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At least 19 recordsLinked to original sources
PubMed1992

Interleukin-8 receptor-mediated chemotaxis of normal human epidermal cells.

Normal human keratinocytes show chemotactic behavior towards interleukin-8 (IL-8). Under physiological conditions this cytokine seems to be present in an equilibrium between monomeric and dimeric forms, as indicated by Western blotting data. Radioligand binding studies suggest that keratinocyte chemotaxis is mediated by receptors specific for IL-8 dimers. IL-8 receptor-specific mRNA can be detected in a keratinocyte cell line by polymerase chain reaction.

3T3 Cells↗
PubMed1992

Interleukin-8 as a macrophage-derived mediator of angiogenesis.

Angiogenic factors produced by monocytes-macrophages are involved in the pathogenesis of chronic inflammatory disorders characterized by persistent angiogenesis. The possibility was tested that interleukin-8 (IL-8), which is a cytokine that is chemotactic for lymphocytes and neutrophils, is also angiogenic. Human recombinant IL-8 was potently angiogenic when implanted in the rat cornea and induced proliferation and chemotaxis of human umbilical vein endothelial cells. Angiogenic activity present in the conditioned media of inflamed human rheumatoid synovial tissue macrophages or lipopolysaccharide-stimulated blood monocytes was equally blocked by antibodies to either IL-8 or tumor necrosis factor-alpha. An IL-8 antisense oligonucleotide specifically blocked the production of monocyte-induced angiogenic activity. These data suggest a function for macrophage-derived IL-8 in angiogenesis-dependent disorders such as rheumatoid arthritis, tumor growth, and wound repair.

Animals↗
PubMed1992

Amino terminus of the interleukin-8 receptor is a major determinant of receptor subtype specificity.

Interleukin-8 (IL-8) is a key mediator in the migration of neutrophils from the circulation to the site of inflammation in the tissue. IL-8 is secreted by many cell types in response to proinflammatory stimuli such as interleukin 1, tumor necrosis factor, and lipopolysaccharide and is a potent chemoattractant and activator of neutrophils. Neutrophil activating peptide-2 (NAP-2) and melanoma growth-stimulatory activity (MGSA/GRO) are structurally and functionally related to IL-8 and, like IL-8, bind to specific G protein-coupled receptors on neutrophils. In the present study two closely related cloned IL-8 receptor subtypes are characterized by expression of the cDNA clones in monkey kidney cells (COS-7) or chinese hamster ovary cells and analysis of their ligand binding profiles. Both receptor subtypes bind 125I-labeled IL-8 with similar high affinity, however, the F3R receptor binds IL-8 exclusively, while the 4Ab receptor binds both IL-8 and MGSA/GRO with high affinity and NAP-2 with lesser affinity. Furthermore, we demonstrate with the use of intersubtype chimeric receptors that the specificity of ligand binding to both IL-8 receptor subtypes is dictated by the heterogeneous NH2-terminal domain. The F3R receptor is representative of a restricted IL-8 receptor subtype, and 4Ab represents a nonrestricted receptor subtype. It is proposed that these subtypes be named IL-8 receptors alpha and beta, respectively.

Amino Acid Sequence↗
PubMed1992

Interleukin-8. A corneal factor that induces neovascularization.

A rabbit corneal pocket model was used to demonstrate that physiologic concentrations of human recombinant (r) IL-8 may induce corneal neovascularization. Computer-assisted analysis of sequential fluorescein angiograms showed that rIL-8 doses ranging from 2 to 40 ng/cornea (P = 0.01), but not high dose rIL-8 (400 ng/cornea), results in neovascularization within 14 days. Repeat fluorescein angiograms 6 weeks after placing angiogenic doses of rIL-8 demonstrated significant regression (P = 0.01) of the vascularity present at 2 weeks, suggesting that IL-8 angiogenesis undergoes dynamic modulation similar to that normally seen in wound healing. To our knowledge, this is the first study showing an angiogenic role for IL-8, a finding that emphasizes the interplay between inflammation and wound healing. Our results imply that corneal-derived IL-8 may be important in corneal neovascularization, in particular, and that IL-8 may modulate wound healing in general. Finally, these results raise the possibility that corneal-derived cytokines, such as IL-8, may obfuscate the effects of agents tested in experimental corneal pocket models.

Angiography↗
PubMed2025

Elevated circulating IL-8 correlates with poor prognosis in urological cancers: a meta-analysis and bioinformatic validation.

BACKGROUND: Interleukin-8 (IL-8) is a key cytokine that has been implicated in multiple aspects of cancer progression and therapeutic resistance. Elevated levels of circulating IL-8 (cIL-8) have been implicated in adverse clinical outcomes among patients with urological cancers. However, definitive evidence consolidating these observations remains lacking. The present study aims to synthesize the existing research findings to provide a comprehensive, evidence-based reference for clinical practice. METHODS: A systematic literature search was conducted to identify relevant studies that reported on the prognostic impact of cIL-8 levels in urological cancer patients. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were extracted and pooled to estimate the overall effect. Furthermore, Kaplan-Meier's survival analyses were conducted using RNA-seq data from The Cancer Genome Atlas (TCGA) through the Gene Expression Profiling Interactive Analysis 2 (GEPIA 2) online tool to validate the observed associations. RESULTS: A total of 19 cohorts encompassing 2740 patients from 12 studies were included in the meta-analysis. The findings revealed that elevated cIL-8 levels were significantly associated with inferior OS (HR: 1.86; 95% confidence intervals (CI): 1.72-2.02) and PFS (HR: 1.59; 95%CI: 1.25-2.03) in patients with urological cancers. The consistency and validity of these results were further supported by survival analyses performed using the GEPIA 2 tool. CONCLUSIONS: This study, which is the first meta-analysis to systematically examine the prognostic significance of cIL-8 in urological cancers, supported by bioinformatics validation, confirms that elevated cIL-8 levels serve as a potential biomarker for predicting adverse outcomes. Our findings underscore the importance of targeting IL-8 as a therapeutic strategy to overcome treatment resistance and improve outcomes for urological cancer patients. Further research into IL-8-targeted therapies and their integration into clinical practice is urgently needed to enhance the treatment landscape for urological cancers.

Humans↗
PubMed1992

Prolongation of survival of human polymorphonuclear neutrophils by granulocyte-macrophage colony-stimulating factor is caused by inhibition of programmed cell death.

In the absence of appropriate stimuli, polymorphonuclear neutrophils (PMN) undergo programmed cell death (PCD), also termed apoptosis. We show that granulocyte-macrophage colony-stimulating factor (GM-CSF), but not the chemotactic factors formyl-methionyl-leucyl-phenylalanine (FMLP), recombinant human (rh) C5a, transforming growth factor (TGF)-beta, and interleukin-8 (IL-8), or other cytokines including IL-3, IL-4, IL-6, and G-CSF, maintains viability of PMN in culture by preventing these cells from undergoing PCD. Prevention from PCD by GM-CSF was associated with induction of RNA and protein synthesis in PMN. Inhibition of RNA and protein synthesis by actinomycin-D and cycloheximide impeded the protection of apoptosis by GM-CSF. Similarly, neutralization of GM-CSF biologic activity by a specific antiserum abrogated GM-CSF-mediated inhibition of PCD.

Apoptosis↗
PubMed2025

Tumor microenvironment governs the prognostic landscape of immunotherapy for head and neck squamous cell carcinoma: A computational model-guided analysis.

Immune checkpoint inhibition (ICI) has emerged as a critical treatment strategy for squamous cell carcinoma of the head and neck (HNSCC) that halts the immune escape of the tumor cells. Increasing evidence suggests that the onset, progression, and lack of/no response of HNSCC to ICI are emergent properties arising from the interactions within the tumor microenvironment (TME). Deciphering how the diversity of cellular and molecular interactions leads to distinct HNSCC TME subtypes subsequently governing the ICI response remains largely unexplored. We developed a cellular-molecular model of the HNSCC TME that incorporates multiple cell types, cellular states, and transitions, and molecularly mediated paracrine interactions. Simulation across the selected parameter space of the HNSCC TME network shows that distinct mechanistic balances within the TME give rise to the five clinically observed TME subtypes such as immune/non-fibrotic, immune/fibrotic, fibrotic only and immune/fibrotic desert. We predict that the cancer-associated fibroblast, beyond a critical proliferation rate, drastically worsens the ICI response by hampering the accessibility of the CD8 + killer T cells to the tumor cells. Our analysis reveals that while an Interleukin-2 (IL-2) + ICI combination therapy may improve response in the immune desert scenario, Osteopontin (OPN) and Leukemia Inhibition Factor (LIF) knockout with ICI yields the best response in a fibro-dominated scenario. Further, we predict Interleukin-8 (IL-8), and lactate can serve as crucial biomarkers for ICI-resistant HNSCC phenotypes. Overall, we provide an integrated quantitative framework that explains a wide range of TME-mediated resistance mechanisms for HNSCC and predicts TME subtype-specific targets that can lead to an improved ICI outcome.

Tumor Microenvironment↗
PubMed1992

Polymorphonuclear leukocyte functions enhanced by chemotaxis.

Human polymorphonuclear leukocytes (PMN) migrate into tissues in response to chemoattractants, yet it is not known whether this process alters the functional capabilities of the PMN. Using recombinant human interleukin-8 (rHIL-8, 100 ng/ml) as a stimulus, we compared a population of PMN that migrated through a polyvinylpyrrolidone-coated polycarbonate filter containing 8.0 microns diameter pores with PMN stimulated in suspension. PMN were analyzed by flow cytometry according to functional and phenotypic criteria. CD11b/CD16 expression was unaltered by chemotaxis. In contrast, chemotaxis enhanced phagocytosis of E. coli, independent of opsonization with IgG. Similarly, chemotaxis increased baseline hydrogen peroxide production. We conclude that the chemotactic motion of PMN "primes" the cell for increased oxidative burst activity and augments the ability of PMN to ingest bacteria. This increased functional capability is distinct from rHIL-8 stimulation and appears to be independent of complement-and Fc-receptor expression.

Antigens, CD↗
PubMedDate not supplied

Endotoxin tolerance: regulation of cytokine production and cellular changes in response to endotoxin application in cancer patients.

Endotoxin (lipopolysaccharide, LPS) has the property of inducing tolerance to its own biological effects. This phenomenon has been extensively studied in animal models but only few studies exist on the regulation in humans. Here we describe experiments designed to determine the cytokine regulation and cellular changes in humans during induction of LPS tolerance after repeated LPS injections. Intravenous administration of purified LPS Salmonella abortus equi to cancer patients induces high amounts of circulating tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-8 (IL-8), granulocyte colony-stimulating factor (G-CSF), and macrophage colony-stimulating factor (M-CSF). Repeated injections of LPS at daily intervals resulted in a marked downregulation of the cytokine response and in the case of TNF-alpha, IL-8, G-CSF, and M-CSF the cytokine response was reduced to baseline levels. In contrast, significant increases in serum IL-6 were detected up to day 5 of repeated LPS injections. Hematological changes included transient decreases in WBCs affecting granulocytes, monocytes, and lymphocytes, followed by a marked granulocytosis. The drop in WBCs remained unaltered throughout the 5 day course of repeated LPS injections whereas the granulocyte overshoot recovery diminished gradually. When PBMCs of the cancer patients were restimulated ex vivo a marked enhancement of the capacity to produce TNF-alpha, IL-113, and IL-6 occurred, which is in contrast to the decreasing TNF-alpha serum levels obtained in vivo. In parallel, a shift in monocyte subpopulations from CD14+/CD16- to CD14+/CD16+ cells was observed. The data provide evidence that different mechanisms are implicated in the cytokine downregulation following repeated LPS injections to cancer patients. Furthermore, PBMCs from LPS tolerant patients do not demonstrate a reduction in their capacity to produce cytokines.

Antigens, CD↗
PubMedDate not supplied

Soluble factors levels in the initial staging of high-grade non-Hodgkin's lymphomas.

Plasma levels of several soluble factors were assayed in 31 untreated patients with high-grade non-Hodgkin's lymphomas (NHL). The results showed statistically significant higher average levels of interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-2 receptor (IL-2r) and transferrin receptor (TF-r) in NHL patients compared to controls (p = 0.045, p = 0.047, p = 0.020, p = 0.026 and p = 0.033 respectively). IL-2, IL-2r and TF-r levels were found more elevated in Stages III/IV than in Stages I/II (p = 0.031, p = 0.016 and p = 0.048 respectively), whereas IL-6 concentrations were higher in patients presenting B symptoms (p = 0.011). Significant correlations were found between the erythrocyte sedimentation rate (ESR) and IL-6 (r = 0.681), and between beta 2 microglobulin (B2-m) and IL-2r (r = 0.622).

Adult↗
PubMed1992

Phenotypic determination of T-lymphocytes responding to chemotactic stimulation from fMLP, IL-8, human IL-10, and epidermal lymphocyte chemotactic factor.

Human T lymphocytes were collected after they had migrated towards N-formyl-methionyl-leukylphenylalanine (fMLP), rIL-8, human IL-10 (hIL-10), and epidermal lymphocyte chemotactic factor (ELCF). They were stained for determination of their phenotype by FACS analysis using anti-CD4, -CD8, -CD18, -CD45R0 and OPD4 antibodies. Human IL-10 increased the percentage of CD8+ T lymphocytes in the migrating cell population by 152% compared with cells migrating towards the medium and decreased the number of CD4+ T lymphocytes by 79%. ELCF increased the number of CD4+ T lymphocytes by 18%, and the number of CD45R0+ T lymphocytes by 52%, while the number of CD8+ T lymphocytes was decreased by 20%. rIL-8 increased the number of CD4+ T lymphocytes and decreased the CD8+ T lymphocytes. The distribution of the different subpopulations of T lymphocytes was not changed significantly by fMLP. The observed changes in the phenotypes did not occur when incubating T lymphocytes with the chemotaxins. Our observations demonstrate that individual chemotactic factors will attract specific subsets of T lymphocytes. They may help to explain the predominance of memory T lymphocytes (CD4R0+, CD4+) in allergic contact dermatitis and certain other skin diseases. They also confirm the results of a recent study, that showed hIL-10 to be selectively chemotactic for CD8+ T lymphocytes.

Antigens, CD↗
PubMed1992

Peptides and cytokines.

In the last decade a number of proteinaceous inflammatory mediators have been structurally characterized. Two of these mediators, tumor necrosis factor alpha (TNF alpha) and Interleukin 1 alpha and beta (IL-1), have pleiotropic properties. Both cytokines are now known to be potent inducers of a number of cell-selective chemotactic cytokines, which belong to a novel superfamily of structurally related low-molecular-weight proteins. One of the most prominent members is termed "IL-8" and represents a neutrophil-selective attractant, whereas another one called "monocyte chemotactic protein 1 (MCP-1)" is a monocyte-selective chemotaxin. Other members seem to be selective chemotaxins for other leukocyte types and subsets. These chemotactic cytokines are produced by a variety of different cells under appropriate stimulation conditions. Large amounts of IL-8 have been detected in scales of psoriatic lesions and may be of importance in explaining predominant neutrophil infiltration in psoriatic lesions. Regulation of gene expression and/or release of these chemotactic cytokines may occur by IL-1 receptor antagonists or soluble TNF-alpha-receptors. So far, natural antagonists to these chemotactic cytokines have not been described; however, pharmacological inhibition of its gene expression and/or release is possible.

Amino Acid Sequence↗
PubMed1992

Interleukin 8 (IL-8) in the bronchoalveolar lavage fluid from patients with the adult respiratory distress syndrome (ARDS) and patients at risk for ARDS.

A sensitive and specific radioimmunoassay was used to measure interleukin 8 (IL-8) in bronchoalveolar lavage fluids from control subjects, patients with the adult respiratory distress syndrome (ARDS) and patients undergoing coronary bypass surgery, a risk factor for developing ARDS. Concentrations of IL-8, albumin, total protein and numbers of neutrophils were higher in both patient groups than in controls. Levels of IL-8 were significantly correlated with the influx of neutrophils, plasma protein extravasation and with the PaO2/FiO2 ratio. These data suggest that IL-8 may mediate the recruitment of neutrophils from the vascular compartment into the alveolar space and may therefore be an important determinant in neutrophil-mediated lung injury. Since increased levels of IL-8 were also found in BAL fluid from patients at risk in whom ARDS did not develop, other factors are likely to be involved and IL-8, as well as other markers of inflammation, are of little prognostic use.

Adult↗
PubMed2026

Common xenobiotics modulate gut microbial responses to low‑calorie sweeteners in vitro.

The gut microbiota is implicated in adverse effects associated with low-calorie sweeteners. Yet, the direct impact of sweeteners on gut bacteria remains largely uncharacterized. Here, we report interactions between 25 phylogenetically diverse gut bacterial strains and 39 commercially used sweeteners. We tested these sweeteners individually and in combination with four commonly co-consumed compounds, viz., advantame, caffeine, vanillin, and duloxetine. Three-quarters of the tested sweeteners individually impacted the growth of at least one tested bacterial strain. Further, over 100 interactions were found between sweeteners and the four co-consumed compounds. Isosteviol, a commonly used sweetener-component, and duloxetine, an antidepressant, synergistically inhibited Roseburia intestinalis, a bacterium previously linked to glucose homeostasis, and Parabacteroides merdae, a prevalent commensal linked to healthy microbiota. Proteomic, metabolomic, and genetic analyses indicate altered small molecule transport underpinning this sweetener-drug synergy. The isosteviol-duloxetine combination also modulated metabolism of a synthetic gut bacterial community, leading to increased toxicity to HeLa cells and altered secretion of inflammation-modulatory cytokines IL-6 and IL-8 by Caco-2 cells. Our data warrant further studies on interactions between low-calorie sweeteners and common xenobiotics.

Humans↗
PubMedDate not supplied

Monocyte chemotaxis and chemotactic cytokine release after exposure to hydroxyethyl starch.

Hydroxyethyl starch (HES) is commonly used in leukapheresis and infused as an alternative to blood components for the treatment of hypotension due to hemorrhage and trauma. Its prolonged intravascular persistence and retention in tissue raise concerns about possible effects on humoral and cell-mediated immunity and white cell (WBC) locomotion, particularly in volunteer WBC donors or in severely burned individuals with immunologic depression and increased risk for infection. This study evaluated the effect of HES on human monocyte migration and chemotaxis and the production of antigen- and mitogen-induced WBC-derived chemotactic cytokine. A bioassay was developed to quantitate the neutrophil chemotactic activity of a cytokine generated by mononuclear WBCs stimulated in vitro by phytohemagglutinin or tuberculin protein. The time- and dose-dependent generation of the chemotactic cytokine was not affected by the presence of HES. HES by itself did not induce the generation of this cytokine, nor were human monocyte chemotaxis and spontaneous migration significantly changed by exposure to HES. These results, with those of other investigators, suggest that HES is a safe red cell-sedimenting agent for leukapheresis and an alternative to the use of blood components in shock resuscitation.

Adult↗
PubMed2026

LncRNA HOTAIR contributes to cigarette smoke-induced pro-inflammatory responses in human airway epithelial cells.

Inhalation of cigarette smoke (CS) is the primary risk factor for chronic obstructive pulmonary disease (COPD), inducing epigenetic changes in the airway epithelium, including dysregulation of long-noncoding RNAs (lncRNAs). LncRNA homeobox gene transcript antisense RNA (HOTAIR) regulates chromatin remodeling and has been implicated in CS-induced malignant transformation. We hypothesized that HOTAIR expression is altered in COPD, leading to airway epithelial abnormalities. HOTAIR expression and overall survival were studied in The Cancer Genome Atlas (TCGA) database. Airway epithelial cells (AECs) were isolated from transplanted lungs of 11 patients with COPD, tracheobronchial tissue of 9 non-COPD donors, and bronchial brushings of ex-smokers with/without COPD (n = 6/group). HOTAIR expression, histone modifications, and production of proinflammatory cytokines (CXCL8 and GM-CSF) were assessed in the absence/presence of CS extract (CSE) and HOTAIR-polycomb inhibitor AQB. High HOTAIR expression correlated with poor overall survival in cancer patients with COPD, but not those without. Although HOTAIR expression was not significantly different between AECs from controls and subjects with COPD at baseline, it was significantly increased by 20% CSE only in COPD-derived AECs. CSE significantly decreased H3K4me3 levels in COPD-derived AECs, but not those from controls. AQB reduced baseline H3K27me3 levels in both groups, with a stronger effect in control-derived AECs. In addition, it reduced H3K4me3 levels in the presence of CSE in both groups. Finally, although AQB significantly suppressed CSE-induced production of GM-CSF and CXCL8 in control AECs, it failed to do so in COPD. Together, these findings suggest that COPD-derived AECs are more susceptible to CSE-induced HOTAIR upregulation, which may have a proinflammatory effect that cannot be inhibited by AQB.NEW & NOTEWORTHY COPD-derived AECs exhibit higher susceptibility to CSE-induced HOTAIR upregulation. CSE induces distinct histone modification patterns (H3K4me3) specifically in COPD-derived AECs. HOTAIR is essential for mediating CSE-induced proinflammatory responses in AECs.

Humans↗
PubMed2026

Functional Variant Discovery Identifies a Novel Genetic Link between SPRY2, Wood Smoke, and Asthma.

As a consequence of climate change and land-use policies, there has been a historic rise in wildfire smoke across the United States and the world. Although the deleterious effects of wildfire smoke and associated air pollution on asthma outcomes are established epidemiologically, genetic risks and molecular mechanisms of how wildfire smoke affects asthma are unknown. This knowledge gap hinders the identification of high-risk individuals and the creation of targeted therapies or recommendations to protect these individuals. We identified 52 genetic risk variants that colocalized with genomic responses to woodsmoke particles (WSPs), a model of wildfire particulate matter, and associated with asthma in the GERA (Genetic Epidemiology Research on Adult Health and Aging) cohort. We used additional filters to prioritize variants for direct testing of allele-dependent transcriptional regulatory function in plasmid reporters. We found that the rs3861144 variant (odds ratioasthma, 1.036) changes SPRY2 responses to WSPs in airway epithelial cells, which are involved in IL-8 secretion, ERK (extracellular signal-related kinase) activation, and mechanical scratch repair in cell culture. These findings provide insights into the molecular pathways through which WSPs may influence asthma risk and propose genetic candidates that warrant further study for their potential as clinical tools for asthma.

Asthma↗