The Experts below are selected from a list of 61971 Experts worldwide ranked by ideXlab platform
Scott G Worthen - One of the best experts on this subject based on the ideXlab platform.
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il 17a and tnf α exert synergistic effects on expression of cxcl5 by alveolar type ii cells in vivo and in vitro
Journal of Immunology, 2011Co-Authors: Linda W Gonzales, Michael Favara, Peggy Zhang, Scott G Worthen, Kenneth C Malcolm, Susan H. Guttentag, Guang Yang, Ping WangAbstract:CXCL5, a member of the CXC family of chemokines, contributes to neutrophil recruitment during lung inflammation, but its regulation is poorly understood. Because the T cell-derived cytokine IL-17A enhances host defense by triggering production of chemokines, particularly in combination with TNF-α, we hypothesized that IL-17A would enhance TNF-α–induced expression of CXCL5. Intratracheal coadministration of IL-17A and TNF-α in mice induced production of CXCL1, CXCL2, and CXCL5, which was associated with increased neutrophil influx in the lung at 8 and 24 h. The synergistic effects of TNF-α and IL17A were greatly attenuated in Cxcl5−/− mice at 24 h, but not 8 h, after exposure, a time when CXCL5 expression was at its peak in wild-type mice. Bone marrow chimeras produced using Cxcl5−/− donors and recipients demonstrated that lung-resident cells were the source of CXCL5. Using differentiated alveolar epithelial type II (ATII) cells derived from human fetal lung, we found that IL-17A enhanced TNF-α–induced CXCL5 transcription and stabilized TNF-α–induced CXCL5 transcripts. Whereas expression of CXCL5 required activation of NF-κB, IL-17A did not increase TNF-α–induced NF-κB activation. Apical costimulation of IL-17A and TNF-α provoked apical secretion of CXCL5 by human ATII cells in a transwell system, whereas basolateral costimulation led to both apical and basolateral secretion of CXCL5. The observation that human ATII cells secrete CXCL5 in a polarized fashion may represent a mechanism to recruit neutrophils in host defense in a fashion that discriminates the site of initial injury.
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cxcl5 regulates chemokine scavenging and pulmonary host defense to bacterial infection
Immunity, 2010Co-Authors: Michael Favara, Teshell K Greene, Scott G Worthen, Samithamby Jeyaseelan, Mortimer PonczAbstract:The chemokine sink hypothesis pertaining to erythrocyte Duffy Antigen Receptor for Chemokines (DARC) during inflammation has received considerable attention, but lacks direct in vivo evidence. Here we demonstrate, using mice with a targeted deletion in CXCL5, that CXCL5 bound erythrocyte DARC and impaired its chemokine scavenging in blood. CXCL5 increased the plasma concentrations of CXCL1 and CXCL2 in part through inhibiting chemokine scavenging, impairing chemokine gradients and desensitizing CXCR2, which led to decreased neutrophil influx to the lung, increased lung bacterial burden and mortality in an Escherichia coli pneumonia model. In contrast, CXCL5 exerted a predominant role in mediating neutrophil influx to the lung during inflammation after LPS inhalation. Platelets and lung resident cells were the sources of homeostatic CXCL5 in blood and inflammatory CXCL5 in the lung respectively. This study presents a paradigm whereby platelets and red cells alter chemokine scavenging and neutrophil-chemokine interaction during inflammation.
Dagmar Scheel-toellner - One of the best experts on this subject based on the ideXlab platform.
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Expression of chemokines CXCL4 and CXCL7 by synovial macrophages defines an early stage of rheumatoid arthritis
Annals of the rheumatic diseases, 2015Co-Authors: Lorraine Yeo, Nichola J Adlard, Maria Juarez, Christopher D. Buckley, Karim Raza, Andrew Filer, Michael Biehl, T. Smallie, Martyn Snow, Dagmar Scheel-toellnerAbstract:Background and objectives For our understanding of the pathogenesis of rheumatoid arthritis (RA), it is important to elucidate the mechanisms underlying early stages of synovitis. Here, synovial cytokine production was investigated in patients with very early arthritis. Methods Synovial biopsies were obtained from patients with at least one clinically swollen joint within 12 weeks of symptom onset. At an 18-month follow-up visit, patients who went on to develop RA, or whose arthritis spontaneously resolved, were identified. Biopsies were also obtained from patients with RA with longer symptom duration (>12 weeks) and individuals with no clinically apparent inflammation. Synovial mRNA expression of 117 cytokines was quantified using PCR techniques and analysed using standard and novel methods of data analysis. Synovial tissue sections were stained for CXCL4, CXCL7, CD41, CD68 and von Willebrand factor. Results A machine learning approach identified expression of mRNA for CXCL4 and CXCL7 as potentially important in the classification of early RA versus resolving arthritis. mRNA levels for these chemokines were significantly elevated in patients with early RA compared with uninflamed controls. Significantly increased CXCL4 and CXCL7 protein expression was observed in patients with early RA compared with those with resolving arthritis or longer established disease. CXCL4 and CXCL7 co-localised with blood vessels, platelets and CD68 + macrophages. Extravascular CXCL7 expression was significantly higher in patients with very early RA compared with longer duration RA or resolving arthritis Conclusions Taken together, these observations suggest a transient increase in synovial CXCL4 and CXCL7 levels in early RA.
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1.66 CXCL4 and CXCL7 expression on macrophages: a potential predictor of disease outcome in patients presenting with early synovitis?
Annals of the Rheumatic Diseases, 2014Co-Authors: Nichola J Adlard, Lorraine Yeo, Debbie L. Hardie, Holly Adams, Maria Juarez, Christopher D. Buckley, Karim Raza, Andrew Filer, Dagmar Scheel-toellnerAbstract:Background and Objectives Within the context of a comprehensive study of the pathology of the early stages of rheumatoid arthritis (RA) we compared cytokine mRNA expression in the synovium of patients with early inflammatory arthritis who later progressed to rheumatoid arthritis with that of patients with a resolving disease course. Interestingly, we found a trend towards higher expression of platelet related chemokines CXCL4 and CXCL7 mRNA in early RA synovium. We therefore investigated CXCL4 and CXCL7 expression at the protein level and its co-localisation with platelets, macrophages and blood vessels. Methods Synovial tissue biopsies were obtained from treatment naive patients presenting with at least one clinically swollen joint within the first 12 weeks of symptom onset. Patients who went on to develop RA (according to the 1987 ACR criteria) at an 18 month follow-up (n = 8), as well as patients whose arthritis spontaneously resolved (n = 9) were included. In addition, biopsies collected from longer duration (> 12 weeks) treatment naive RA patients (n = 10) and patients with mechanical symptoms undergoing knee arthroscopy without obvious signs of inflammation were included as controls (n = 7). Synovial tissue sections were stained with antibodies specific to CXCL4 or CXCL7, CD41, CD68 and vWF using immunofluorescence and staining was quantified using Zeiss imaging software. Specificity of CXCL7 staining was confirmed by blocking with recombinant cytokine. Results We observed a statistically significant increase of CXCL4 and CXCL7 protein expression in patients with early RA when compared to early resolvers (CXCL4 p = 0.036, CXCL7 p = 0.011). This increase reflected a transient stage of early disease, as in treatment-naive patients with more than 12 weeks disease duration the expression level of these chemokines was found at levels comparable to non-inflamed synovium. Both CXCL4 and CXCL7 co-localised with blood vessels, platelets and CD68 + macrophages within the synovial tissue. However, only staining found outside blood vessels, which co-localised largely with CD68 as a marker for macrophages, differed between synovium from patients with resolving, early and established arthritis (CXCL4 p = 0.063, CXCL7 p = 0.028). Conclusions We have identified two chemokines, CXCL4 and CXCL7, that are expressed at higher levels on macrophages during a transient phase in early RA. Future work will investigate whether these chemokines play a role in disease progression and/or may be used as biomarkers for prediction of disease outcome.
Mattias Collin - One of the best experts on this subject based on the ideXlab platform.
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human chemokines as antimicrobial peptides with direct parasiticidal effect on leishmania mexicana in vitro
PLOS ONE, 2013Co-Authors: Sara Karlsson Sobirk, Matthias Morgelin, Arne Egesten, Paul A Bates, Oonagh Shannon, Mattias CollinAbstract:Chemokines and chemokine receptor-mediated effects are important mediators of the immunological response and cure in human leishmaniasis. However, in addition to their signalling properties for leukocytes, many chemokines have also been shown to act directly as antimicrobial peptides on bacteria and fungi. We screened ten human chemokines (CXCL2, CXCL6, CXCL8, CXCL9, CXCL10, CCL2, CCL3, CCL20, CCL27, CCL28) for antimicrobial effects on the promastigote form of the protozoan parasite Leishmania mexicana, and observed direct parasiticidal effects of several, CCL28 being the most potent. Damage to the plasma membrane integrity could be visualised by entrance of propidium iodide, as measured with flow cytometry, and by scanning electron microscopy, which showed morphological changes and aggregation of cells. The findings were in concordance with parasiticidal activity, measured by decreased mitochondrial activity in an MTT-assay. This is the first report of direct antimicrobial activity by chemokines on parasites. This component of immunity against Leishmania parasites identified here warrants further investigation that might lead to new insight in the mechanisms of human infection and/or new therapeutic approaches.
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SpeB of Streptococcus pyogenes Differentially Modulates Antibacterial and Receptor Activating Properties of Human Chemokines
PloS one, 2009Co-Authors: Arne Egesten, Matthias Morgelin, Anders I. Olin, Helena M. Linge, Manisha Yadav, Anna Karlsson, Mattias CollinAbstract:BACKGROUND: CXC chemokines are induced by inflammatory stimuli in epithelial cells and some, like MIG/CXCL9, IP-10/CXCL10 and I-TAC/CXCL11, are antibacterial for Streptococcus pyogenes. METHODOLOGY/PRINCIPAL FINDINGS: SpeB from S. pyogenes degrades a wide range of chemokines (i.e. IP10/CXCL10, I-TAC/CXCL11, PF4/CXCL4, GROalpha/CXCL1, GRObeta/CXCL2, GROgamma/CXCL3, ENA78/CXCL5, GCP-2/CXCL6, NAP-2/CXCL7, SDF-1/CXCL12, BCA-1/CXCL13, BRAK/CXCL14, SRPSOX/CXCL16, MIP-3alpha/CCL20, Lymphotactin/XCL1, and Fractalkine/CX3CL1), has no activity on IL-8/CXCL8 and RANTES/CCL5, partly degrades SRPSOX/CXCL16 and MIP-3alpha/CCL20, and releases a 6 kDa CXCL9 fragment. CXCL10 and CXCL11 loose receptor activating and antibacterial activities, while the CXCL9 fragment does not activate the receptor CXCR3 but retains its antibacterial activity. CONCLUSIONS/SIGNIFICANCE: SpeB destroys most of the signaling and antibacterial properties of chemokines expressed by an inflamed epithelium. The exception is CXCL9 that preserves its antibacterial activity after hydrolysis, emphasizing its role as a major antimicrobial on inflamed epithelium. (Less)
Lorraine Yeo - One of the best experts on this subject based on the ideXlab platform.
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Expression of chemokines CXCL4 and CXCL7 by synovial macrophages defines an early stage of rheumatoid arthritis
Annals of the rheumatic diseases, 2015Co-Authors: Lorraine Yeo, Nichola J Adlard, Maria Juarez, Christopher D. Buckley, Karim Raza, Andrew Filer, Michael Biehl, T. Smallie, Martyn Snow, Dagmar Scheel-toellnerAbstract:Background and objectives For our understanding of the pathogenesis of rheumatoid arthritis (RA), it is important to elucidate the mechanisms underlying early stages of synovitis. Here, synovial cytokine production was investigated in patients with very early arthritis. Methods Synovial biopsies were obtained from patients with at least one clinically swollen joint within 12 weeks of symptom onset. At an 18-month follow-up visit, patients who went on to develop RA, or whose arthritis spontaneously resolved, were identified. Biopsies were also obtained from patients with RA with longer symptom duration (>12 weeks) and individuals with no clinically apparent inflammation. Synovial mRNA expression of 117 cytokines was quantified using PCR techniques and analysed using standard and novel methods of data analysis. Synovial tissue sections were stained for CXCL4, CXCL7, CD41, CD68 and von Willebrand factor. Results A machine learning approach identified expression of mRNA for CXCL4 and CXCL7 as potentially important in the classification of early RA versus resolving arthritis. mRNA levels for these chemokines were significantly elevated in patients with early RA compared with uninflamed controls. Significantly increased CXCL4 and CXCL7 protein expression was observed in patients with early RA compared with those with resolving arthritis or longer established disease. CXCL4 and CXCL7 co-localised with blood vessels, platelets and CD68 + macrophages. Extravascular CXCL7 expression was significantly higher in patients with very early RA compared with longer duration RA or resolving arthritis Conclusions Taken together, these observations suggest a transient increase in synovial CXCL4 and CXCL7 levels in early RA.
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1.66 CXCL4 and CXCL7 expression on macrophages: a potential predictor of disease outcome in patients presenting with early synovitis?
Annals of the Rheumatic Diseases, 2014Co-Authors: Nichola J Adlard, Lorraine Yeo, Debbie L. Hardie, Holly Adams, Maria Juarez, Christopher D. Buckley, Karim Raza, Andrew Filer, Dagmar Scheel-toellnerAbstract:Background and Objectives Within the context of a comprehensive study of the pathology of the early stages of rheumatoid arthritis (RA) we compared cytokine mRNA expression in the synovium of patients with early inflammatory arthritis who later progressed to rheumatoid arthritis with that of patients with a resolving disease course. Interestingly, we found a trend towards higher expression of platelet related chemokines CXCL4 and CXCL7 mRNA in early RA synovium. We therefore investigated CXCL4 and CXCL7 expression at the protein level and its co-localisation with platelets, macrophages and blood vessels. Methods Synovial tissue biopsies were obtained from treatment naive patients presenting with at least one clinically swollen joint within the first 12 weeks of symptom onset. Patients who went on to develop RA (according to the 1987 ACR criteria) at an 18 month follow-up (n = 8), as well as patients whose arthritis spontaneously resolved (n = 9) were included. In addition, biopsies collected from longer duration (> 12 weeks) treatment naive RA patients (n = 10) and patients with mechanical symptoms undergoing knee arthroscopy without obvious signs of inflammation were included as controls (n = 7). Synovial tissue sections were stained with antibodies specific to CXCL4 or CXCL7, CD41, CD68 and vWF using immunofluorescence and staining was quantified using Zeiss imaging software. Specificity of CXCL7 staining was confirmed by blocking with recombinant cytokine. Results We observed a statistically significant increase of CXCL4 and CXCL7 protein expression in patients with early RA when compared to early resolvers (CXCL4 p = 0.036, CXCL7 p = 0.011). This increase reflected a transient stage of early disease, as in treatment-naive patients with more than 12 weeks disease duration the expression level of these chemokines was found at levels comparable to non-inflamed synovium. Both CXCL4 and CXCL7 co-localised with blood vessels, platelets and CD68 + macrophages within the synovial tissue. However, only staining found outside blood vessels, which co-localised largely with CD68 as a marker for macrophages, differed between synovium from patients with resolving, early and established arthritis (CXCL4 p = 0.063, CXCL7 p = 0.028). Conclusions We have identified two chemokines, CXCL4 and CXCL7, that are expressed at higher levels on macrophages during a transient phase in early RA. Future work will investigate whether these chemokines play a role in disease progression and/or may be used as biomarkers for prediction of disease outcome.
Rakesh K. Singh - One of the best experts on this subject based on the ideXlab platform.
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Abstract 693: Evaluating the role of CXCR2 receptor and its ligand in breast cancer therapy resistance
Cancer Research, 2011Co-Authors: Bhawna Sharma, Dhananjay M. Nawandar, Michelle L. Varney, Rakesh K. SinghAbstract:Breast cancer is the second leading cause of cancer deaths among women after lung cancer, accounting for more than 40,000 deaths each year. Although there has been advancement in the treatment and diagnosis of breast cancer, therapy resistance and relapse are still big hurdles in the way. Recent reports and our preliminary studies suggest that malignant cells that survive the initial chemo- and radiation therapy express higher levels of CXCR2 ligands which might provide a survival benefit to malignant tumors leading to therapy resistance. The specific objective for this study involves targeting CXCR2 receptor and its ligands mediated signaling for therapy resistance in mammary tumor cells. Our hypothesis is that CXCR2 along with its ligands plays an important role in therapy resistance and that targeting this signaling pathway will provide an effective strategy to overcome the problem. We used mammary tumor cells expressing different levels of CXCR2 (Cl66-wt and Cl66-shCXCR2) and examined their response to Paclitaxel and Doxorubicin. We observed significant enhancement of paclitaxel and doxorubicin-mediated toxicity at lower concentrations in Cl66-shCXCR2 cells as compared to Cl66-wt cells. Moreover, we observed an increase in the expression of CXCL1, a CXCR2 ligand, with increasing doses of drugs. However, paclitaxel and doxorubicin induced CXCL-1 levels was significantly lower in Cl66-shCXCR2 cells as compared to Cl66-wt cells. To further validate our findings we selected Cl66 against paclitaxel and doxorubicin resistant cells by treating with increasing doses of these drugs. Cells were maintained in 500nM doxorubicin and 400nM paclitaxel. We analyzed the sensitivity of these cells to doxorubicin and paclitaxel in comparison to wild type parent cells. We observed that resistant cells survive even at higher concentrations (higher than at which they are maintained) of drugs. Although, paclitaxel resistant cells appears to be sensitive at higher doses of paclitaxel when compared to doxorubicin resistant cells in the same set of experiments. Further studies showed an increase in the expression of CXCL1 in the supernatant of these cells after drug treatment. The expression of CXCL1 was higher even at the basal level in the resistant cells in comparison to the parent cells. As it has been shown that expression of CXCR2 ligands increase after chemotherapy, we examined the expression profile of various CXCR2 ligands in these cells at the mRNA level. We observed that these cells express higher levels of CXCL5, CXCL3 and CXCL7, in comparison to parent Cl66 cells. Together, these results demonstrate that i) CXCR2 and its ligand-mediated signaling plays an important role in the drug resistance of mammary tumors cells; ii) that paclitaxel seems to be more effective against mammary tumor cells in comparison to doxorubicin; and iii) targeting CXCR2 expression enhanced chemotherapeutic responses. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 693. doi:10.1158/1538-7445.AM2011-693
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Constitutive expression of growth regulated oncogene (gro) in human colon carcinoma cells with different metastatic potential and its role in regulating their metastatic phenotype
Clinical & Experimental Metastasis, 2005Co-Authors: Aihua Li, Michelle L. Varney, Rakesh K. SinghAbstract:The purpose of this study was to examine the expression and functional significance of the growth-regulated oncogene ( gro ) family in human colon carcinoma growth and metastasis. We examined constitutive expression of CXCL1 ( gro - α ), CXCL2 ( gro - β ), CXCL3 ( gro - γ ) and their receptor, CXCR2 in human colon carcinoma cells with different metastatic potentials. Non-metastatic and low metastatic cells expressed lower levels of CXCL1 and CXCR2 mRNA and protein as compared to high metastatic colon carcinoma cells. No difference in CXCL2 and CXCL3 mRNA expression levels was observed. Colon carcinoma cells expressing higher levels of CXCL1 exhibit increased proliferation and invasive potential. Furthermore, exogenous addition of recombinant human CXCL1 significantly enhanced the proliferation and invasiveness of colon carcinoma cells. Furthermore, treatment of KM12C cells with exogenous CXCL1 enhanced their invasiveness. Neutralizing antibody to CXCL1 in combination with antibody to CXCR2 inhibited highly metastatic KM12L4 (high CXCL1 expressor) cell proliferation. These data demonstrate that the constitutive expression of CXCL1 and its receptor CXCR2 is associated with metastatic potential and modulates colon cancer cell proliferation and an invasive phenotype.
