 1/2A may have a differential role in the regulation of the expression of each of the chemokine genes. Synovial fibroblasts also secreted IL-8 and IL-6 peptide when stimulated with either IL-1/TNF alpha or calyculin A. The amount of IL-8 and IL-6 peptide produced in response to calyculin A was significantly increased above that produced by untreated synovial cells, though it was much less than the amount induced by IL-1 or TNF alpha. Calyculin A also acted synergistically with IL-1 or TNF alpha to cause a 2-fold potentiation of IL-1- or TNF alpha-induced IL-8 mRNA and peptide and RANTES mRNA expression. These results suggest that although inhibition of a protein phosphatase may be able to regulate the magnitude of IL-1-induced chemokine gene expression, the IL-1 signal transduction pathway involves components in addition to phosphatase inhibition, possibly including the activation of a protein kinase, the action of which may be opposed by a protein phosphatase inhibited by calyculin A. Images Figure 1 Figure 2 Figure 3

  2. Microglial Kv1.3 Channels and P2Y12 Receptors Differentially Regulate Cytokine and Chemokine Release from Brain Slices of Young Adult and Aged Mice

    PubMed Central

    Eder, Claudia

    2015-01-01

    Brain tissue damage following stroke or traumatic brain injury is accompanied by neuroinflammatory processes, while microglia play a central role in causing and regulating neuroinflammation via production of proinflammatory substances, including cytokines and chemokines. Here, we used brain slices, an established in situ brain injury model, from young adult and aged mice to investigate cytokine and chemokine production with particular focus on the role of microglia. Twenty four hours after slice preparation, higher concentrations of proinflammatory cytokines, i.e. TNF-α and IL-6, and chemokines, i.e. CCL2 and CXCL1, were released from brain slices of aged mice than from slices of young adult mice. However, maximal microglial stimulation with LPS for 24 h did not reveal age-dependent differences in the amounts of released cytokines and chemokines. Mechanisms underlying microglial cytokine and chemokine production appear to be similar in young adult and aged mice. Inhibition of microglial Kv1.3 channels with margatoxin reduced release of IL-6, but not release of CCL2 and CXCL1. In contrast, blockade of microglial P2Y12 receptors with PSB0739 inhibited release of CCL2 and CXCL1, whereas release of IL-6 remained unaffected. Cytokine and chemokine production was not reduced by inhibitors of Kir2.1 K+ channels or adenosine receptors. In summary, our data suggest that brain tissue damage-induced production of cytokines and chemokines is age-dependent, and differentially regulated by microglial Kv1.3 channels and P2Y12 receptors. PMID:26011191

  3. Gene profile of chemokines on hepatic stellate cells of schistosome-infected mice and antifibrotic roles of CXCL9/10 on liver non-parenchymal cells.

    PubMed

    Liang, Yue-jin; Luo, Jie; Lu, Qiao; Zhou, Ying; Wu, Hai-wei; Zheng, Dan; Ren, Yong-ya; Sun, Ke-yi; Wang, Yong; Zhang, Zhao-song

    2012-01-01

    Hepatic stellate cells (HSCs) play a key role in the development of liver fibrosis caused by schistosomiasis. Chemokines were widely expressed and involved in cellular activation, proliferation and migration in inflammatory and infectious diseases. However, little is known about the expressions of chemokines on HSCs in the schistosoma infection. In addition, the roles of chemokines in pathogenesis of liver fibrosis are not totally clear. In our study, we used microarray to analyze the temporal gene expressions of primary HSCs isolated from mice with both acute and chronic schistosomiasis. Our microarray data showed that most of the chemokines expressed on HSCs were upregulated at 3 weeks post-infection (p.i) when the egg granulomatous response was not obviously evoked in the liver. However, some of them like CXCL9, CXCL10 and CXCL11 were subsequently decreased at 6 weeks p.i when the granulomatous response reached the peak. In the chronic stage, most of the differentially expressed chemokines maintained persistent high-abundances. Furthermore, several chemokines including CCR2, CCR5, CCR7, CXCR3, CXCR4, CCL2, CCL5, CCL21, CXCL9 and CXCL10 were expressed by HCSs and the abundances of them were changed following the praziquantel treatment in the chronic stage, indicating that chemokines were possibly necessary for the persistence of the chronic stage. In vitro experiments, hepatic non-parenchymal cells, primary HSCs and human HSCs line LX-2 were stimulated by chemokines. The results showed that CXCL9 and CXCL10, but not CXCL11 or CXCL4, significantly inhibited the gene expressions of Col1α1, Col3α1 and α-SMA, indicating the potential anti-fibrosis effect of CXCL9 and CXCL10 in schistosomiasis. More interestingly, soluble egg antigen (SEA) of Schistosoma japonicum was able to inhibit transcriptional expressions of some chemokines by LX-2 cells, suggesting that SEA was capable of regulating the expression pattern of chemokine family and modulating the hepatic immune

  4. Comparison of hardwood and softwood dust-induced expression of cytokines and chemokines in mouse macrophage RAW 264.7 cells.

    PubMed

    Määttä, Juha; Luukkonen, Ritva; Husgafvel-Pursiainen, Kirsti; Alenius, Harri; Savolainen, Kai

    2006-01-20

    Numerous epidemiological studies have shown that occupational exposure to wood dust can induce several respiratory diseases such as allergic rhinitis, chronic bronchitis, asthma, and sino-nasal adenocarcinoma. However, comparison of the harmful potential of different wood dust species on the basis of epidemiological studies is complicated because in the occupational environment workers are usually exposed to several wood dust species simultaneously. In the present study, we have characterized and compared the effects of two hardwood dusts, beech and teak, and two softwood dusts, pine and spruce, on cytokine and chemokine expression utilizing an in vitro model, murine macrophage cell line RAW 264.7. The expression patterns of selected cytokines and chemokines were assessed by real-time quantitative PCR and by ELISA. All the tested hardwood and softwood dusts induced TNF-alpha expression and inhibited IL-1beta expression. Similarly, all the wood dusts induced the expression of CCL2, CCL3, CCL4, and CXCL2/3 chemokines and inhibited CCL24 expression. Our results indicate that both hardwood and softwood dusts influence the cytokine and chemokine expression of RAW 264.7 cells. Although some differences could be detected in the magnitude of responses to different wood dust species, the two tested wood dust groups, hardwoods and softwoods, have quite similar effects on cytokine and chemokine expression in RAW 264.7 cell line. PMID:16202497

  5. Functions of the chemokine receptor CXCR4 in the central nervous system and its regulation by μ-opioid receptors.

    PubMed

    Nash, Bradley; Meucci, Olimpia

    2014-01-01

    Activation of the G protein-coupled receptor CXCR4 by its chemokine ligand CXCL12 regulates a number of physiopathological functions in the central nervous system, during development as well as later in life. In addition to the more classical roles of the CXCL12/CXCR4 axis in the recruitment of immune cells or migration and proliferation of neural precursor cells, recent studies suggest that CXCR4 signaling also modulates synaptic function and neuronal survival in the mature brain, through direct and indirect effects on neurons and glia. These effects, which include regulation of glutamate receptors and uptake, and of dendritic spine density, can significantly alter the ability of neurons to face excitotoxic insults. Therefore, they are particularly relevant to neurodegenerative diseases featuring alterations of glutamate neurotransmission, such as HIV-associated neurocognitive disorders. Importantly, CXCR4 signaling can be dysregulated by HIV viral proteins, host HIV-induced factors, and opioids. Potential mechanisms of opioid regulation of CXCR4 include heterologous desensitization, transcriptional regulation and changes in receptor expression levels, opioid-chemokine receptor dimer or heteromer formation, and the newly described modulation by the protein ferritin heavy chain-all leading to inhibition of CXCR4 signaling. After reviewing major effects of chemokines and opioids in the CNS, this chapter discusses chemokine-opioid interactions in neuronal and immune cells, focusing on their potential contribution to HIV-associated neurocognitive disorders. PMID:25175863

  6. Comprehensive analysis of chemokine-induced cAMP-inhibitory responses using a real-time luminescent biosensor.

    PubMed

    Felouzis, Virginia; Hermand, Patricia; de Laissardière, Guy Trambly; Combadière, Christophe; Deterre, Philippe

    2016-01-01

    Chemokine receptors are members of the G-protein-coupled receptor (GPCR) family coupled to members of the Gi class, whose primary function is to inhibit the cellular adenylate cyclase. We used a cAMP-related and PKA-based luminescent biosensor (GloSensor™ F-22) to monitor the real-time downstream response of chemokine receptors, especially CX3CR1 and CXCR4, after activation with their cognate ligands CX3CL1 and CXCL12. We found that the amplitudes and kinetic profiles of the chemokine responses were conserved in various cell types and were independent of the nature and concentration of the molecules used for cAMP prestimulation, including either the adenylate cyclase activator forskolin or ligands mediating Gs-mediated responses like prostaglandin E2 or beta-adrenergic agonist. We conclude that the cAMP chemokine response is robustly conserved in various inflammatory conditions. Moreover, the cAMP-related luminescent biosensor appears as a valuable tool to analyze the details of Gi-mediated cAMP-inhibitory cellular responses, even in native conditions and could help to decipher their precise role in cell function. PMID:26515128

  7. Differential Expression of Chemokine Receptors and their Roles in Cancer Imaging

    PubMed Central

    Nimmagadda, Sridhar

    2012-01-01

    Chemokine/chemokine receptor interactions play diverse roles in cell migration and homeostasis. Emerging evidence suggests that cancer cells co-opt chemokine networks for survival, proliferation, immune evasion, and metastasis. Most of the chemokine receptors are reported to be involved in tumor progression. Given their extensive implication in cancer progression, several chemokine receptor/ligand axes are considered as potential therapeutic targets. This review provides a survey of chemokine receptor expression in cancer and evaluates the potential of chemokine receptor imaging as a tool for molecular characterization of cancer. PMID:22662317

  8. Angiogenic CXC chemokine expression during differentiation of human mesenchymal stem cells towards the osteoblastic lineage.

    PubMed

    Bischoff, D S; Zhu, J H; Makhijani, N S; Kumar, A; Yamaguchi, D T

    2008-02-15

    The potential role of ELR(+) CXC chemokines in early events in bone repair was studied using human mesenchymal stem cells (hMSCs). Inflammation, which occurs in the initial phase of tissue healing in general, is critical to bone repair. Release of cytokines from infiltrating immune cells and injured bone can lead to recruitment of MSCs to the region of repair. CXC chemokines bearing the Glu-Leu-Arg (ELR) motif are also released by inflammatory cells and serve as angiogenic factors stimulating chemotaxis and proliferation of endothelial cells. hMSCs, induced to differentiate with osteogenic medium (OGM) containing ascorbate, beta-glycerophosphate (beta-GP), and dexamethasone (DEX), showed an increase in mRNA and protein secretion of the ELR(+) CXC chemokines CXCL8 and CXCL1. CXCL8 mRNA half-life studies reveal an increase in mRNA stability upon OGM stimulation. Increased expression and secretion is a result of DEX in OGM and is dose-dependent. Inhibition of the glucocorticoid receptor with mifepristone only partially inhibits DEX-stimulated CXCL8 expression indicating both glucocorticoid receptor dependent and independent pathways. Treatment with signal transduction inhibitors demonstrate that this expression is due to activation of the ERK and p38 mitogen-activated protein kinase (MAPK) pathways and is mediated through the G(alphai)-coupled receptors. Angiogenesis assays demonstrate that OGM-stimulated conditioned media containing secreted CXCL8 and CXCL1 can induce angiogenesis of human microvascular endothelial cells in an in vitro Matrigel assay. PMID:17583554

  9. Neutrophil chemokines in epithelial inflammatory processes of human tonsils

    PubMed Central

    Sachse, F; Ahlers, F; Stoll, W; Rudack, C

    2005-01-01

    CXC chemokines are thought to play an important role at sites of inflammation. Because ELR+ CXC chemokines are expressed in different types of tonsillitis we investigated the role of the surface/crypt epithelium of human tonsils in producing ELR+ CXC chemokines: interleukin (IL)-8 (CXCL8), ENA-78 (CXCL5), GRO-α (CXCL1) and GCP-2 (CXCL6). Tonsillar tissue was obtained from patients undergoing tonsillectomy and chemokine expression was investigated by means of immunohistochemistry. A549 cells were used as a model to study kinetics of chemokine expression in epithelial cells. Cells were stimulated with tumour necrosis factor (TNF)-α, lipopolysaccharide (LPS) and supernatants derived from aerobic/anaerobic Staphylococcus aureus strains. Chemokine expression was measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). We observed epithelial expression of IL-8, GRO-α and GCP-2 in different types of tonsillitis, whereas ENA-78 was rarely expressed. In A549 cells abundant expression of ENA-78 was detected. IL-8 and GCP-2 are expressed in an acute type of tonsillitis whereas GRO-α was frequently detectable both in chronically and acutely inflamed tonsils. ENA-78 does not seem to play a pivotal role in tonsillitis in vivo. PMID:15807854

  10. Emerging Concepts and Approaches for Chemokine-Receptor Drug Discovery

    PubMed Central

    O’Hayre, Morgan; Salanga, Catherina L.; Handel, Tracy M.; Hamel, Damon J.

    2010-01-01

    Importance of the field Chemokine receptors are G protein-coupled receptors (GPCRs) most noted for their role in cell migration. However, inappropriate utilization or regulation of these receptors is implicated in many inflammatory diseases, cancer and HIV, making them important drug targets. Areas covered in this review Allostery, oligomerization, and ligand bias are presented as they pertain to chemokine receptors and their associated pathologies. Specific examples of each are described from the recent literature and their implications are discussed in terms of drug discovery efforts targeting chemokine receptors. What the reader will gain Insight into the expanding view of the multitude of pharmacological variables that need to be considered or that may be exploited in chemokine receptor drug discovery. Take home message Since 2007, two drugs targeting chemokine receptors have been approved by the FDA, Maraviroc for preventing HIV infection and Mozobil™ for hematopoietic stem cell mobilization. While these successes permit optimism for chemokine receptors as drug targets, only recently has the complexity of this system begun to be appreciated. The concepts of allosteric inhibitors, biased ligands and functional selectivity raise the possibility that drugs with precisely-defined properties can be developed. Other complexities such as receptor oligomerization and tissue-specific functional states of receptors also offer opportunities for increased target and response specificity, although it will be more challenging to translate these ideas into approved therapeutics compared to traditional approaches. PMID:21132095

  11. Differential chemokine responses in the murine brain following lyssavirus infection.

    PubMed

    Hicks, D J; Núñez, A; Banyard, A C; Williams, A; Ortiz-Pelaez, A; Fooks, A R; Johnson, N

    2013-11-01

    The hallmark of lyssavirus infection is lethal encephalomyelitis. Previous studies have reported distinct lyssavirus isolate-related differences in severity of cellular recruitment into the encephalon in a murine model of infection following peripheral inoculation with rabies virus (RABV) and European bat lyssavirus (EBLV)-1 and -2. In order to understand the role of chemokines in this process, comparative studies of the chemokine pattern, distribution and production in response to infection with these lyssaviruses were undertaken. Expression of CCL2, CCL5 and CXCL10 was observed throughout the murine brain with a distinct caudal bias in distribution, similar to both inflammatory changes and virus antigen distribution. CCL2 immunolabelling was localized to neuronal and astroglial populations. CCL5 immunolabelling was only detected in the astroglia, while CXCL10 labelling, although present in the astroglia, was more prominent in neurons. Isolate-dependent differences in the amount of chemokine immunolabelling in specific brain regions and chemokine production by neurons in vitro were observed, with a greater expression of CCL5 in vivo and CXCL10 production in vitro after EBLV infection. Additionally, strong positive associations between chemokine immunolabelling and perivascular cuffing and, to a lesser extent, virus antigen score were also observed. These differences in chemokine expression may explain the variation in severity of encephalitic changes observed in animals infected with different lyssavirus isolates. PMID:23746482

  12. Impaired lymphoid chemokine-mediated migration due to a block on the chemokine receptor switch in human cytomegalovirus-infected dendritic cells.

    PubMed

    Moutaftsi, Magdalena; Brennan, Paul; Spector, Stephen A; Tabi, Zsuzsanna

    2004-03-01

    Dendritic cell (DC) migration from the site of infection to the site of T-cell priming is a crucial event in the generation of antiviral T-cell responses. Here we present to our knowledge the first functional evidence that human cytomegalovirus (HCMV) blocks the migration of infected monocyte-derived DCs toward lymphoid chemokines CCL19 and CCL21. DC migration is blocked by viral impairment of the chemokine receptor switch at the level of the expression of CCR7 molecules. The inhibition occurs with immediate-early-early kinetics, and viral interference with NF-kappaB signaling is likely to be at least partially responsible for the lack of CCR7 expression. DCs which migrate from the infected cultures are HCMV antigen negative, and consequently they do not stimulate HCMV-specific CD8(+) T cells, while CD4(+)-T-cell activation is not impaired. Although CD8(+) T cells can also be activated by alternative antigen presentation mechanisms, the spatial segregation of naive T cells and infected DCs seems a potent mechanism of delaying the generation of primary CD8(+)-T-cell responses and aiding early viral spread. PMID:14990723

  13. Impaired Lymphoid Chemokine-Mediated Migration due to a Block on the Chemokine Receptor Switch in Human Cytomegalovirus-Infected Dendritic Cells

    PubMed Central

    Moutaftsi, Magdalena; Brennan, Paul; Spector, Stephen A.; Tabi, Zsuzsanna

    2004-01-01

    Dendritic cell (DC) migration from the site of infection to the site of T-cell priming is a crucial event in the generation of antiviral T-cell responses. Here we present to our knowledge the first functional evidence that human cytomegalovirus (HCMV) blocks the migration of infected monocyte-derived DCs toward lymphoid chemokines CCL19 and CCL21. DC migration is blocked by viral impairment of the chemokine receptor switch at the level of the expression of CCR7 molecules. The inhibition occurs with immediate-early-early kinetics, and viral interference with NF-κB signaling is likely to be at least partially responsible for the lack of CCR7 expression. DCs which migrate from the infected cultures are HCMV antigen negative, and consequently they do not stimulate HCMV-specific CD8+ T cells, while CD4+-T-cell activation is not impaired. Although CD8+ T cells can also be activated by alternative antigen presentation mechanisms, the spatial segregation of naive T cells and infected DCs seems a potent mechanism of delaying the generation of primary CD8+-T-cell responses and aiding early viral spread. PMID:14990723

  14. Neolignans from the Arils of Myristica fragrans as Potent Antagonists of CC Chemokine Receptor 3.

    PubMed

    Morikawa, Toshio; Hachiman, Ikuko; Matsuo, Kazuhiko; Nishida, Eriko; Ninomiya, Kiyofumi; Hayakawa, Takao; Yoshie, Osamu; Muraoka, Osamu; Nakayama, Takashi

    2016-08-26

    CC chemokine receptor 3 (CCR3) is expressed selectively in eosinophils, basophils, and some Th2 cells and plays a major role in allergic diseases. A methanol extract from the arils of Myristica fragrans inhibited CC chemokine ligand 11-induced chemotaxis in CCR3-expressing L1.2 cells at 100 μg/mL. From this extract, eight new neolignans, maceneolignans A-H (1-8), were isolated, and their stereostructures were elucidated from their spectroscopic values and chemical properties. Of those constituents, compounds 1, 4, 6, and 8 and (+)-erythro-(7S,8R)-Δ(8')-7-hydroxy-3,4-methylenedioxy-3',5'-dimethoxy-8-O-4'-neolignan (11), (-)-(8R)-Δ(8')-3,4-methylenedioxy-3',5'-dimethoxy-8-O-4'-neolignan (17), (+)-licarin A (20), nectandrin B (25), verrucosin (26), and myristicin (27) inhibited CCR3-mediated chemotaxis at a concentration of 1 μM. Among them, 1 (EC50 1.6 μM), 6 (1.5 μM), and 8 (1.4 μM) showed relatively strong activities, which were comparable to that of a synthetic CCR3 selective antagonist, SB328437 (0.78 μM). PMID:27419473

  15. M-sec regulates polarized secretion of inflammatory endothelial chemokines and facilitates CCL2-mediated lymphocyte transendothelial migration.

    PubMed

    Barzilai, Sagi; Blecher-Gonen, Ronnie; Barnett-Itzhaki, Zohar; Zauberman, Ayelet; Lebel-Haziv, Yaeli; Amit, Ido; Alon, Ronen

    2016-06-01

    Activation of endothelial cells by IL-1β triggers the expression of multiple inflammatory cytokines and leukocyte-attracting chemokines. The machineries involved in the secretion of these inducible proteins are poorly understood. With the use of genome-wide transcriptional analysis of inflamed human dermal microvascular endothelial cells, we identified several IL-1β-induced candidate regulators of these machineries and chose to focus our study on TNF-α-induced protein 2 (myeloid-secretory). The silencing of myeloid-secretory did not affect the ability of inflamed endothelial cells to support the adhesion and crawling of effector T lymphocytes. However, the ability of these lymphocytes to complete transendothelial migration across myeloid-secretory-silenced human dermal microvascular endothelial cells was inhibited significantly. These observed effects on lymphocyte transendothelial migration were recovered completely when exogenous promigratory chemokine CXCL12 was overlaid on the endothelial barrier. A polarized secretion assay suggested that the silencing of endothelial myeloid-secretory impairs T effector transendothelial migration by reducing the preferential secretion of endothelial-produced CCL2, a key transendothelial migration-promoting chemokine for these lymphocytes, into the basolateral endothelial compartment. Myeloid-secretory silencing also impaired the preferential secretion of other endothelial-produced inflammatory chemokines, as well as cytokines, such as IL-6 and GM-CSF, into the basolateral endothelial compartment. This is the first evidence of a novel inflammation-inducible machinery that regulates polarized secretion of endothelial CCL2 and other inflammatory chemokines and cytokines into basolateral endothelial compartments and facilitates the ability of endothelial CCL2 to promote T cell transendothelial migration. PMID:26701136

  16. Characterization of oak and birch dust-induced expression of cytokines and chemokines in mouse macrophage RAW 264.7 cells.

    PubMed

    Määttä, Juha; Majuri, Marja-Leena; Luukkonen, Ritva; Lauerma, Antti; Husgafvel-Pursiainen, Kirsti; Alenius, Harri; Savolainen, Kai

    2005-11-01

    Occupational exposure to wood dust is related to several respiratory diseases, such as allergic rhinitis, chronic bronchitis, and asthma. However, virtually nothing is known about molecular mechanisms behind wood dust-induced pulmonary inflammation. To elucidate the effects of wood dust exposure on cytokine and chemokine expression in murine macrophage cell line cells, mouse RAW 264.7 cells were exposed to two selected hardwood dusts, oak and birch. TiO2 and LPS were used as controls. Expression patterns of several cytokines, chemokines, and chemokine receptors were assessed by real-time quantitative PCR system and by ELISA. Exposure to birch dust caused a major increase in TNF-alpha and IL-6 protein levels whereas a weaker induction of TNF-alpha protein was found after exposure to oak dust. Inorganic TiO2 dust did not induce significant cytokine expression. With respect to the chemokines, a dose-dependent, about 10-fold induction of CCL2 mRNA and protein was found after exposure to birch dust. Oak dust induced weakly CCL2 protein. Similarly, birch dust induced a strong expression of CCL3, CCL4, and CXCL2/3 mRNA whereas only moderate levels of these chemokine mRNAs were detected after oak dust exposure. In contrast, expression of CCL24 mRNA was inhibited by more than 40-fold by both oak and birch dusts. TiO2 dust induced about five-fold expression of CCL3 and CCL4 mRNA but did not affect significantly other chemokines. These results suggest that exposure to birch or oak dusts may influence the development of the inflammatory process in the airways by modulating the expression of macrophage-derived cytokines and chemokines. PMID:16122864

  17. High-dose hydrocortisone reduces expression of the pro-inflammatory chemokines CXCL8 and CXCL10 in SARS coronavirus-infected intestinal cells.

    PubMed

    Cinatl, Jindrich; Michaelis, Martin; Morgenstern, Birgit; Doerr, Hans Wilhelm

    2005-02-01

    Clinical observations and our high-density oligonucleotide microarray results demonstrated increased expression of proinflammatory chemokines after SARS-CoV infection. Here, we investigated the influence of SARS-CoV infection on CXCL8 (interleukin 8) and CXCL10 (interferon-gamma-inducible protein 10) in human intestinal epithelial (Caco2) cells. RT-PCR and ELISA showed time-dependent up-regulation of both chemokines after SARS-CoV infection. Electric mobility shift assay revealed increased DNA binding activity of the cellular transcription factors activator protein 1 (AP-1) and nuclear factor (B (NF-kappaB) in SARS-CoV infected cells. High hydrocortisone concentrations (> or =50 microg/ml) completely prevented increased DNA binding activity of AP-1 and NF-kappaB and inhibited up-regulation of CXCL8 and CXCL10, but did not reduce chemokine expression to basal levels. Ribavirin that does not inhibit SARS-CoV replication in Vero cells inhibited SARS-CoV replication in Caco2 cells at therapeutical concentrations. Hydrocortisone neither influenced SARS-CoV titres alone nor in combination with ribavirin. Our results show that corticosteroids may be of limited benefit in the suppression of chemokine production by SARS-CoV-infected cells. PMID:15647850

  18. Evasin-4, a tick-derived chemokine-binding protein with broad selectivity can be modified for use in preclinical disease models.

    PubMed

    Déruaz, Maud; Bonvin, Pauline; Severin, India C; Johnson, Zoë; Krohn, Sonja; Power, Christine A; Proudfoot, Amanda E I

    2013-10-01

    Rhipicephalus sanguineus, the common brown dog tick, produces several chemokine-binding proteins which are secreted into the host in its saliva to modulate the host response during feeding. Two of these demonstrate very restricted selectivity profiles. Here, we describe the characterization of the third, which we named Evasin-4. Evasin-4 was difficult to produce recombinantly using its native signal peptide in HEK cells, but expressed very well using the urokinase-type plasminogen activator signal peptide. Using SPR, Evasin-4 was shown to bind most CC chemokines. Investigation of the neutralization properties by inhibition of chemokine-induced chemotaxis showed that binding and neutralization did not correlate in all cases. Two major anomalies were observed: no binding was observed to CCL2 and CCL13, yet Evasin-4 was able to inhibit chemotaxis induced by these chemokines. Conversely, binding to CCL25 was observed, but Evasin-4 did not inhibit CCL25-induced chemotaxis. Size-exclusion chromatography confirmed that Evasin-4 forms a complex with CCL2 and CCL18. In accordance with the standard properties of unmodified small proteins, Evasin-4 was rapidly cleared following in vivo administration. To enhance the in vivo half-life and optimize its potential as a therapeutic agent, Fc fusions of Evasin-4 were created. Both the N- and C-terminal fusions were shown to retain binding activity, with the C-terminal fusion showing a modest reduction in potency. PMID:23910450

  19. Chemokine expression is upregulated in chondrocytes in diabetic fracture healing.

    PubMed

    Alblowi, Jazia; Tian, Chen; Siqueira, Michelle F; Kayal, Rayyan A; McKenzie, Erin; Behl, Yugal; Gerstenfeld, Louis; Einhorn, Thomas A; Graves, Dana T

    2013-03-01

    Chemokines are thought to play an important role in several aspects of bone metabolism including the recruitment of leukocytes and the formation of osteoclasts. We investigated the impact of diabetes on chemokine expression in normal and diabetic fracture healing. Fracture of the femur was performed in streptozotocin-induced diabetic and matched normoglycemic control mice. Microarray analysis was carried out and chemokine mRNA levels in vivo were assessed. CCL4 were examined in fracture calluses by immunohistochemistry and the role of TNF in diabetes-enhanced expression was investigated by treatment of animals with the TNF-specific inhibitor, pegsunercept. In vitro studies were conducted with ATDC5 chondrocytes. Diabetes significantly upregulated mRNA levels of several chemokines in vivo including CCL4, CCL8, CCL6, CCL11, CCL20, CCL24, CXCL2, CXCL5 and chemokine receptors CCR5 and CXCR4. Chondrocytes were identified as a significant source of CCL4 and its expression in diabetic fractures was dependent on TNF (P<0.05). TNF-α significantly increased mRNA levels of several chemokines in vitro which were knocked down with FOXO1 siRNA (P<0.05). CCL4 expression at the mRNA and proteins levels was induced by FOXO1 over-expression and reduced by FOXO1 knockdown. The current studies point to the importance of TNF-α as a mechanism for diabetes enhanced chemokine expression by chondrocytes, which may contribute to the accelerated loss of cartilage observed in diabetic fracture healing. Moreover, in vitro results point to FOXO1 as a potentially important transcription factor in mediating this effect. PMID:23262028

  20. Selected CC and CXC chemokines in children with atopic asthma

    PubMed Central

    Machura, Edyta; Mazur, Bogdan; Chrobak, Ewelina; Ziora, Katarzyna; Ziora, Dariusz; Kasperska-Zajac, Alicja

    2016-01-01

    Introduction There are only limited data on CC and CXC chemokines regulation in children with asthma. Aim We compared the serum profile of selected CC and CXC chemokines in patients with atopic asthma and healthy children. Material and methods Serum concentration of CC chemokines RANTES, MCP-1, and CXC chemokines IP-10, MIG, IL-8, RANTES was measured using cytometric bead array in 44 children with atopic asthma and 17 healthy subjects. Results The concentration of RANTES was significantly higher and the MIG level was lower in all children with asthma as compared to their control counterparts. We observed increased RANTES and decreased MIG levels also in patients with stable asthma when compared with children in the control group. The IP-10 concentration was similar between the whole asthma group and healthy controls, while significantly increased levels of this chemokine in acute asthma have been observed when compared to stable asthma. For MCP-1 and IL-8, the serum concentration was similar in all compared groups. The MIG concentration correlated positively with IP-10, IL-8, and CRP levels and negatively with the eosinophil count. A negative correlation between the IP-10 and eosinophil count and a negative correlation between FEV1 and IP-10 were found. Conclusions An increased serum RANTES level in children with asthma may result in enhancement of Th2 lymphocyte recruitment into the airway. A decreased expression of Th1 chemokine MIG in children with stable asthma may contribute to a diminished antagonizing effect on Th2 cytokine production and hence intensify Th2 predominance. An increased IP-10 level in children during an asthma attack suggest that this chemokine is a serological marker of disease exacerbation. PMID:27279817

  1. Biased and G Protein-Independent Signaling of Chemokine Receptors

    PubMed Central

    Steen, Anne; Larsen, Olav; Thiele, Stefanie; Rosenkilde, Mette M.

    2014-01-01

    Biased signaling or functional selectivity occurs when a 7TM-receptor preferentially activates one of several available pathways. It can be divided into three distinct forms: ligand bias, receptor bias, and tissue or cell bias, where it is mediated by different ligands (on the same receptor), different receptors (with the same ligand), or different tissues or cells (for the same ligand–receptor pair). Most often biased signaling is differentiated into G protein-dependent and β-arrestin-dependent signaling. Yet, it may also cover signaling differences within these groups. Moreover, it may not be absolute, i.e., full versus no activation. Here we discuss biased signaling in the chemokine system, including the structural basis for biased signaling in chemokine receptors, as well as in class A 7TM receptors in general. This includes overall helical movements and the contributions of micro-switches based on recently published 7TM crystals and molecular dynamics studies. All three forms of biased signaling are abundant in the chemokine system. This challenges our understanding of “classic” redundancy inevitably ascribed to this system, where multiple chemokines bind to the same receptor and where a single chemokine may bind to several receptors – in both cases with the same functional outcome. The ubiquitous biased signaling confers a hitherto unknown specificity to the chemokine system with a complex interaction pattern that is better described as promiscuous with context-defined roles and different functional outcomes in a ligand-, receptor-, or cell/tissue-defined manner. As the low number of successful drug development plans implies, there are great difficulties in targeting chemokine receptors; in particular with regard to receptor antagonists as anti-inflammatory drugs. Un-defined and putative non-selective targeting of the complete cellular signaling system could be the underlying cause of lack of success. Therefore, biased ligands could be the solution

  2. The chemokine (C-C motif) ligand protein synthesis inhibitor bindarit prevents cytoskeletal rearrangement and contraction of human mesangial cells.

    PubMed

    Paccosi, Sara; Giachi, Matelda; Di Gennaro, Paola; Guglielmotti, Angelo; Parenti, Astrid

    2016-09-01

    Intraglomerular mesangial cells (MCs) maintain structural and functional integrity of renal glomerular microcirculation and homeostasis of mesangial matrix. Following different types of injury, MCs change their phenotype upregulating the expression of α-smooth muscle actin (α-SMA), changing contractile abilities and increasing the production of matrix proteins, chemokines and cytokines. CCL2 is a chemokine known to be involved in the pathogenesis of renal diseases. Its glomerular upregulation correlates with the extent of renal damage. Bindarit is an indazolic derivative endowed with anti-inflammatory activity when tested in experimental diseases. It selectively inhibits the synthesis of inflammatory C-C chemokines including CCL2, CCL7 and CCL8. This work aims to analyse bindarit effects on ET1-, AngII- and TGFβ-induced mesangial cell dysfunction. Bindarit significantly reduced AngII-, ET1- and TGFβ-induced α-SMA upregulation. In a collagen contraction assay, bindarit reduced AngII-, ET1- and TGFβ-induced HRMC contraction. Within 3-6h stimulation, vinculin organization and phosphorylation was significantly impaired by bindarit in AngII-, ET1- and TGFβ-stimulated cells without any effect on F-actin distribution. Conversely, p38 phosphorylation was not significantly inhibited by bindarit. Our data strengthen the importance of CCL2 on ET-1, AngII- and TGFβ-induced mesangial cell dysfunction, adding new insights into the cellular mechanisms responsible of bindarit protective effects in human MC dysfunction. PMID:27309675

  3. The chemokine system in arteriogenesis and hind limb ischemia.

    PubMed

    Shireman, Paula K

    2007-06-01

    Chemokines (chemotactic cytokines) are important in the recruitment of leukocytes to injured tissues and, as such, play a pivotal role in arteriogenesis and the tissue response to ischemia. Hind limb ischemia represents a complex model with arteriogenesis (collateral artery formation) occurring in tissues with normal perfusion while areas exhibiting ischemic necrosis undergo angiogenesis and skeletal muscle regeneration; monocytes and macrophages play an important role in all three of these processes. In addition to leukocyte trafficking, chemokines are produced by and chemokine receptors are present on diverse cell types, including myoblasts, endothelial, and smooth muscle cells. Thus, the chemokine system may have direct effects as well as inflammatory-mediated effects on arteriogenesis, angiogenesis, and skeletal muscle regeneration. This article reviews the complexity of the hind limb ischemia model and the role of the chemokine system in arteriogenesis and the tissue response to ischemia. Special emphasis will be placed on the roles of monocytes/macrophages and CCL2/monocyte chemotactic protein-1 (MCP-1) in these processes. PMID:17544024

  4. Chemokines and the Signaling Modules Regulating Integrin Affinity

    PubMed Central

    Montresor, Alessio; Toffali, Lara; Constantin, Gabriela; Laudanna, Carlo

    2012-01-01

    Integrin-mediated adhesion is a general concept referring to a series of adhesive phenomena including tethering–rolling, affinity, valency, and binding stabilization altogether controlling cell avidity (adhesiveness) for the substrate. Arrest chemokines modulate each aspect of integrin activation, although integrin affinity regulation has been recognized as the prominent event in rapid leukocyte arrest induced by chemokines. A variety of inside-out and outside-in signaling mechanisms have been related to the process of integrin-mediated adhesion in different cellular models, but only few of them have been clearly contextualized to rapid integrin affinity modulation by arrest chemokines in primary leukocytes. Complex signaling processes triggered by arrest chemokines and controlling leukocyte integrin activation have been described for ras-related rap and for rho-related small GTPases. We summarize the role of rap and rho small GTPases in the regulation of rapid integrin affinity in primary leukocytes and provide a modular view of these pro-adhesive signaling events. A potential, albeit still speculative, mechanism of rho-mediated regulation of cytoskeletal proteins controlling the last step of integrin activation is also discussed. We also discuss data suggesting a functional integration between the rho- and rap-modules of integrin activation. Finally we examine the universality of signaling mechanisms regulating integrin triggering by arrest chemokines. PMID:22654882

  5. The sweet spot: how GAGs help chemokines guide migrating cells.

    PubMed

    Monneau, Yoan; Arenzana-Seisdedos, Fernando; Lortat-Jacob, Hugues

    2016-06-01

    Glycosaminoglycans are polysaccharides that occur both at the cell surface and within extracellular matrices. Through their ability to bind to a large array of proteins, almost 500 of which have been identified to date, including most chemokines, these molecules regulate key biologic processes at the cell-tissue interface. To do so, glycosaminoglycans can provide scaffolds to ensure that proteins mediating specific functions will be presented at the correct site and time and can also directly contribute to biologic activities or signaling processes. The binding of chemokines to glycosaminoglycans, which, at the biochemical level, has been mostly studied using heparin, has traditionally been thought of as a mechanism for maintaining haptotactic gradients within tissues along which cells can migrate directionally. Many aspects of chemokine-glycosaminoglycan interactions, however, also suggest that the formation of these complexes could serve additional purposes that go well beyond a simple immobilization process. In addition, progress in glycobiology has revealed that glycosaminoglycan structures, in term of length, sulfation, and epimerization pattern, are specific for cell, tissue, and developmental stage. Glycosaminoglycan regulation and glycosaminoglycan diversity, which cannot be replicated using heparin, thus suggests that these molecules may fine-tune the immune response by selectively recruiting specific chemokines to cell surfaces. In this context, the aim of the present text is to review the chemokine-glycosaminoglycan complexes described to date and provide a critical analysis of the tools, molecules, and strategies that can be used to structurally and functionally investigate the formation of these complexes. PMID:26701132

  6. Chemokines and their receptors in the allergic airway inflammatory process.

    PubMed

    Velazquez, Juan Raymundo; Teran, Luis Manuel

    2011-08-01

    The development of the allergic airway disease conveys several cell types, such as T-cells, eosinophils, mast cells, and dendritic cells, which act in a special and temporal synchronization. Cellular mobilization and its complex interactions are coordinated by a broad range of bioactive mediators known as chemokines. These molecules are an increasing family of small proteins with common structural motifs and play an important role in the recruitment and cell activation of both leukocytes and resident cells at the allergic inflammatory site via their receptors. Trafficking and recruitment of cell populations with specific chemokines receptors assure the presence of reactive allergen-specific T-cells in the lung, and therefore the establishment of an allergic inflammatory process. Different approaches directed against chemokines receptors have been developed during the last decades with promising therapeutic results in the treatment of asthma. In this review we explore the role of the chemokines and chemokine receptors in allergy and asthma and discuss their potential as targets for therapy. PMID:20352527

  7. DISTINCT CONFORMATIONS OF THE CHEMOKINE RECEPTOR CCR4 WITH IMPLICATIONS FOR ITS TARGETING IN ALLERGY

    PubMed Central

    Viney, Jonathan M.; Andrew, David P.; Phillips, Rhian M.; Meiser, Andrea; Patel, Pallavi; Lennartz-Walker, Melissa; Cousins, David J.; Barton, Nicholas P.; Hall, David A.; Pease, James E.

    2014-01-01

    The chemokine receptor CCR4 is expressed by Th2 and Tregs and directs their migration along gradients of the chemokines CCL17 and CCL22. Both chemokines and receptor are upregulated in allergic disease, making CCR4 a therapeutic target for the treatment of allergy. We set out to assess the mechanisms underlying a previous report that CCL22 is a dominant ligand of CCR4, which may have implications for its therapeutic targeting. Human T-cells expressing endogenous CCR4 and transfectants engineered to express CCR4 were assessed for receptor function using assays of calcium release, chemotaxis, receptor endocytosis and ligand binding. Despite the two ligands having equal potency in calcium flux and chemotaxis assays, CCL22 showed dominance in both receptor endocytosis assays and heterologous competitive binding assays. Using two different CCR4-specific antibodies, we showed that CCR4 exists in at least two distinct conformations, which are differentially activated by ligand. A major population is activated by both CCL17 and CCL22, whilst a minor population is activated only by CCL22. Mutation of a single C-terminal residue K310 within a putative CCR4 antagonist binding site, ablated activation of CCR4 by CCL17 but not by CCL22, despite having no effect on the binding of either ligand. We conclude that CCL17 and CCL22 are conformationally selective ligands of CCR4 and interact with the receptor by substantially different mechanisms. This suggests that the selective blockade of CCR4 in allergy may be feasible where one CCR4 ligand dominates, allowing the inhibition of Th2 signalling via one ligand whilst sparing Treg recruitment via another. PMID:24563252

  8. The chemokines CCR1 and CCRL2 have a role in colorectal cancer liver metastasis.

    PubMed

    Akram, Israa G; Georges, Rania; Hielscher, Thomas; Adwan, Hassan; Berger, Martin R

    2016-02-01

    C-C chemokine receptor type 1 (CCR1) and chemokine C-C motif receptor-like 2 (CCRL2) have not yet been sufficiently investigated for their role in colorectal cancer (CRC). Here, we investigated their expression in rat and human CRC samples, their modulation of expression in a rat liver metastasis model, as well as the effects on cellular properties resulting from their knockdown. One rat and five human colorectal cancer cell lines were used. CC531 rat colorectal cells were injected via the portal vein into rats and re-isolated from rat livers after defined periods. Following mRNA isolation, the gene expression was investigated by microarray. In addition, all cell lines were screened for mRNA expression of CCR1 and CCRL2 by reverse transcription polymerase chain reaction (RT-PCR). Cell lines with detectable expression were used for knockdown experiments; and the respective influence was determined on the cells' proliferation, scratch closure, and colony formation. Finally, specimens from the primaries of 50 patients with CRC were monitored by quantitative RT-PCR for CCR1 and CCRL2 expression levels. The microarray studies showed peak increases of CCR1 and CCRL2 in the early phase of liver colonization. Knockdown was sufficient at mRNA but only moderate at protein levels and resulted in modest but significant inhibition of proliferation (p < 0.05), scratch closure, and colony formation (p < 0.05). All human CRC samples were positive for CCR1 and CCRL2 and showed a significant pairwise correlation (p < 0.0004), but there was no correlation with tumor stage or age of patients. In summary, the data point to an important role of CCR1 and CCRL2 under conditions of organ colonization and both chemokine receptors qualify as targets of treatment during early colorectal cancer liver metastasis. PMID:26383527

  9. Antimycotics suppress the Malassezia extract-induced production of CXC chemokine ligand 10 in human keratinocytes.

    PubMed

    Hau, Carren S; Kanda, Naoko; Makimura, Koichi; Watanabe, Shinichi

    2014-02-01

    Malassezia, a lipophilic yeast, exacerbates atopic dermatitis. Malassezia products can penetrate the disintegrated stratum corneum and encounter subcorneal keratinocytes in the skin of atopic dermatitis patients. Type 1 helper T (Th1) cells infiltrate chronic lesions with atopic dermatitis, and antimycotic agents improve its symptoms. We aimed to identify Malassezia-induced chemokines in keratinocytes and examine whether antimycotics suppressed this induction. Normal human keratinocytes were incubated with a Malassezia restricta extract and antimycotics. Chemokine expression was analyzed by enzyme-linked immunosorbent assays and real-time polymerase chain reaction. Signal transducer and activator of transcription (STAT)1 activity was examined by luciferase assays. The tyrosine-phosphorylation of STAT1 was analyzed by western blotting. The M. restricta extract increased the mRNA and protein expression of Th1-attracting CXC chemokine ligand (CXCL)10 and STAT1 activity and phosphorylation in keratinocytes, which was suppressed by a Janus kinase inhibitor. The antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine and amorolfine suppressed M. restricta extract-induced CXCL10 mRNA and protein expression and STAT1 activity and phosphorylation. These effects were similarly induced by 15-deoxy-Δ-(12,14) -prostaglandin J2 (15d-PGJ2 ), a prostaglandin D2 metabolite. Antimycotics increased the release of 15d-PGJ2 from keratinocytes. The antimycotic-induced suppression of CXCL10 production and STAT1 activity was counteracted by a lipocalin-type prostaglandin D synthase inhibitor. The antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine and amorolfine may suppress the M. restricta-induced production of CXCL10 by inhibiting STAT1 through an increase in 15d-PGJ2 production in keratinocytes. These antimycotics may block the Th1-mediated inflammation triggered by Malassezia in the chronic phase of atopic dermatitis. PMID

  10. Esophageal Squamous Cell Carcinoma Cells Modulate Chemokine Expression and Hyaluronan Synthesis in Fibroblasts.

    PubMed

    Kretschmer, Inga; Freudenberger, Till; Twarock, Sören; Yamaguchi, Yu; Grandoch, Maria; Fischer, Jens W

    2016-02-19

    The aim of this study was to characterize the interaction of KYSE-410, an esophageal squamous cell carcinoma cell line, and fibroblasts with respect to the extracellular matrix component hyaluronan (HA) and chemokine expression. KYSE-410 cells induced the mRNA expression of HA synthase 2 (Has2) in normal skin fibroblasts (SF) only in direct co-cultures. Parallel to Has2 mRNA, Has2 antisense RNA (Has2os2) was up-regulated in co-cultures. Knockdown of LEF1, a downstream target of Wnt signaling, abrogated Has2 and Has2os2 induction. After knockdown of Has2 in SF, significantly less α-smooth muscle actin expression was detected in co-cultures. Moreover, it was investigated whether the phenotype of KYSE-410 was affected in co-culture with SF and whether Has2 knockdown in SF had an impact on KYSE-410 cells in co-culture. However, no effects on epithelial-mesenchymal transition markers, proliferation, and migration were detected. In addition to Has2 mRNA, the chemokine CCL5 was up-regulated and CCL11 was down-regulated in SF in co-culture. Furthermore, co-cultures of KYSE-410 cells and cancer-associated fibroblasts (CAF) were investigated. Similar to SF, Has2 and Ccl5 were up-regulated and Ccl11 was down-regulated in CAF in co-culture. Importantly and in contrast to SF, inhibiting HA synthesis by 4-methylumbelliferone abrogated the effect of co-culture on Ccl5 in CAF. Moreover, HA was found to promote adhesion of CD4(+) but not CD8(+) cells to xenogaft tumor tissues. In conclusion, direct co-culture of esophageal squamous cell carcinoma and fibroblasts induced stromal HA synthesis via Wnt/LEF1 and altered the chemokine profile of stromal fibroblasts, which in turn may affect the tumor immune response. PMID:26699196

  11. Activation of prostaglandin E2-EP4 signaling reduces chemokine production in adipose tissue.

    PubMed

    Tang, Eva H C; Cai, Yin; Wong, Chi Kin; Rocha, Viviane Z; Sukhova, Galina K; Shimizu, Koichi; Xuan, Ge; Vanhoutte, Paul M; Libby, Peter; Xu, Aimin

    2015-02-01

    Inflammation of adipose tissue induces metabolic derangements associated with obesity. Thus, determining ways to control or inhibit inflammation in adipose tissue is of clinical interest. The present study tested the hypothesis that in mouse adipose tissue, endogenous prostaglandin E2 (PGE2) negatively regulates inflammation via activation of prostaglandin E receptor 4 (EP4). PGE2 (5-500 nM) attenuated lipopolysaccharide-induced mRNA and protein expression of chemokines, including interferon-γ-inducible protein 10 and macrophage-inflammatory protein-1α in mouse adipose tissue. A selective EP4 antagonist (L161,982) reversed, and two structurally different selective EP4 agonists [CAY10580 and CAY10598] mimicked these actions of PGE2. Adipose tissue derived from EP4-deficient mice did not display this response. These findings establish the involvement of EP4 receptors in this anti-inflammatory response. Experiments performed on adipose tissue from high-fat-fed mice demonstrated EP4-dependent attenuation of chemokine production during diet-induced obesity. The anti-inflammatory actions of EP4 became more important on a high-fat diet, in that EP4 activation suppressed a greater variety of chemokines. Furthermore, adipose tissue and systemic inflammation was enhanced in high-fat-fed EP4-deficient mice compared with wild-type littermates, and in high-fat-fed untreated C57BL/6 mice compared with mice treated with EP4 agonist. These findings provide in vivo evidence that PGE2-EP4 signaling limits inflammation. In conclusion, PGE2, via activation of EP4 receptors, functions as an endogenous anti-inflammatory mediator in mouse adipose tissue, and targeting EP4 may mitigate adipose tissue inflammation. PMID:25510249

  12. Production of CXC and CC chemokines by human antigen-presenting cells in response to Lassa virus or closely related immunogenic viruses, and in cynomolgus monkeys with lassa fever.

    PubMed

    Pannetier, Delphine; Reynard, Stéphanie; Russier, Marion; Carnec, Xavier; Baize, Sylvain

    2014-01-01

    The pathogenesis of Lassa fever (LF), a hemorrhagic fever endemic to West Africa, remains unclear. We previously compared Lassa virus (LASV) with its genetically close, but nonpathogenic homolog Mopeia virus (MOPV) and demonstrated that the strong activation of antigen-presenting cells (APC), including type I IFN production, observed in response to MOPV probably plays a crucial role in controlling infection. We show here that human macrophages (MP) produce large amounts of CC and CXC chemokines in response to MOPV infection, whereas dendritic cells (DC) release only moderate amounts of CXC chemokines. However, in the presence of autologous T cells, DCs produced CC and CXC chemokines. Chemokines were produced in response to type I IFN synthesis, as the levels of both mediators were strongly correlated and the neutralization of type I IFN resulted in an inhibition of chemokine production. By contrast, LASV induced only low levels of CXCL-10 and CXCL-11 production. These differences in chemokine production may profoundly affect the generation of virus-specific T-cell responses and may therefore contribute to the difference of pathogenicity between these two viruses. In addition, a recombinant LASV (rLASV) harboring the NP-D389A/G392A mutations, which abolish the inhibition of type I IFN response by nucleoprotein (NP), induced the massive synthesis of CC and CXC chemokines in both DC and MP, confirming the crucial role of arenavirus NP in immunosuppression and pathogenicity. Finally, we confirmed, using PBMC samples and lymph nodes obtained from LASV-infected cynomolgus monkeys, that LF was associated with high levels of CXC chemokine mRNA synthesis, suggesting that the very early synthesis of these mediators may be correlated with a favourable outcome. PMID:24421914

  13. Production of CXC and CC Chemokines by Human Antigen-Presenting Cells in Response to Lassa Virus or Closely Related Immunogenic Viruses, and in Cynomolgus Monkeys with Lassa Fever

    PubMed Central

    Russier, Marion; Carnec, Xavier; Baize, Sylvain

    2014-01-01

    The pathogenesis of Lassa fever (LF), a hemorrhagic fever endemic to West Africa, remains unclear. We previously compared Lassa virus (LASV) with its genetically close, but nonpathogenic homolog Mopeia virus (MOPV) and demonstrated that the strong activation of antigen-presenting cells (APC), including type I IFN production, observed in response to MOPV probably plays a crucial role in controlling infection. We show here that human macrophages (MP) produce large amounts of CC and CXC chemokines in response to MOPV infection, whereas dendritic cells (DC) release only moderate amounts of CXC chemokines. However, in the presence of autologous T cells, DCs produced CC and CXC chemokines. Chemokines were produced in response to type I IFN synthesis, as the levels of both mediators were strongly correlated and the neutralization of type I IFN resulted in an inhibition of chemokine production. By contrast, LASV induced only low levels of CXCL-10 and CXCL-11 production. These differences in chemokine production may profoundly affect the generation of virus-specific T-cell responses and may therefore contribute to the difference of pathogenicity between these two viruses. In addition, a recombinant LASV (rLASV) harboring the NP-D389A/G392A mutations, which abolish the inhibition of type I IFN response by nucleoprotein (NP), induced the massive synthesis of CC and CXC chemokines in both DC and MP, confirming the crucial role of arenavirus NP in immunosuppression and pathogenicity. Finally, we confirmed, using PBMC samples and lymph nodes obtained from LASV-infected cynomolgus monkeys, that LF was associated with high levels of CXC chemokine mRNA synthesis, suggesting that the very early synthesis of these mediators may be correlated with a favourable outcome. PMID:24421914

  14. Structural basis of the herpesvirus M3-chemokine interaction.

    PubMed

    Alcami, Antonio

    2003-05-01

    Viruses have been fighting the immune systems of their hosts for millions of years and have evolved evasion strategies to ensure their survival. Viruses can teach us efficient mechanisms to control the immune system, and this information can be used to design new strategies of immune modulation that we might apply to diminish immunopathological responses that cause human diseases. Large DNA viruses, such as poxviruses and herpesviruses, encode proteins that are secreted from infected cells, bind cytokines and neutralize their activity. A subgroup of these viral proteins binds chemokines, a complex family of cytokines that control the recruitment of cells to sites of infection and inflammation. One of the major unresolved questions in the field was to understand how these viral secreted proteins bind chemokines with high affinity, despite having no amino acid sequence similarity to the host chemokine receptors, which are seven-transmembrane-domain proteins that cannot be engineered as soluble proteins. PMID:12781515

  15. Chemokines as markers for parasite-induced inflammation and tumors.

    PubMed

    Trakatelli, C; Frydas, S; Hatzistilianou, M; Papadopoulos, E; Simeonidou, I; Founta, A; Paludi, D; Petrarca, C; Castellani, M L; Papaioannou, N; Salini, V; Conti, P; Kempuraj, D; Vecchiet, J

    2005-01-01

    Chemokines are a group of small secreted proteins (8-10 kDa) produced and released by a wide variety of cell types. They were originally described as mediators of leukocyte recruitment, which is essential in acute and chronic inflammation. They also play a critical role in many pathophysiological processes such as allergic responses, infections and autoimmune diseases, tumor growth and hematopoietic development. This review introduces the three supergene families of chemokines (CXC, CC and C) with emphasis on their important role in different states in humans and in animal models with parasitic diseases. The concentration of transcription and translation of the cytokines and chemokines in the parasitic diseases may be an important marker for evaluation of the inflammatory state. PMID:16398400

  16. Chemokines as Potential Markers in Pediatric Renal Diseases

    PubMed Central

    Simões e Silva, Ana Cristina; Pereira, André Barreto; Teixeira, Mauro Martins; Teixeira, Antônio Lúcio

    2014-01-01

    Glomerular diseases and obstructive uropathies are the two most frequent causes of chronic kidney disease (CKD) in children. Recently, biomarkers have become a focus of clinical research as potentially useful diagnostic tools in pediatric renal diseases. Among several putative biomarkers, chemokines emerge as promising molecules since they play relevant roles in the pathophysiology of pediatric renal diseases. The evaluation of these inflammatory mediators might help in the management of diverse renal diseases in children and the detection of patients at high risk to develop CKD. The aim of this paper is to revise general aspects of chemokines and the potential link between chemokines and the most common pediatric renal diseases by including experimental and clinical evidence. PMID:24692841

  17. RelB regulation of chemokine expression modulates local inflammation.

    PubMed Central

    Xia, Y.; Pauza, M. E.; Feng, L.; Lo, D.

    1997-01-01

    The resolution of acute inflammation is incompletely understood but presumably requires the elimination of both inflammatory cells and production of inflammatory cytokines. In the case of recruited bone-marrow-derived inflammatory cells such as granulocytes and macrophages, their short life span helps eliminate these cells and the cytokines they produce. By contrast, resident permanent cells such as fibroblasts require other mechanisms to stop the production of chemokines generated in response to inflammatory triggers such as lipopolysaccharide. Here we demonstrate that RelB is an important regulator of chemokine expression in fibroblasts, thereby playing a key role in the resolution of acute inflammation. Activation of normal fibroblasts by lipopolysaccharide induced a transient production of chemokines, closely followed by induction of RelB expression. However, stimulated RelB-/- fibroblasts exhibited dramatic persistent induction of seven chemokines (RANTES, MIP-1 alpha, MIP-1 beta, MIP-2, IP-10, JE/MCP-1, and KC/CINC). The persistent overexpression of chemokines correlated with increased NF- kappa B binding as well as with increased p50, p65/RelA, and I kappa B alpha expression. Transfection of RelB cDNA into RelB-deficient fibroblasts reversed the lipopolysaccharide-induced chemokine overexpression. In vivo, activated RelB-/- fibroblasts dramatically increased recruitment of granulocytes into tissues. In view of the apparent role of RelB in the resolution of acute inflammation in tissues and previous work showing a requirement for RelB in the initiation of immune responses through the differentiation of antigen-presenting cells, RelB may be an important factor regulating the transition from innate to adaptive immunity. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 PMID:9250151

  18. A meta-analysis of chemokines in major depression.

    PubMed

    Eyre, Harris A; Air, Tracy; Pradhan, Alyssa; Johnston, James; Lavretsky, Helen; Stuart, Michael J; Baune, Bernhard T

    2016-07-01

    Chemokines are increasingly recognised as playing a role in depression. Here we meta-analyse the data on concentrations of all chemokines in patients diagnosed with a major depression versus healthy controls. We included studies which utilised Diagnostic and Statistical Manual (DSM)-IV diagnostic criteria for major depression, participants free from major medical conditions, studies with healthy controls, and unstimulated measurements of chemokines. We only included chemokines which had ≥3 studies performed. Two chemokines and 15 studies in total met criteria for this meta-analysis; 8 for Monocyte Chemotactic Protein (MCP)-1/CCL2 (n=747), and 7 for Interleukin (IL)-8/CXCL8 (n=560). There were significantly higher concentrations of CCL2/MCP-1 in depressed subjects compared with control subjects - overall mean difference of 36.43pg/mL (95% CI: 2.43 to 70.42). There was significant heterogeneity across these studies (I2=98.5%). The estimates of mean difference between the control and depression groups did not remain significant when the trim-and-fill procedure was used to correct for publication bias. There was no significant difference in concentrations of IL-8/CXCL8 in depressed subjects compared with control subjects. Significant heterogeneity was found across these studies (I2=96.7%). The estimates of mean difference between the control and depression groups remained non-significant when the trim-and-fill procedure was used to correct for publication bias. This meta-analysis reports significantly heterogeneity in this field among studies. There are higher concentrations of the chemokine MCP-1/CCL2 in depressed subjects compared with control subjects, and no differences for IL-8/CXCL8. More high quality research and consistent methodologies are needed in this important area of enquiry. PMID:26903140

  19. Chemokine antagonism in chronic hepatitis C virus infection.

    PubMed

    Charles, Edgar D; Dustin, Lynn B

    2011-01-01

    Immune responses to hepatitis C virus (HCV) fail to clear the virus in most individuals. Why patients who are less likely to clear HCV infection have high plasma levels of CXCL10 (also known as IP-10), a chemokine that directs T cells to sites of infection, has long been unclear. In this issue of the JCI, Casrouge and colleagues shed light on this paradox by showing that CXCL10 in the plasma of many HCV patients is enzymatically processed to produce a CXCL10 receptor antagonist. These findings introduce a role for chemokine antagonism during HCV infection and unveil new avenues for improved HCV diagnosis and therapy. PMID:21183783

  20. Heme oxygenase-1 induction alters chemokine regulation and ameliorates human immunodeficiency virus-type-1 infection in lipopolysaccharide-stimulated macrophages

    SciTech Connect

    Zhou, Zhao-Hua; Kumari, Namita; Nekhai, Sergei; Clouse, Kathleen A.; Wahl, Larry M.; Yamada, Kenneth M.; Dhawan, Subhash

    2013-06-07

    Highlights: •Lipopolysaccharide stimulation of heme oxygenase-1 (HO-1) ameliorated HIV-1 infection of primary human macrophages. •The partial protection by HO-1 against HIV infection was associated with induction of chemokines such as MIP1α and MIP1β. •This mechanism explains lipopolysaccharide-stimulated HO-1-mediated inhibition of HIV-1 infection of macrophages. -- Abstract: We have elucidated a putative mechanism for the host resistance against HIV-1 infection of primary human monocyte-derived macrophages (MDM) stimulated with lipopolysaccharide (LPS). We show that LPS-activated MDM both inhibited HIV-1 entry into the cells and were refractory to post-entry productive viral replication. LPS-treated cells were virtually negative for mature virions as revealed by transmission electron microscopy. LPS activation of MDM markedly enhanced the expression of heme oxygenase-1 (HO-1), a potent inducible cytoprotective enzyme. Increased HO-1 expression was accompanied by elevated production of macrophage inflammatory chemokines (MIP1α and MIP1β) by LPS-activated MDM, significantly decreased surface chemokine receptor-5 (CCR-5) expression, and substantially reduced virus replication. Treatment of cells with HO-1 inhibitor SnPP IX (tin protoporphyrin IX) attenuated the LPS-mediated responses, HIV-1 replication and secretion of MIP1α, MIP1β, and LD78β chemokines with little change in surface CCR-5 expression. These results identify a novel role for HO-1 in the modulation of host immune response against HIV infection of MDM.

  1. Endothelial Cells Enhance Tumor Cell Invasion through a Crosstalk Mediated by CXC Chemokine Signaling1

    PubMed Central

    Warner, Kristy A; Miyazawa, Marta; Cordeiro, Mabel M R; Love, William J; Pinsky, Matthew S; Neiva, Kathleen G; Spalding, Aaron C; Nör, Jacques E

    2008-01-01

    Field cancerization involves the lateral spread of premalignant or malignant disease and contributes to the recurrence of head and neck tumors. The overall hypothesis underlying this work is that endothelial cells actively participate in tumor cell invasion by secreting chemokines and creating a chemotactic gradient for tumor cells. Here we demonstrate that conditioned medium from head and neck tumor cells enhance Bcl-2 expression in neovascular endothelial cells. Oral squamous cell carcinoma-3 (OSCC3) and Kaposi's sarcoma (SLK) show enhanced invasiveness when cocultured with pools of human dermal microvascular endothelial cells stably expressing Bcl-2 (HDMEC-Bcl-2), compared to cocultures with empty vector controls (HDMEC-LXSN). Xenografted OSCC3 tumors vascularized with HDMEC-Bcl-2 presented higher local invasion than OSCC3 tumors vascularized with control HDMEC-LXSN. CXCL1 and CXCL8 were upregulated in primary endothelial cells exposed to vascular endothelial growth factor (VEGF), as well as in HDMEC-Bcl-2. Notably, blockade of CXCR2 signaling, but not CXCR1, inhibited OSCC3 and SLK invasion toward endothelial cells. These data demonstrate that CXC chemokines secreted by endothelial cells induce tumor cell invasion and suggest that the process of lateral spread of tumor cells observed in field cancerization is guided by chemotactic signals that originated from endothelial cells. PMID:18283335

  2. Peroxisome proliferator-activated receptor {alpha} agonists modulate Th1 and Th2 chemokine secretion in normal thyrocytes and Graves' disease

    SciTech Connect

    Antonelli, Alessandro; Ferrari, Silvia Martina; Frascerra, Silvia; Corrado, Alda; Pupilli, Cinzia; Bernini, Giampaolo; Benvenga, Salvatore; Ferrannini, Ele; Fallahi, Poupak

    2011-07-01

    Until now, no data are present about the effect of peroxisome proliferator-activated receptor (PPAR){alpha} activation on the prototype Th1 [chemokine (C-X-C motif) ligand (CXCL)10] (CXCL10) and Th2 [chemokine (C-C motif) ligand 2] (CCL2) chemokines secretion in thyroid cells. The role of PPAR{alpha} and PPAR{gamma} activation on CXCL10 and CCL2 secretion was tested in Graves' disease (GD) and control primary thyrocytes stimulated with interferon (IFN){gamma} and tumor necrosis factor (TNF){alpha}. IFN{gamma} stimulated both CXCL10 and CCL2 secretion in primary GD and control thyrocytes. TNF{alpha} alone stimulated CCL2 secretion, while had no effect on CXCL10. The combination of IFN{gamma} and TNF{alpha} had a synergistic effect both on CXCL10 and CCL2 chemokines in GD thyrocytes at levels comparable to those of controls. PPAR{alpha} activators inhibited the secretion of both chemokines (stimulated with IFN{gamma} and TNF{alpha}) at a level higher (for CXCL10, about 60-72%) than PPAR{gamma} agonists (about 25-35%), which were confirmed to inhibit CXCL10, but not CCL2. Our data show that CCL2 is modulated by IFN{gamma} and TNF{alpha} in GD and normal thyrocytes. Furthermore we first show that PPAR{alpha} activators inhibit the secretion of CXCL10 and CCL2 in thyrocytes, suggesting that PPAR{alpha} may be involved in the modulation of the immune response in the thyroid.

  3. Coy decoy with a new ploy: interceptor controls the levels of homeostatic chemokines.

    PubMed

    Haraldsen, Guttorm; Rot, Antal

    2006-07-01

    A new subfamily of chemokine receptors is emerging that do not signal along classical G-protein-mediated pathways. Instead, these "silent" receptors efficiently internalize their cognate chemokine ligands, hence their suggested name, "chemokine interceptors", for internalizing receptors. Two of these interceptors, DARC and D6, possess intriguing patterns of tissue expression and are believed to be involved in controlling the local levels of proinflammatory chemokines. In this issue of the European Journal of Immunology, the biochemical properties of a third silent chemokine receptor, CCX-CKR, have been characterized and it is suggested that it may act as a scavenger for homeostatic chemokines, pointing to a broad and significant role for this group of chemokine binding molecules in chemokine biology. PMID:16791884

  4. The emerging role of CXC chemokines and their receptors in cancer.

    PubMed

    Vinader, Victoria; Afarinkia, Kamyar

    2012-05-01

    Chemokines and their receptors have a multifaceted role in tumor biology and are implicated in nearly all aspects of cancer growth, survival and dissemination. Modulation of the interaction between chemokines and their cell surface receptor is, therefore, a promising area for the development of new cancer medicines. In this review, we look at the compelling evidence that is emerging to support targeting CXC chemokines, also known as family α chemokines, as novel therapeutic strategies in the treatment of cancer. PMID:22571611

  5. Chemokine interaction with synergy-inducing molecules: fine tuning modulation of cell trafficking.

    PubMed

    Cecchinato, Valentina; D'Agostino, Gianluca; Raeli, Lorenzo; Uguccioni, Mariagrazia

    2016-06-01

    Directed migration and arrest of leukocytes during homeostasis, inflammation, and tumor development is mediated by the chemokine system, which governs leukocyte migration and activities. Although we understand well the effects of different chemokines one by one, much less was known about the potential consequences of the concomitant expression of multiple chemokines or of their interaction with inflammatory molecules on leukocyte migration and functions. In the past 10 yr, several studies revealed the existence of additional features of chemokines: they can antagonize chemokine receptors or synergize with other chemokines, also by forming heterocomplexes. Moreover, recent data show that not only chemokines but also the alarmin high-mobility group box 1 can for a complex with CXCL12, enhancing its potency on CXCR4. The molecular mechanism underlying the effect of the heterocomplex has been partially elucidated, whereas its structure is a matter of current investigations. The present review discusses the current knowledge and relevance of the functions of heterocomplexes formed between chemokines or between the chemokine CXCL12 and the alarmin high-mobility group box 1. These studies highlight the importance of taking into account, when approaching innovative therapies targeting the chemokine system, also the fact that some chemokines and molecules released in inflammation, can considerably affect the activity of chemokine receptor agonists. PMID:26715684

  6. Zebrafish as a model to study chemokine function.

    PubMed

    Kochhan, Eva; Siekmann, Arndt F

    2013-01-01

    Zebrafish have emerged as a powerful model organism to study embryo morphogenesis. Due to their optical clarity, they are uniquely suited for time-lapse imaging studies, providing insights into the dynamic processes underlying tissue formation and cell migration. These studies have been tremendously facilitated by the availability of transgenic zebrafish lines, labelling distinct embryonic structures, individual cells, or even subcellular structures, such as the nucleus. Zebrafish studies have revealed that the migration of several different cell types in the embryo is controlled by chemokines, small vertebrate-specific proteins. Here, we report methods to analyze the expression pattern of a given chemokine and its receptor in transgenic zebrafish using fluorescent in situ hybridization in combination with an anti-green fluorescent protein (GFP) antibody staining. We furthermore illustrate how to image migrating cell populations using time-lapse microscopy in double-transgenic embryos. We show how to investigate cell number and direction of migration by using a nuclear-localized GFP. The combination of this transgene with a membrane-targeted red fluorescent protein allows for the simultaneous determination of changes in cell shape, such as the formation of filopodial extensions. We exemplify this by describing how a mutation in the chemokine receptor cxcr4a affects endothelial cell migration and blood vessel formation. Finally, we provide a method to perform fluorescent angiography to monitor blood vessel perfusion in chemokine receptor mutants. PMID:23625497

  7. Characterization of the "CCR5" Chemokine Receptor Gene

    ERIC Educational Resources Information Center

    Thomas, John C.

    2004-01-01

    The life cycle of retroviruses is an essential topic of modern cell biology instruction. Furthermore, the process of HIV viral entry into the cell is a question of great interest in basic and clinical biology. This paper describes how students can easily recover their own DNA, amplify a portion of the "CCR5" chemokine receptor gene, characterize…

  8. Functions of the Chemokine Receptor CXCR4 in the Central Nervous System and Its Regulation by μ-Opioid Receptors

    PubMed Central

    Nash, Bradley; Meucci, Olimpia

    2015-01-01

    Activation of the G protein-coupled receptor CXCR4 by its chemokine ligand CXCL12 regulates a number of physiopathological functions in the central nervous system, during development as well as later in life. In addition to the more classical roles of the CXCL12/CXCR4 axis in the recruitment of immune cells or migration and proliferation of neural precursor cells, recent studies suggest that CXCR4 signaling also modulates synaptic function and neuronal survival in the mature brain, through direct and indirect effects on neurons and glia. These effects, which include regulation of glutamate receptors and uptake, and of dendritic spine density, can significantly alter the ability of neurons to face excitotoxic insults. Therefore, they are particularly relevant to neurodegenerative diseases featuring alterations of glutamate neurotransmission, such as HIV-associated neurocognitive disorders. Importantly, CXCR4 signaling can be dysregulated by HIV viral proteins, host HIV-induced factors, and opioids. Potential mechanisms of opioid regulation of CXCR4 include heterologous desensitization, transcriptional regulation and changes in receptor expression levels, opioid–chemokine receptor dimer or heteromer formation, and the newly described modulation by the protein ferritin heavy chain—all leading to inhibition of CXCR4 signaling. After reviewing major effects of chemokines and opioids in the CNS, this chapter discusses chemokine–opioid interactions in neuronal and immune cells, focusing on their potential contribution to HIV-associated neurocognitive disorders. PMID:25175863

  9. CXCL9 Contributes to Antimicrobial Protection of the Gut during Citrobacter rodentium Infection Independent of Chemokine-Receptor Signaling

    PubMed Central

    Reid-Yu, Sarah A.; Tuinema, Brian R.; Small, Cherrie N.; Xing, Lydia; Coombes, Brian K.

    2015-01-01

    Chemokines have been shown to be effective bactericidal molecules against a variety of bacteria and fungi in vitro. These direct antimicrobial effects are independent of their chemotactic activities involving immunological receptors. However, the direct biological role that these proteins may play in host defense, particularly against intestinal pathogens, is poorly understood. Here, we show that CXCL9, an ELR- chemokine, exhibits direct antimicrobial activity against Citrobacter rodentium, an attaching/effacing pathogen that infects the gut mucosa. Inhibition of this antimicrobial activity in vivo using anti-CXCL9 antibodies increases host susceptibility to C. rodentium infection with pronounced bacterial penetration into crypts, increased bacterial load, and worsened tissue pathology. Using Rag1-/- mice and CXCR3-/- mice, we demonstrate that the role for CXCL9 in protecting the gut mucosa is independent of an adaptive response or its immunological receptor, CXCR3. Finally, we provide evidence that phagocytes function in tandem with NK cells for robust CXCL9 responses to C. rodentium. These findings identify a novel role for the immune cell-derived CXCL9 chemokine in directing a protective antimicrobial response in the intestinal mucosa. PMID:25643352

  10. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages.

    PubMed

    Kitamura, Takanori; Qian, Bin-Zhi; Soong, Daniel; Cassetta, Luca; Noy, Roy; Sugano, Gaël; Kato, Yu; Li, Jiufeng; Pollard, Jeffrey W

    2015-06-29

    Pulmonary metastasis of breast cancer cells is promoted by a distinct population of macrophages, metastasis-associated macrophages (MAMs), which originate from inflammatory monocytes (IMs) recruited by the CC-chemokine ligand 2 (CCL2). We demonstrate here that, through activation of the CCL2 receptor CCR2, the recruited MAMs secrete another chemokine ligand CCL3. Genetic deletion of CCL3 or its receptor CCR1 in macrophages reduces the number of lung metastasis foci, as well as the number of MAMs accumulated in tumor-challenged lung in mice. Adoptive transfer of WT IMs increases the reduced number of lung metastasis foci in Ccl3 deficient mice. Mechanistically, Ccr1 deficiency prevents MAM retention in the lung by reducing MAM-cancer cell interactions. These findings collectively indicate that the CCL2-triggered chemokine cascade in macrophages promotes metastatic seeding of breast cancer cells thereby amplifying the pathology already extant in the system. These data suggest that inhibition of CCR1, the distal part of this signaling relay, may have a therapeutic impact in metastatic disease with lower toxicity than blocking upstream targets. PMID:26056232

  11. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages

    PubMed Central

    Kitamura, Takanori; Qian, Bin-Zhi; Soong, Daniel; Cassetta, Luca; Noy, Roy; Sugano, Gaël; Kato, Yu; Li, Jiufeng

    2015-01-01

    Pulmonary metastasis of breast cancer cells is promoted by a distinct population of macrophages, metastasis-associated macrophages (MAMs), which originate from inflammatory monocytes (IMs) recruited by the CC-chemokine ligand 2 (CCL2). We demonstrate here that, through activation of the CCL2 receptor CCR2, the recruited MAMs secrete another chemokine ligand CCL3. Genetic deletion of CCL3 or its receptor CCR1 in macrophages reduces the number of lung metastasis foci, as well as the number of MAMs accumulated in tumor-challenged lung in mice. Adoptive transfer of WT IMs increases the reduced number of lung metastasis foci in Ccl3 deficient mice. Mechanistically, Ccr1 deficiency prevents MAM retention in the lung by reducing MAM–cancer cell interactions. These findings collectively indicate that the CCL2-triggered chemokine cascade in macrophages promotes metastatic seeding of breast cancer cells thereby amplifying the pathology already extant in the system. These data suggest that inhibition of CCR1, the distal part of this signaling relay, may have a therapeutic impact in metastatic disease with lower toxicity than blocking upstream targets. PMID:26056232

  12. The Anti-Atherosclerotic Effect of Naringin Is Associated with Reduced Expressions of Cell Adhesion Molecules and Chemokines through NF-κB Pathway.

    PubMed

    Hsueh, Tun-Pin; Sheen, Jer-Ming; Pang, Jong-Hwei S; Bi, Kuo-Wei; Huang, Chao-Chun; Wu, Hsiao-Ting; Huang, Sheng-Teng

    2016-01-01

    Naringin has been reported to have an anti-atherosclerosis effect but the underlying mechanism is not fully understood. The aim of this study is to investigate the impact of naringin on the TNF-α-induced expressions of cell adhesion molecules, chemokines and NF-κB signaling pathway in human umbilical vein endothelial cells (HUVECs). The experiments revealed that naringin, at concentrations without cytotoxicity, dose-dependently inhibited the adhesion of THP-1 monocytes to the TNF-α-stimulated HUVECs. The TNF-α-induced expressions of cell adhesion molecules, including VCAM-1, ICAM-1 and E-selectin, at both the mRNA and protein levels, were significantly suppressed by naringin in a dose dependent manner. In addition, the TNF-α-induced mRNA and protein levels of chemokines, including fractalkine/CX3CL1, MCP-1 and RANTES, were also reduced by naringin. Naringin significantly inhibited TNF-α-induced nuclear translocation of NF-κB, which resulted from the inhibited phosphorylation of IKKα/β, IκB-α and NF-κB. Altogether, we proposed that naringin modulated TNF-α-induced expressions of cell adhesion molecules and chemokines through the inhibition of TNF-α-induced activation of IKK/NF-κB signaling pathway to exert the anti-atherosclerotic effect. PMID:26861272

  13. Duffy Antigen Receptor for Chemokines Regulates Post-Fracture Inflammation

    PubMed Central

    Rundle, Charles H.; Mohan, Subburaman; Edderkaoui, Bouchra

    2013-01-01

    There is now considerable experimental data to suggest that inflammatory cells collaborate in the healing of skeletal fractures. In terms of mechanisms that contribute to the recruitment of inflammatory cells to the fracture site, chemokines and their receptors have received considerable attention. Our previous findings have shown that Duffy antigen receptor for chemokines (Darc), the non-classical chemokine receptor that does not signal, but rather acts as a scavenger of chemokines that regulate cell migration, is a negative regulator of peak bone density in mice. Furthermore, because Darc is expressed by inflammatory and endothelial cells, we hypothesized that disruption of Darc action will affect post-fracture inflammation and consequently will affect fracture healing. To test this hypothesis, we evaluated fracture healing in mice with targeted disruption of Darc and corresponding wild type (WT) control mice. We found that fracture callus cartilage formation was significantly greater (33%) at 7 days post-surgery in Darc-KO compared to WT mice. The increased cartilage was associated with greater Collagen (Col) II expression at 3 days post-fracture and Col-X at 7 days post-fracture compared to WT mice, suggesting that Darc deficiency led to early fracture cartilage formation and differentiation. We then compared the expression of cytokine and chemokine genes known to be induced during inflammation. Interleukin (Il)-1β, Il-6, and monocyte chemotactic protein 1 were all down regulated in the fractures derived from Darc-KO mice at one day post-fracture, consistent with an altered inflammatory response. Furthermore, the number of macrophages was significantly reduced around the fractures in Darc-KO compared to WT mice. Based on these data, we concluded that Darc plays a role in modulating the early inflammatory response to bone fracture and subsequent cartilage formation. However, the early cartilage formation was not translated with an early bone formation at the

  14. Diagnostic value of cytokines and chemokines in lyme neuroborreliosis.

    PubMed

    Cerar, T; Ogrinc, K; Lotric-Furlan, S; Kobal, J; Levicnik-Stezinar, S; Strle, F; Ruzić-Sabljic, E

    2013-10-01

    The aims of the present study were to assess the concentrations of different cytokines and chemokines in blood serum and cerebrospinal fluid (CSF) samples of patients with Lyme neuroborreliosis and to identify the possible marker(s) that would enable a distinction between clinically evident and suspected Lyme neuroborreliosis, as well as between Lyme neuroborreliosis and tick-borne encephalitis (TBE). Our additional interest was to evaluate the relationship between cytokine and chemokine concentrations and Borrelia burgdorferi sensu lato isolation from CSF, as well as intrathecal synthesis of specific borrelial antibodies. We found that higher concentrations of CXCL13 and lower concentrations of interleukin 10 (IL-10) in serum were associated with higher odds for clinically evident Lyme neuroborreliosis compared to suspected Lyme neuroborreliosis, as well as to TBE. The concentrations of IL-2, IL-5, IL-6, IL-10, and CXCL13 in the CSF were higher in patients with evident Lyme neuroborreliosis than in those who were only suspected to have the disease. A comparison of CSF cytokine and chemokine levels in patients with and without intrathecal synthesis of specific borrelial antibodies revealed that CXCL13 CSF concentration is significantly associated with intrathecal synthesis of borrelial antibodies. A comparison of the cytokine and chemokine CSF concentrations in patients with clinically evident Lyme neuroborreliosis according to CSF culture results revealed that higher concentrations of gamma interferon (IFN-γ) were associated with lower odds of Borrelia isolation. Although several differences in the blood serum and CSF concentrations of various cytokines and chemokines between the groups were found, the distinctive power of the majority of these findings is low. Further research on well-defined groups of patients is needed to appraise the potential diagnostic usefulness of these concentrations. PMID:23945160

  15. Dual targeting of the chemokine receptors CXCR4 and ACKR3 with novel engineered chemokines.

    PubMed

    Hanes, Melinda S; Salanga, Catherina L; Chowdry, Arnab B; Comerford, Iain; McColl, Shaun R; Kufareva, Irina; Handel, Tracy M

    2015-09-11

    The chemokine CXCL12 and its G protein-coupled receptors CXCR4 and ACKR3 are implicated in cancer and inflammatory and autoimmune disorders and are targets of numerous antagonist discovery efforts. Here, we describe a series of novel, high affinity CXCL12-based modulators of CXCR4 and ACKR3 generated by selection of N-terminal CXCL12 phage libraries on live cells expressing the receptors. Twelve of 13 characterized CXCL12 variants are full CXCR4 antagonists, and four have Kd values <5 nm. The new variants also showed high affinity for ACKR3. The variant with the highest affinity for CXCR4, LGGG-CXCL12, showed efficacy in a murine model for multiple sclerosis, demonstrating translational potential. Molecular modeling was used to elucidate the structural basis of binding and antagonism of selected variants and to guide future designs. Together, this work represents an important step toward the development of therapeutics targeting CXCR4 and ACKR3. PMID:26216880

  16. Chemokines, macrophage inflammatory protein-2 and stromal cell-derived factor-1α, suppress amyloid β-induced neurotoxicity

    PubMed Central

    Raman, Dayanidhi; Milatovic, Snjezana-Zaja; Milatovic, Dejan; Splittgerber, Ryan; Fan, Guo-Huang; Richmond, Ann

    2011-01-01

    Alzheimer’s disease (AD) is characterized by a progressive cognitive decline and accumulation of neurotoxic oligomeric peptides amyloid-β (Aβ). Although the molecular events are not entirely known, it has become evident that inflammation, environmental and other risk factors may play a causal, disruptive and/or protective role in the development of AD. The present study investigated the ability of the chemokines, macrophage inflammatory protein-2 (MIP-2) and stromal cell-derived factor-1α (SDF-1α), the respective ligands for chemokine receptors CXCR2 and CXCR4, to suppress Aβ-induced neurotoxicity in vitro and in vivo. Pretreatment with MIP-2 or SDF-1α significantly protected neurons from Aβ-induced dendritic regression and apoptosis in vitro through activation of Akt, ERK1/2 and maintenance of metalloproteinase ADAM17 especially with SDF-1α. Intra-cerebroventricular (ICV) injection of Aβ led to reduction in dendritic length and spine density of pyramidal neurons in the CA1 area of the hippocampus and increased oxidative damage 24 h following the exposure. The Aβ-induced morphometric changes of neurons and increase in biomarkers of oxidative damage, F2-isoprostanes, was significantly inhibited by pretreatment with the chemokines MIP-2 or SDF-1α. Additionally, MIP-2 or SDF-1α was able to suppress the aberrant mislocalization of p21-activated kinase (PAK), one of the proteins involved in the maintenance of dendritic spines. Furthermore, MIP-2 also protected neurons against Aβ neurotoxicity in CXCR2−/− mice, potentially through observed up regulation of CXCR1 mRNA. Understanding the neuroprotective potential of chemokines is crucial in defining the role for their employment during the early stages of neurodegeneration. PMID:21704645

  17. The Chemokine Receptor CCR1 Is Constitutively Active, Which Leads to G Protein-independent, β-Arrestin-mediated Internalization*

    PubMed Central

    Gilliland, C. Taylor; Salanga, Catherina L.; Kawamura, Tetsuya; Trejo, JoAnn; Handel, Tracy M.

    2013-01-01

    Activation of G protein-coupled receptors by their associated ligands has been extensively studied, and increasing structural information about the molecular mechanisms underlying ligand-dependent receptor activation is beginning to emerge with the recent expansion in GPCR crystal structures. However, some GPCRs are also able to adopt active conformations in the absence of agonist binding that result in the initiation of signal transduction and receptor down-modulation. In this report, we show that the CC-type chemokine receptor 1 (CCR1) exhibits significant constitutive activity leading to a variety of cellular responses. CCR1 expression is sufficient to induce inhibition of cAMP formation, increased F-actin content, and basal migration of human and murine leukocytes. The constitutive activity leads to basal phosphorylation of the receptor, recruitment of β-arrestin-2, and subsequent receptor internalization. CCR1 concurrently engages Gαi and β-arrestin-2 in a multiprotein complex, which may be accommodated by homo-oligomerization or receptor clustering. The data suggest the presence of two functional states for CCR1; whereas receptor coupled to Gαi functions as a canonical GPCR, albeit with high constitutive activity, the CCR1·β-arrestin-2 complex is required for G protein-independent constitutive receptor internalization. The pertussis toxin-insensitive uptake of chemokine by the receptor suggests that the CCR1·β-arrestin-2 complex may be related to a potential scavenging function of the receptor, which may be important for maintenance of chemokine gradients and receptor responsiveness in complex fields of chemokines during inflammation. PMID:24056371

  18. Chemokines and their receptors play important roles in the development of hepatocellular carcinoma

    PubMed Central

    Liang, Chun-Min; Chen, Long; Hu, Heng; Ma, Hui-Ying; Gao, Ling-Ling; Qin, Jie; Zhong, Cui-Ping

    2015-01-01

    The chemokine system consists of four different subclasses with over 50 chemokines and 19 receptors. Their functions in the immune system have been well elucidated and research during the last decades unveils their new roles in hepatocellular carcinoma (HCC). The chemokines and their receptors in the microenvironment influence the development of HCC by several aspects including: inflammation, effects on immune cells, angiogenesis, and direct effects on HCC cells. Regarding these aspects, pre-clinical research by targeting the chemokine system has yielded promising data, and these findings bring us new clues in the chemokine-based therapies for HCC. PMID:26052384

  19. Ingramon, a Peptide Inhibitor of MCP-1 Chemokine, Reduces Migration of Blood Monocytes Stimulated by Glioma-Conditioned Medium.

    PubMed

    Krasnikova, T L; Arefieva, T I; Pylaeva, E A; Sidorova, M V

    2016-02-01

    Malignant gliomas are most common and fatal primary brain tumors. In addition to neoplastic cells, the tumor tissue contains microglial cells and monocyte-derived macrophages. It is an established fact that monocyte recruiting promotes the tumor growth and dissemination. Monocyte chemotactic protein-1 (MCP-1) is the major attractant for monocytes. We have previously synthesized an MCP-1 antagonist ingramon, a synthetic peptide fragment (65-76) of this chemokine. In the present study, we demonstrated that glioma-conditioned medium contains MCP-1 and stimulates migration of blood monocytes. Ingramon inhibited the effect of glioma-conditioned medium on monocyte migration. PMID:26906197

  20. The chemokine system -- a major regulator of angiogenesis in health and disease.

    PubMed

    Rosenkilde, Mette M; Schwartz, Thue W

    2004-01-01

    The chemokine system controls leukocyte trafficking during homeostasis as well as during inflammation and is necessary for the linkage between innate and adaptive immunity. Tissue regulation outside the hematopoietic compartment, for instance, angiogenesis, organogenesis and tumor development, growth and metastasis, is another important function of the chemokine system. The chemokine-mediated regulation of angiogenesis is highly sophisticated and fine tuned, and involves pro-angiogenic chemokines, for instance, CXCL8/IL8 interacting with the CXCR2 receptor, and anti-angiogenic (i.e. angiostatic) chemokines, for instance, CXCL10/IP10 interacting with the CXCR3 receptor. Chemokines also regulate angiogenesis in a receptor-independent manner by means of a perturbation of bFGF and VEGF function. The current review focuses on the influence of the chemokine system in angiogenesis. Examples of the delicate angiogenesis regulation by the chemokine system in, for instance, wound healing and of the dysregulation in, for instance, tumor development are provided along with the interesting phenomenon of molecular piracy of host-encoded genes within the chemokine system. This phenomenon is a general strategy to circumvent and exploit the immune system -- and thereby improve survival -- for many viruses. Yet, a certain group of herpesviruses -- the gamma2-herpesviruses -- encode a functional CXCR2 receptor homolog that is activated by angiogenic chemokines and antagonized by angiostatic chemokines, and this particular gene seems to cause the development of a vascular tumor -- Kaposi's sarcoma -- in the host. PMID:15563311

  1. The fine balance of chemokines during disease: trafficking, inflammation and homeostasis

    PubMed Central

    Cardona, Sandra M.; Garcia, Jenny A.; Cardona, Astrid E.

    2014-01-01

    Summary The action of chemokines (or ‘chemotactic cytokines’) is recognized as an integral part of inflammatory and regulatory processes. Leukocyte mobilization during physiological conditions, trafficking of various cell types during pathological conditions, cell activation and angiogenesis are among the target functions exerted by chemokines upon signaling via their specific receptors. Current research is focused in analyzing changes in chemokine/chemokine receptor patterns during various diseases with the aim to modulate pathological trafficking of cells, or to attract particular cell types to specific tissues. This review focuses on defining the role(s) of certain chemokine ligands and receptors in inflammatory neurological conditions such as multiple sclerosis. In addition, the role(s) of chemokines in neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease are also described, as well as the contribution of chemokines to the pathogenesis of cancer, diabetes and cardiovascular disease. PMID:23625489

  2. Chemokines derived from soluble fusion proteins expressed in Escherichia coli are biologically active

    SciTech Connect

    Magistrelli, Giovanni; Gueneau, Franck; Muslmani, Machadiya; Ravn, Ulla; Kosco-Vilbois, Marie; Fischer, Nicolas . E-mail: nfischer@novimmune.com

    2005-08-26

    Chemokines are a class of low molecular weight proteins that are involved in leukocytes trafficking. Due to their involvement in recruiting immune cells to sites of inflammation, chemokines, and chemokine receptors have become an attractive class of therapeutic targets. However, when expressed in Escherichia coli chemokines are poorly soluble and accumulate in inclusion bodies. Several purification methods have been described but involve time-consuming refolding, buffer exchange, and purification steps that complicate expression of these proteins. Here, we describe a simple and reliable method to express chemokines as fusions to the protein NusA. The fusion proteins were largely found in the soluble fraction and could be readily purified in a single step. Proteolytic cleavage was used to obtain soluble recombinant chemokines that were found to be very active in a novel in vitro chemotaxis assays. This method could be applied to several {alpha} and {beta} human chemokines, suggesting that it is generally applicable to this class of proteins.

  3. IL-1β produced by aggressive breast cancer cells is one of the factors that dictate their interactions with mesenchymal stem cells through chemokine production

    PubMed Central

    Serret, Julien; Bièche, Ivan; Brigitte, Madly; Caicedo, Andres; Sanchez, Elodie; Vacher, Sophie; Vignais, Marie-Luce; Bourin, Philippe; Geneviève, David; Molina, Franck; Jorgensen, Christian; Lazennec, Gwendal

    2015-01-01

    The aim of this work was to understand whether the nature of breast cancer cells could modify the nature of the dialog of mesenchymal stem cells (MSCs) with cancer cells. By treating MSCs with the conditioned medium of metastatic Estrogen-receptor (ER)-negative MDA-MB-231, or non-metastatic ER-positive MCF-7 breast cancer cells, we observed that a number of chemokines were produced at higher levels by MSCs treated with MDA-MB-231 conditioned medium (CM). MDA-MB-231 cells were able to induce NF-κB signaling in MSC cells. This was shown by the use of a NF-kB chemical inhibitor or an IκB dominant negative mutant, nuclear translocation of p65 and induction of NF-κB signature. Our results suggest that MDA-MB-231 cells exert their effects on MSCs through the secretion of IL-1β, that activates MSCs and induces the same chemokines as the MDA-MB-231CM. In addition, inhibition of IL-1β secretion in the MDA-MB-231 cells reduces the induced production of a panel of chemokines by MSCs, as well the motility of MDA-MB-231 cells. Our data suggest that aggressive breast cancer cells secrete IL-1β, which increases the production of chemokines by MSCs. PMID:26362269

  4. Polysialylation controls dendritic cell trafficking by regulating chemokine recognition.

    PubMed

    Kiermaier, Eva; Moussion, Christine; Veldkamp, Christopher T; Gerardy-Schahn, Rita; de Vries, Ingrid; Williams, Larry G; Chaffee, Gary R; Phillips, Andrew J; Freiberger, Friedrich; Imre, Richard; Taleski, Deni; Payne, Richard J; Braun, Asolina; Förster, Reinhold; Mechtler, Karl; Mühlenhoff, Martina; Volkman, Brian F; Sixt, Michael

    2016-01-01

    The addition of polysialic acid to N- and/or O-linked glycans, referred to as polysialylation, is a rare posttranslational modification that is mainly known to control the developmental plasticity of the nervous system. Here we show that CCR7, the central chemokine receptor controlling immune cell trafficking to secondary lymphatic organs, carries polysialic acid. This modification is essential for the recognition of the CCR7 ligand CCL21. As a consequence, dendritic cell trafficking is abrogated in polysialyltransferase-deficient mice, manifesting as disturbed lymph node homeostasis and unresponsiveness to inflammatory stimuli. Structure-function analysis of chemokine-receptor interactions reveals that CCL21 adopts an autoinhibited conformation, which is released upon interaction with polysialic acid. Thus, we describe a glycosylation-mediated immune cell trafficking disorder and its mechanistic basis. PMID:26657283

  5. Chemokines and their receptors in lung cancer progression and metastasis*

    PubMed Central

    Cheng, Zeng-hui; Shi, Yu-xin; Yuan, Min; Xiong, Dan; Zheng, Jiang-hua; Zhang, Zhi-yong

    2016-01-01

    Lung cancer is the leading cause of cancer-related mortality around the world. Despite advancements in diagnosis, surgical techniques, and neoadjuvant chemoradiotherapy over the last decade, the mortality rate is still high and the 5-year survival is a dismal 15%. Fortunately, early detection by low-dose computed tomography (LDCT) scans has reduced mortality by 20%; yet, overall, 5-year-survival remains low at less than 20%. Therefore, in order to ameliorate this situation, a thorough understanding of the underlying molecular mechanisms is urgently needed. Chemokines and their receptors, crucial microenvironmental factors, play important roles in lung tumor genesis, progression, and metastasis, and exploring the mechanisms of this might bring new insights into early diagnosis and precisely targeted treatment. Consequently, this review will mainly focus on recent advancements on the axes of chemokines and their receptors of lung cancer. PMID:27143261

  6. Langerhans cell histiocytosis: a cytokine/chemokine-mediated disorder?

    PubMed

    Garabedian, Lara; Struyf, Sofie; Opdenakker, Ghislain; Sozzani, Silvano; Van Damme, Jo; Laureys, Geneviève

    2011-09-01

    Langerhans cell histiocytosis (LCH) is a rare disorder characterized by an abnormal accumulation and/or proliferation of cells with a Langerhans cell phenotype. Although no clear cause of LCH has been identified, it has been postulated that LCH might be the consequence of an immune dysregulation, causing Langerhans cells to migrate to and accumulate at various sites. Production of cytokines and chemokines is a central feature of immune regulation. Cytokines are abundantly present within LCH lesions. We review here the potential role of cytokines and chemokines in the pathogenesis of LCH. The type, distribution, and number of different cytokines released within lesions can provide clues to the possible aetiology of LCH and, ultimately, might offer therapeutic possibilities using recombinant cytokines or antagonists for this disorder. PMID:22001902

  7. Epithelial Anion Transport as Modulator of Chemokine Signaling

    PubMed Central

    Schnúr, Andrea; Hegyi, Péter; Rousseau, Simon; Lukacs, Gergely L.; Veit, Guido

    2016-01-01

    The pivotal role of epithelial cells is to secrete and absorb ions and water in order to allow the formation of a luminal fluid compartment that is fundamental for the epithelial function as a barrier against environmental factors. Importantly, epithelial cells also take part in the innate immune system. As a first line of defense they detect pathogens and react by secreting and responding to chemokines and cytokines, thus aggravating immune responses or resolving inflammatory states. Loss of epithelial anion transport is well documented in a variety of diseases including cystic fibrosis, chronic obstructive pulmonary disease, asthma, pancreatitis, and cholestatic liver disease. Here we review the effect of aberrant anion secretion with focus on the release of inflammatory mediators by epithelial cells and discuss putative mechanisms linking these transport defects to the augmented epithelial release of chemokines and cytokines. These mechanisms may contribute to the excessive and persistent inflammation in many respiratory and gastrointestinal diseases. PMID:27382190

  8. Manipulating leukocyte interactions in vivo through optogenetic chemokine release.

    PubMed

    Sarris, Milka; Olekhnovitch, Romain; Bousso, Philippe

    2016-06-01

    Light-mediated release of signaling ligands, such as chemoattractants, growth factors, and cytokines is an attractive strategy for investigation and therapeutic targeting of leukocyte communication and immune responses. We introduce a versatile optogenetic method to control ligand secretion, combining UV-conditioned endoplasmic reticulum-to-Golgi trafficking and a furin-processing step. As proof of principle, we achieved light-triggered chemokine secretion and demonstrated that a brief pulse of chemokine release can mediate a rapid flux of leukocyte contacts with target cells in vitro and in vivo. This approach opens new possibilities for dynamic investigation of leukocyte communication in vivo and may confer the potential to control the local release of soluble mediators in the context of immune cell therapies. PMID:27057000

  9. Tropoelastin regulates chemokine expression in fibroblasts in Costello syndrome

    SciTech Connect

    Tatano, Yutaka; Fujinawa, Reiko; Kozutsumi, Yasunori; Takahashi, Tsutomu; Tsuji, Daisuke; Takeuchi, Naohiro; Tsuta, Kohji; Takada, Goro; Sakuraba, Hitoshi; Itoh, Kohji

    2008-08-08

    Costello syndrome is a multiple congenital anomaly associated with growth and mental retardation, cardiac and skeletal anomalies, and a predisposition to develop neoplasia. Comprehensive expression analysis revealed remarkable up-regulation of several cytokines and chemokines including Gro family proteins, interleukin-1{beta} (IL-1{beta}), IL-8 and MCP-1 but down-regulation of extracellular matrix components including collagens and proteoglycans of skin fibroblasts derived from a Japanese Costello syndrome patient characterized by significantly reduced tropoelastin mRNA, impaired elastogenesis and enhanced cell proliferation. In contrast, decreases in these chemokines and IL-1{beta} expression were observed in Costello fibroblastic cell lines stably expressing the bovine tropoelastin (btEln) gene and in restored elastic fibers. These results strongly suggest that the human TE gene (ELN) transfer could be applicable for the gene therapy of a group of Costello syndrome patients with reduced ELN gene expression.

  10. Systemic chemokine levels, coronary heart disease, and ischemic stroke events

    PubMed Central

    Canouï-Poitrine, F.; Luc, G.; Mallat, Z.; Machez, E.; Bingham, A.; Ferrieres, J.; Ruidavets, J.-B.; Montaye, M.; Yarnell, J.; Haas, B.; Arveiler, D.; Morange, P.; Kee, F.; Evans, A.; Amouyel, P.; Ducimetiere, P.

    2011-01-01

    Objectives: To quantify the association between systemic levels of the chemokine regulated on activation normal T-cell expressed and secreted (RANTES/CCL5), interferon-γ-inducible protein-10 (IP-10/CXCL10), monocyte chemoattractant protein-1 (MCP-1/CCL2), and eotaxin-1 (CCL11) with future coronary heart disease (CHD) and ischemic stroke events and to assess their usefulness for CHD and ischemic stroke risk prediction in the PRIME Study. Methods: After 10 years of follow-up of 9,771 men, 2 nested case-control studies were built including 621 first CHD events and 1,242 matched controls and 95 first ischemic stroke events and 190 matched controls. Standardized hazard ratios (HRs) for each log-transformed chemokine were estimated by conditional logistic regression. Results: None of the 4 chemokines were independent predictors of CHD, either with respect to stable angina or to acute coronary syndrome. Conversely, RANTES (HR = 1.70; 95% confidence interval [CI] 1.05–2.74), IP-10 (HR = 1.53; 95% CI 1.06–2.20), and eotaxin-1 (HR = 1.59; 95% CI 1.02–2.46), but not MCP-1 (HR = 0.99; 95% CI 0.68–1.46), were associated with ischemic stroke independently of traditional cardiovascular risk factors, hs-CRP, and fibrinogen. When the first 3 chemokines were included in the same multivariate model, RANTES and IP-10 remained predictive of ischemic stroke. Their addition to a traditional risk factor model predicting ischemic stroke substantially improved the C-statistic from 0.6756 to 0.7425 (p = 0.004). Conclusions: In asymptomatic men, higher systemic levels of RANTES and IP-10 are independent predictors of ischemic stroke but not of CHD events. RANTES and IP-10 may improve the accuracy of ischemic stroke risk prediction over traditional risk factors. PMID:21849651