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Publication
Journal: Critical Reviews in Oncology/Hematology
May/12/2008
Abstract
The link between inflammation and cancer proposed more than a century ago by Rudolf Virchow, who noticed the infiltration of leukocytes in malignant tissues, has recently found a number of genetic and molecular confirmations. Experimental, clinical and epidemiological studies have revealed that chronic inflammation contributes to cancer progression and even predisposes to different types of cancer. Cancer-associated inflammation includes: the presence of leukocyte infiltration; the expression of cytokines such as tumor necrosis factor (TNF) or interleukin (IL)-1; chemokines such as CCL2 and CXCL8; active tissue remodelling and neo-angiogenesis. Tumor-associated macrophages (TAM) are key regulators of the link between inflammation and cancer. Many observations indicate that, in the tumor micro-environment, TAM have several protumoral functions, including expression of growth factors, matrix proteases, promotion of angiogenesis and suppression of adaptive immunity. In this review we will discuss the role of TAM in the inflammatory micro-environment of solid tumors and will try to identify potential target for future therapeutic approaches.
Publication
Journal: Neuro-Oncology
May/25/2005
Abstract
Interleukin-8 (IL-8, or CXCL8), which is a chemokine with a defining CXC amino acid motif that was initially characterized for its leukocyte chemotactic activity, is now known to possess tumorigenic and proangiogenic properties as well. In human gliomas, IL-8 is expressed and secreted at high levels both in vitro and in vivo, and recent experiments suggest it is critical to glial tumor neovascularity and progression. Levels of IL-8 correlate with histologic grade in glial neoplasms, and the most malignant form, glioblastoma, shows the highest expression in pseudopalisading cells around necrosis, suggesting that hypoxia/anoxia may stimulate expression. In addition to hypoxia/anoxia stimulation, increased IL-8 in gliomas occurs in response to Fas ligation, death receptor activation, cytosolic Ca(2+), TNF-alpha, IL-1, and other cytokines and various cellular stresses. The IL-8 promoter contains binding sites for the transcription factors NF-kappaB, AP-1, and C-EBP/NF-IL-6, among others. AP-1 has been shown to mediate IL-8 upregulation by anoxia in gliomas. The potential tumor suppressor ING4 was recently shown to be a critical regulator of NF-kappaB-mediated IL-8 transcription and subsequent angiogenesis in gliomas. The IL-8 receptors that could contribute to IL-8-mediated tumorigenic and angiogenic responses include CXCR1 and CXCR2, both of which are G-protein coupled, and the Duffy antigen receptor for cytokines, which has no defined intracellular signaling capabilities. The proangiogenic activity of IL-8 occurs predominantly following binding to CXCR2, but CXCR1 appears to contribute as well through independent, small-GTPase activity. A precise definition of the mechanisms by which IL-8 exerts its proangiogenic functions requires further study for the development of effective IL-8-targeted therapies.
Publication
Journal: Cytokine and Growth Factor Reviews
May/24/2020
Abstract
In 2019-2020 a new coronavirus named SARS-CoV-2 was identified as the causative agent of a several acute respiratory infection named COVID-19, which is causing a worldwide pandemic. There are still many unresolved questions regarding the pathogenesis of this disease and especially the reasons underlying the extremely different clinical course, ranging from asymptomatic forms to severe manifestations, including the Acute Respiratory Distress Syndrome (ARDS). SARS-CoV-2 showed phylogenetic similarities to both SARS-CoV and MERS-CoV viruses, and some of the clinical features are shared between COVID-19 and previously identified beta-coronavirus infections. Available evidence indicate that the so called "cytokine storm" an uncontrolled over-production of soluble markers of inflammation which, in turn, sustain an aberrant systemic inflammatory response, is a major responsible for the occurrence of ARDS. Chemokines are low molecular weight proteins with powerful chemoattractant activity which play a role in the immune cell recruitment during inflammation. This review will be aimed at providing an overview of the current knowledge on the involvement of the chemokine/chemokine-receptor system in the cytokine storm related to SARS-CoV-2 infection. Basic and clinical evidences obtained from previous SARS and MERS epidemics and available data from COVID-19 will be taken into account.
Keywords: COVID-19; CXCL10; CXCL8; Chemokines; Coronavirus; Cytokine storm.
Publication
Journal: Blood
January/27/2010
Abstract
Interleukin-17A (IL-17A) and IL-17F are 2 of several cytokines produced by T helper 17 cells (Th17), which are able to indirectly induce the recruitment of neutrophils. Recently, human Th17 cells have been phenotypically characterized and shown to express discrete chemokine receptors, including CCR2 and CCR6. Herein, we show that highly purified neutrophils cultured with interferon-gamma plus lipopolysaccharide produce the CCL2 and CCL20 chemokines, the known ligands of CCR2 and CCR6, respectively. Accordingly, supernatants from activated neutrophils induced chemotaxis of Th17 cells, which was greatly suppressed by anti-CCL20 and anti-CCL2 antibodies. We also discovered that activated Th17 cells could directly chemoattract neutrophils via the release of biologically active CXCL8. Consistent with this reciprocal recruitment, neutrophils and Th17 cells were found in gut tissue from Crohn disease and synovial fluid from rheumatoid arthritis patients. Finally, we report that, although human Th17 cells can directly interact with freshly isolated or preactivated neutrophils via granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, and interferon-gamma release, these latter cells cannot be activated by IL-17A and IL-17F, because of their lack of IL-17RC expression. Collectively, our results reveal a novel chemokine-dependent reciprocal cross-talk between neutrophils and Th17 cells, which may represent a useful target for the treatment of chronic inflammatory diseases.
Publication
Journal: Stem Cells
June/29/2006
Abstract
Stromal cells isolated from bone marrow (BMSCs), often referred to as mesenchymal stem cells, are currently under investigation for a variety of therapeutic applications. However, limited data are available regarding receptors that can influence their homing to and positioning within the bone marrow. In the present study, we found that second passage BMSCs express a unique set of chemokine receptors: three CC chemokine receptors (CCR1, CCR7, and CCR9) and three CXC chemokine receptors (CXCR4, CXCR5, and CXCR6). BMSCs cultured in serum-free medium secrete several chemokine ligands (CCL2, CCL4, CCL5, CCL20, CXCL12, CXCL8, and CX3CL1). The surface-expressed chemokine receptors were functional by several criteria. Stimulation of BMSCs with chemokine ligands triggers phosphorylation of the mitogen-activated protein kinase (e.g., extracellular signal-related kinase [ERK]-1 and ERK-2) and focal adhesion kinase signaling pathways. In addition, CXCL12 selectively activates signal transducer and activator of transcription (STAT)-5 whereas CCL5 activates STAT-1. In cell biologic assays, all of the chemokines tested stimulate chemotaxis of BMSCs, and CXCL12 induces cytoskeleton F-actin polymerization. Studies of culture-expanded BMSCs, for example, 12-16 passages, indicate loss of surface expression of all chemokine receptors and lack of chemotactic response to chemokines. The loss in chemokine receptor expression is accompanied by a decrease in expression of adhesion molecules (ICAM-1, ICAM-2, and vascular cell adhesion molecule 1) and CD157, while expression of CD90 and CD105 is maintained. The change in BMSC phenotype is associated with slowing of cell growth and increased spontaneous apoptosis. These findings suggest that several chemokine axes may operate in BMSC biology and may be important parameters in the validation of cultured BMSCs intended for cell therapy.
Publication
Journal: Cancer Research
July/10/2011
Abstract
Lactate generated from pyruvate fuels production of intracellular NAD(+) as an end result of the glycolytic process in tumors. Elevated lactate concentration represents a good indicator of the metabolic adaptation of tumors and is actually correlated to clinical outcome in a variety of human cancers. In this study, we investigated whether lactate could directly modulate the endothelial phenotype and thereby tumor vascular morphogenesis and perfusion. We found that lactate could enter endothelial cells through the monocarboxylate transporter MCT-1, trigger the phosphorylation/degradation of IκBα, and then stimulate an autocrine NF-κB/IL-8 (CXCL8) pathway driving cell migration and tube formation. These effects were prevented by 2-oxoglutarate and reactive oxygen species (ROS) inhibitors, pointing to a role for prolyl-hydroxylase and ROS in the integration of lactate signaling in endothelial cells. PHD2 silencing in endothelial cells recapitulated the proangiogenic effects of lactate, whereas a blocking IL-8 antibody or IL-8-targeting siRNA prevented them. Finally, we documented in mouse xenograft models of human colorectal and breast cancer that lactate release from tumor cells through the MCT4 (and not MCT1) transporter is sufficient to stimulate IL-8-dependent angiogenesis and tumor growth. In conclusion, our findings establish a signaling role for lactate in endothelial cells and they identify the lactate/NF-κB/IL-8 pathway as an important link between tumor metabolism and angiogenesis.
Publication
Journal: Nature Medicine
August/14/2008
Abstract
Reactive oxygen species (ROS) induce chemokines responsible for the recruitment of inflammatory cells to sites of injury or infection. Here we show that the plasma membrane Ca(2+)-permeable channel TRPM2 controls ROS-induced chemokine production in monocytes. In human U937 monocytes, hydrogen peroxide (H(2)O(2)) evokes Ca(2+) influx through TRPM2 to activate Ca(2+)-dependent tyrosine kinase Pyk2 and amplify Erk signaling via Ras GTPase. This elicits nuclear translocation of nuclear factor-kappaB essential for the production of the chemokine interleukin-8 (CXCL8). In monocytes from Trpm2-deficient mice, H(2)O(2)-induced Ca(2+) influx and production of the macrophage inflammatory protein-2 (CXCL2), the mouse CXCL8 functional homolog, were impaired. In the dextran sulfate sodium-induced colitis inflammation model, CXCL2 expression, neutrophil infiltration and ulceration were attenuated by Trpm2 disruption. Thus, TRPM2 Ca(2+) influx controls the ROS-induced signaling cascade responsible for chemokine production, which aggravates inflammation. We propose functional inhibition of TRPM2 channels as a new therapeutic strategy for treating inflammatory diseases.
Publication
Journal: Frontiers in Bioscience - Landmark
December/10/2007
Abstract
Neutrophils are the first to be recruited to a site of infection or a diseased site. Among various inflammatory mediators, CXC chemokines including IL-8 (CXCL8), MIP-2 (CXCL2), and KC (CXCL1) are the most critical for such recruitment. Neutrophils have been considered as effector cells that kill bacteria or destroy affected tissues mainly through the production of reactive oxygen species. Recent studies, however, revealed that neutrophils are involved in the production of chemokines in response to a variety of stimulants including LPS, TNF-alpha, and IFN-gamma, thereby contributing to immunomodulation. These functions are also regulated by selectins during infiltration into various sites. In this review, I summarize the current knowledge on this area and propose that neutrophils are a fascinating target for basic as well as clinical scientists.
Publication
Journal: Science Translational Medicine
October/26/2014
Abstract
Suppression of the host's immune system plays a major role in cancer progression. Tumor signaling of programmed death 1 (PD1) on T cells and expansion of myeloid-derived suppressor cells (MDSCs) are major mechanisms of tumor immune escape. We sought to target these pathways in rhabdomyosarcoma (RMS), the most common soft tissue sarcoma of childhood. Murine RMS showed high surface expression of PD-L1, and anti-PD1 prevented tumor growth if initiated early after tumor inoculation; however, delayed anti-PD1 had limited benefit. RMS induced robust expansion of CXCR2(+)CD11b(+)Ly6G(hi) MDSCs, and CXCR2 deficiency prevented CD11b(+)Ly6G(hi) MDSC trafficking to the tumor. When tumor trafficking of MDSCs was inhibited by CXCR2 deficiency, or after anti-CXCR2 monoclonal antibody therapy, delayed anti-PD1 treatment induced significant antitumor effects. Thus, CXCR2(+)CD11b(+)Ly6G(hi) MDSCs mediate local immunosuppression, which limits the efficacy of checkpoint blockade in murine RMS. Human pediatric sarcomas also produce CXCR2 ligands, including CXCL8. Patients with metastatic pediatric sarcomas display elevated serum CXCR2 ligands, and elevated CXCL8 is associated with diminished survival in this population. We conclude that accumulation of MDSCs in the tumor bed limits the efficacy of checkpoint blockade in cancer. We also identify CXCR2 as a novel target for modulating tumor immune escape and present evidence that CXCR2(+)CD11b(+)Ly6G(hi) MDSCs are an important suppressive myeloid subset in pediatric sarcomas. These findings present a translatable strategy to improve the efficacy of checkpoint blockade by preventing trafficking of MDSCs to the tumor site.
Publication
Journal: Respiratory Research
December/12/2006
Abstract
BACKGROUND
The role of Th2 cells (producing interleukin (IL-)4, IL-5 and IL-13) in allergic asthma is well-defined. A distinct proinflammatory T cell lineage has recently been identified, called Th17 cells, producing IL-17A, a cytokine that induces CXCL8 (IL-8) and recruits neutrophils. Neutrophilic infiltration in the airways is prominent in severe asthma exacerbations and may contribute to airway gland hypersecretion, bronchial hyper-reactivity and airway wall remodelling in asthma.
OBJECTIVE
to study the production of IL-17 in asthmatic airways at the mRNA level, and to correlate this with IL-8 mRNA, neutrophilic inflammation and asthma severity.
METHODS
We obtained airway cells by sputum induction from healthy individuals (n = 15) and from asthmatic patients (n = 39). Neutrophils were counted on cytospins and IL-17A and IL-8 mRNA expression was quantified by real-time RT-PCR (n = 11 controls and 33 asthmatics).
RESULTS
Sputum IL-17A and IL-8 mRNA levels are significantly elevated in asthma patients compared to healthy controls. IL-17 mRNA levels are significantly correlated with CD3gamma mRNA levels in asthmatic patients and mRNA levels of IL-17A and IL-8 correlated with each other and with sputum neutrophil counts. High sputum IL-8 and IL-17A mRNA levels were also found in moderate-to-severe (persistent) asthmatics on inhaled steroid treatment.
CONCLUSIONS
The data suggest that Th17 cell infiltration in asthmatic airways links T cell activity with neutrophilic inflammation in asthma.
Publication
Journal: Circulation
April/15/2009
Abstract
BACKGROUND
Atherosclerosis is an inflammatory disease in which interferon (IFN)-gamma, the signature cytokine of Th1 cells, plays a central role. We investigated whether interleukin (IL)-17, the signature cytokine of Th17 cells, is also associated with human coronary atherosclerosis.
RESULTS
Circulating IL-17 and IFN-gamma were detected in a subset of patients with coronary atherosclerosis and in referent outpatients of similar age without cardiac disease but not in young healthy individuals. IL-17 plasma levels correlated closely with those of the IL-12/IFN-gamma/CXCL10 cytokine axis but not with known Th17 inducers such as IL-1beta, IL-6, and IL-23. Both IL-17 and IFN-gamma were produced at higher levels by T cells within cultured atherosclerotic coronary arteries after polyclonal activation than within nondiseased vessels. Combinations of proinflammatory cytokines induced IFN-gamma but not IL-17 secretion. Blockade of IFN-gamma signaling increased IL-17 synthesis, whereas neutralization of IL-17 responses decreased IFN-gamma synthesis; production of both cytokines was inhibited by transforming growth factor-beta1. Approximately 10-fold fewer coronary artery-infiltrating T helper cells were IL-17 producers than IFN-gamma producers, and unexpectedly, IL-17/IFN-gamma double producers were readily detectable within the artery wall. Although IL-17 did not modulate the growth or survival of cultured vascular smooth muscle cells, IL-17 interacted cooperatively with IFN-gamma to enhance IL-6, CXCL8, and CXCL10 secretion.
CONCLUSIONS
Our findings demonstrate that IL-17 is produced concomitantly with IFN-gamma by coronary artery-infiltrating T cells and that these cytokines act synergistically to induce proinflammatory responses in vascular smooth muscle cells.
Publication
Journal: Journal of Immunology
November/28/2005
Abstract
In this study, we examined the biological action of IL-17 on human non-small cell lung cancer (NSCLC). Although IL-17 had no direct effect on the in vitro growth rate of NSCLC, IL-17 selectively augmented the secretion of an array of angiogenic CXC chemokines, including CXCL1, CXCL5, CXCL6, and CXCL8 but not angiostatic chemokines, by three different NSCLC lines. Endothelial cell chemotactic activity (as a measure of net angiogenic potential) was increased in response to conditioned medium from NSCLC stimulated with IL-17 compared with those from unstimulated NSCLC. Enhanced chemotactic activity was suppressed by neutralizing mAb(s) to CXCL1, CXCL5, and CXCL8 or to CXCR-2 but not to vascular endothelial growth factor-A. Transfection with IL-17 into NSCLC had no effect on the in vitro growth, whereas IL-17 transfectants grew more rapidly compared with controls when transplanted in SCID mice. This IL-17-elicited enhancement of NSCLC growth was associated with increased tumor vascularity. Moreover, treatment with anti-mouse CXCR-2-neutralizing Ab significantly attenuated the growth of both neomycin phosphotransferase gene-transfected and IL-17-transfected NSCLC tumors in SCID mice. A potential role for IL-17 in modulation of the human NSCLC phenotype was supported by the findings that, in primary NSCLC tissues, IL-17 expression was frequently detected in accumulating and infiltrating inflammatory cells and that high levels of IL-17 expression were associated with increased tumor vascularity. These results demonstrate that IL-17 increases the net angiogenic activity and in vivo growth of NSCLC via promoting CXCR-2-dependent angiogenesis and suggest that targeting CXCR-2 signaling may be a novel promising strategy to treat patients with NSCLC.
Publication
Journal: Journal of Leukocyte Biology
March/4/2007
Abstract
High mobility group box-1 (HMGB1) protein is a nonhistone, DNA-binding protein that plays a critical role in regulating gene transcription. Recently, HMGB1 has also been shown to act as a late mediator of endotoxic shock and to exert a variety of proinflammatory, extracellular activities. Here, we report that HMGB1 simultaneously acts as a chemoattractant and activator of dendritic cells (DCs). HMGB1 induced the migration of monocyte-derived, immature DCs (Mo-iDCs) but not mature DCs. The chemotactic effect of HMGB1 on iDCs was pertussis toxin-inhibitable and also inhibited by antibody against the receptor of advanced glycation end products (RAGE), suggesting that HMGB1 chemoattraction of iDCs is mediated by RAGE in a Gi protein-dependent manner. In addition, HMGB1 treatment of Mo-iDCs up-regulated DC surface markers (CD80, CD83, CD86, and HLA-A,B,C), enhanced DC production of cytokines (IL-6, CXCL8, IL-12p70, and TNF-alpha), switched DC chemokine responsiveness from CCL5-sensitive to CCL21-sensitive, and acquired the capacity to stimulate allogeneic T cell proliferation. Based on its dual DC-attracting and -activating activities as well as its reported capacity to promote an antigen-specific immune response, we consider HMGB1 to have the properties of an immune alarmin.
Publication
Journal: Journal of Biological Chemistry
April/22/2003
Abstract
Angiogenesis plays a critical role in metastasis and tumor growth. Human tumors, including colorectal adenocarcinoma, secrete angiogenic factors, inducing proliferation and chemotaxis of microvascular endothelial cells, eventually leading to tumor neovascularization. The chemokine interleukin 8 (IL-8; CXCL8) exerts potent angiogenic properties on endothelial cells through interaction with its cognate receptors CXCR1 and CXCR2. As CXCR1 and CXCR2 expression is differentially regulated in tissue-specific endothelial cells and effects of IL-8 on intestinal endothelial cells are not defined, we characterized the potential IL-8-induced angiogenic mechanisms in primary cultures of human intestinal microvascular endothelial cells (HIMEC) and IL-8 receptor expression in human intestinal microvessels. CXCR1 and CXCR2 expression on HIMEC were defined using reverse transcriptase-PCR, immunohistochemistry, flow cytometry, and Western blot analysis. IL-8-induced downstream signaling events were assessed using immunoblot analysis and immunofluorescence. The angiogenic effects of IL-8 on HIMEC were determined using proliferation and chemotaxis assays. HIMEC responded to IL-8 with rapid stress fiber assembly, chemotaxis, enhanced proliferation, and phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK 1/2). HIMEC express CXCR2, but not CXCR1. Neutralizing antibodies to CXCR2 diminished IL-8-induced chemotaxis and stress fiber assembly. Specific inhibitors of ERK 1/2 and phosphoinositide 3-kinase abrogated endothelial tube formation and IL-8-induced chemotaxis in HIMEC. IL-8 elicits angiogenic responses in microvascular endothelial cells isolated from human intestine by engaging CXCR2. We confirmed tissue expression of CXCR2 in human intestinal microvessels. Supported by the notion that malignant colonic epithelial cells overexpress IL-8, CXCR2 blockade may be a novel target for anti-angiogenic therapy in colorectal adenocarcinoma.
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Publication
Journal: Journal of Leukocyte Biology
February/20/2002
Abstract
Natural killer (NK) cells participate in innate and adaptive immune responses to obligate intracellular pathogens and malignant tumors. Two major NK cell subsets have been identified in humans: CD56(dim) CD16+ and CD56(bright) CD16-. Resting CD56(dim) CD16+ NK cells express CXCR1, CXCR2, CXCR3, CXCR4, and CX3CR1 but no detectable levels of CC chemokine receptors on the cell surface. They migrate vigorously in response to CXCL12 and CXC3L1. In contrast, resting CD56(bright) CD16- NK cells express little CXCR1, CXCR2, and CXC3R1 but high levels of CCR5 and CCR7. Chemotaxis of CD56(bright) CD16- NK cells is stimulated most potently by CCL19, CCL21, CXCL10, CXCL11, and CXCL12. Following activation, NK cells can migrate in response to additional CC and CXC chemokines. Cytolytic activity of NK cells is augmented by CCL2, CCL3, CCL4, CCL5, CCL10, and CXC3L1. Moreover, proliferation of CD56(dim) CD16+ NK cells is costimulated by CCL19 and CCL21. Activated NK cells produce XCL1, CCL1, CCL3, CCL4, CCL5, CCL22, and CXCL8. Chemokines secreted by NK cells may recruit other effector cells during immune responses. Furthermore, CCL3, CCL4, and CCL5 produced by NK cells can inhibit in vitro replication of HIV. CCL3 and CXL10 expression appear to be required for protective NK cell responses in vivo to murine cytomegalovirus or Leishmania major, respectively. Moreover, NK cells participate in the in vivo rejection of transduced tumor cells that produce CCL19 or CCL21. Thus, chemokines appear to play an important role in afferent and efferent NK cell responses to infected and neoplastic cells.
Publication
Journal: Journal of Cerebral Blood Flow and Metabolism
April/1/2010
Abstract
Chemokines and their receptors have crucial roles in the trafficking of leukocytes, and are of particular interest in the context of the unique immune responses elicited in the central nervous system (CNS). The chemokine system CC ligand 2 (CCL2) with its receptor CC receptor 2 (CCR2), as well as the receptor CXCR2 and its multiple ligands CXCL1, CXCL2 and CXCL8, have been implicated in a wide range of neuropathologies, including trauma, ischemic injury and multiple sclerosis. This review aims to overview the current understanding of chemokines as mediators of leukocyte migration into the CNS under neuroinflammatory conditions. We will specifically focus on the involvement of two chemokine networks, namely CCL2/CCR2 and CXCL8/CXCR2, in promoting macrophage and neutrophil infiltration, respectively, into the lesioned parenchyma after focal traumatic brain injury. The constitutive brain expression of these chemokines and their receptors, including their recently identified roles in the modulation of neuroprotection, neurogenesis, and neurotransmission, will be discussed. In conclusion, the value of evidence obtained from the use of Ccl2- and Cxcr2-deficient mice will be reported, in the context of potential therapeutics inhibiting chemokine activity which are currently in clinical trial for various inflammatory diseases.
Publication
Journal: Journal of Biological Chemistry
April/26/2009
Abstract
Vascular endothelial growth factor (VEGF) is a potent mitogen and permeability factor for endothelial cells that plays a central role in angiogenesis, vascular maintenance, inflammation, and cancer. VEGF also mediates the homeostatic adaptation to hypoxic conditions by promoting an increase in vascular density to compensate for decreased oxygenation. This process is triggered by an oxygen-sensitive transcription factor, hypoxia-inducible factor-1 (HIF1alpha), which becomes active in hypoxic tissues, leading to the synthesis and secretion of VEGF. The role of HIF1alpha in other processes that involve angiogenesis such as in inflammation is less clear. Of interest, endothelial cells not only respond to but also store and secrete VEGF, which is required for the maintenance of the integrity of the vascular system. How this intracellular pool of VEGF is regulated is still not understood. Here, we found that CXCL8/IL8, a potent proangiogenic and inflammatory chemokine, up-regulates VEGF mRNA and protein levels in endothelial cells by acting on its cognate receptor, CXCR2, and that this results in the autocrine activation of VEGFR2. Surprisingly, this process does not involve HIF1alpha but instead requires the activation of the transcription factor NFkappaB. Furthermore, we identified the components of the CBM complex, Carma3, Bcl10, and Malt1, as key mediators of the CXCL8/IL8-induced NFkappaB activation and VEGF up-regulation. Together, these findings support the existence of an NFkappaB-mediated pathway by which the proinflammatory chemokine CXCL8/IL8 controls the expression of VEGF in endothelial cells, thereby promoting the activation of VEGF receptors in an autocrine fashion.
Publication
Journal: Nature Medicine
February/3/2009
Abstract
Atherosclerosis is characterized by chronic inflammation of the arterial wall due to chemokine-driven mononuclear cell recruitment. Activated platelets can synergize with chemokines to exacerbate atherogenesis; for example, by deposition of the chemokines platelet factor-4 (PF4, also known as CXCL4) and RANTES (CCL5), triggering monocyte arrest on inflamed endothelium. Homo-oligomerization is required for the recruitment functions of CCL5, and chemokine heteromerization has more recently emerged as an additional regulatory mechanism, as evidenced by a mutual modulation of CXCL8 and CXCL4 activities and by enhanced monocyte arrest resulting from CCL5-CXCL4 interactions. The CCL5 antagonist Met-RANTES reduces diet-induced atherosclerosis; however, CCL5 antagonism may not be therapeutically feasible, as suggested by studies using Ccl5-deficient mice which imply that direct CCL5 blockade would severely compromise systemic immune responses, delay macrophage-mediated viral clearance and impair normal T cell functions. Here we determined structural features of CCL5-CXCL4 heteromers and designed stable peptide inhibitors that specifically disrupt proinflammatory CCL5-CXCL4 interactions, thereby attenuating monocyte recruitment and reducing atherosclerosis without the aforementioned side effects. These results establish the in vivo relevance of chemokine heteromers and show the potential of targeting heteromer formation to achieve therapeutic effects.
Publication
Journal: The Journal of investigative dermatology
February/11/2007
Abstract
Keratinocytes are continuously in contact with external stimuli and have the capacity to produce several soluble mediators. Pathogen-associated molecular patterns (PAMPs) are recognized, among others, by Toll-like receptors (TLRs). The functional responses of keratinocytes to different PAMPs have not yet been fully established. Here we show that keratinocytes constitutively express TLR1, 2, 3, 4, 5, 6, 9, and 10 mRNA, but not TLR7 and 8. Stimulation of keratinocytes with TLR3, 4, 5, and 9 ligands resulted in differential immune-associated responses. Tumor necrosis factor-alpha, CXC chemokine ligand 8 (CXCL8), CCL2, and C chemokine ligand 20 (CCL20) release was enhanced in response to all PAMPs tested, in a time- and dose-dependent manner. Only TLR9 ligand CpG-oligodeoxynucleotides (ODNs) and TLR3 ligand poly-I:C could additionally induce type I IFNs. CCL27 production was selectively induced by poly-I:C and flagellin, whereas CXCL9 and CXCL10 were exclusively induced by CpG-ODNs and/or poly-I:C. Upregulation of ICAM-1, HLA-DR, HLA-ABC, FasR, and CD40 was mainly observed in response to poly-I:C, flagellin, and lipopolysaccharide. Furthermore, PAMP triggering resulted in the phosphorylation of phosphorylated-IkappaB alpha and in the nucleus translocation of NF-kappaB p65. Altogether, these findings stress an unexpectedly multifaceted role of keratinocytes in innate immunity as evident by their differential, TLR-mediated responses to PAMPs associated with different classes of pathogens.
Publication
Journal: Cancer Microenvironment
November/9/2011
Abstract
Experimental and epidemiological studies indicate a strong link between chronic inflammation and tumor progression. Human colorectal cancer (CRC), a major cause of cancer-related death in Western countries, represents a paradigm for this link. Key features of cancer-related inflammation in CRC are the activation of transcription factors (e.g. NF-κB, STAT3), the expression of inflammatory cytokines and chemokines (e.g. TNFα, IL-6, CCL2, CXCL8) as well as a prominent leukocyte infiltrate. While considerable evidence indicates that the presence of lymphocytes of adaptive immunity may positively influence patient survival and clinical outcome in CRC, the role of tumor-associated macrophages (TAM) and of other lymphoid populations (e.g. Th17, Treg) is still unclear. In this review we will summarize the different and controversial effects that TAM play in CRC-related inflammation and progression of disease. The characterization of the most relevant inflammatory pathways in CRC is instrumental for the identification of new target molecules that could lead to improved diagnosis and treatment.
Publication
Journal: American Journal of Physiology - Lung Cellular and Molecular Physiology
April/9/2003
Abstract
Fifteen years have passed since the first description of interleukin (IL)-8/CXCL8 as a potent neutrophil chemotactic factor. Accumulating evidence has demonstrated that various types of cells can produce a large amount of IL-8/CXCL8 in response to a wide variety of stimuli, including proinflammatory cytokines, microbes and their products, and environmental changes such as hypoxia, reperfusion, and hyperoxia. Numerous observations have established IL-8/CXCL8 as a key mediator in neutrophil-mediated acute inflammation due to its potent actions on neutrophils. However, several lines of evidence indicate that IL-8/CXCL8 has a wide range of actions on various types of cells, including lymphocytes, monocytes, endothelial cells, and fibroblasts, besides neutrophils. The discovery of these biological functions suggests that IL-8/CXCL8 has crucial roles in various pathological conditions such as chronic inflammation and cancer. Here, an overview of its protein structure, mechanisms of production, and receptor system will be discussed as well as the pathophysiological roles of IL-8/CXCL8 in various types of lung pathologies.
Publication
Journal: Blood
June/4/2007
Abstract
Chemerin is a chemotactic agonist recently identified as the ligand of ChemR23, a serpentine receptor expressed by mononuclear phagocytes and dendritic cells (DCs). This study shows that blood CD56(low)CD16(+) natural killer (NK) cells selectively express functional ChemR23 and that this receptor is coexpressed with CXCR1, the CXCL8 receptor, and the KIR receptors. In vitro culturing of NK cells with IL-2 or IL-15 induced a delayed and time-dependent down-regulation of ChemR23 that was associated with the inhibition of NK cell migration to chemerin. Biopsies obtained from patients with oral lichen planus presented an infiltration of CD94(+)CD3(-)CD56(+) NK cells that coexpressed ChemR23. The same biopsies were infiltrated by myeloid, DC-SIGN(+) and plasmacytoid, CD123(+)BDCA2(+), ChemR23(+) dendritic cells that were occasionally associated with NK cells. In the same histologic sections, chemerin was expressed by inflamed dermal endothelium. These findings propose a role for the ChemR23/chemerin axis in the recruitment of blood NK cells and strongly implicate chemerin as a key factor for the colocalization of NK cells and DC subsets in pathologic peripheral tissues.
Publication
Journal: Journal of Cellular Biochemistry
June/5/2007
Abstract
The recruitment of bone marrow CD34- mesenchymal stem- and progenitor cells (MSC) and their subsequent differentiation into distinct tissues is the precondition for in situ tissue engineering. The objective of this study was to determine the entire chemokine receptor expression profile of human MSC and to investigate their chemotactic response to the selected chemokines CCL2, CXCL8 and CXCL12. Human MSC were isolated from iliac crest bone marrow aspirates and showed a homogeneous population presenting a typical MSC-related cell surface antigen profile (CD14-, CD34-, CD44+, CD45-, CD166+, SH-2+). The expression profile of all 18 chemokine receptors was determined by real-time PCR and immunohistochemistry. Both methods consistently demonstrated that MSC express CC, CXC, C and CX(3)C receptors. Gene expression and immunohistochemical analysis documented that MSC express chemokine receptors CCR2, CCR8, CXCR1, CXCR2 and CXCR3. A dose-dependent chemotactic activity of CXCR4 and CXCR1/CXCR2 ligands CXCL12 and CXCL8 (interleukin-8) was demonstrated using a 96-well chemotaxis assay. In contrast, the CCR2 ligand CCL2 (monocyte chemoattractant protein-1, MCP-1) did not recruited human MSC. In conclusion, we report that the chemokine receptor expression profile of human MSC is much broader than known before. Furthermore, for the first time, we demonstrate that human MSC migrate upon stimulation with CXCL8 but not CCL2. In combination with already known data on MSC recruitment and differentiation these are promising results towards in situ regenerative medicine approaches based on guiding of MSC to sites of degenerated tissues.
Publication
Journal: Journal of Clinical Investigation
November/26/2007
Abstract
Triggering receptor expressed on myeloid cells-1 (TREM-1) potently amplifies acute inflammatory responses by enhancing degranulation and secretion of proinflammatory mediators. Here we demonstrate that TREM-1 is also crucially involved in chronic inflammatory bowel diseases (IBD). Myeloid cells of the normal intestine generally lack TREM-1 expression. In experimental mouse models of colitis and in patients with IBD, however, TREM-1 expression in the intestine was upregulated and correlated with disease activity. TREM-1 significantly enhanced the secretion of relevant proinflammatory mediators in intestinal macrophages from IBD patients. Blocking TREM-1 by the administration of an antagonistic peptide substantially attenuated clinical course and histopathological alterations in experimental mouse models of colitis. This effect was also seen when the antagonistic peptide was administered only after the first appearance of clinical signs of colitis. Hence, TREM-1-mediated amplification of inflammation contributes not only to the exacerbation of acute inflammatory disorders but also to the perpetuation of chronic inflammatory disorders. Furthermore, interfering with TREM-1 engagement leads to the simultaneous reduction of production and secretion of a variety of pro-inflammatory mediators such as TNF, IL-6, IL-8 (CXCL8), MCP-1 (CCL2), and IL-1beta. Therefore, TREM-1 may also represent an attractive target for the treatment of chronic inflammatory disorders.
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