interleukin-8 and Urinary-Tract-Infections

In recent years, researchers have been looking for tools and biomarkers to identify urinary tract infections (UTI) in children. Since there exists no systematic reviews and meta-analyses on the matter, the present study intends to determine the diagnostic value of serum and urinary levels of interleukins (IL) in the diagnosis of febrile UTI in children and adolescents.. Medline, Embase, Scopus, and Web of Science were searched until the end of 2020, using keywords related to UTI and serum and urinary ILs. Two independent researchers included relevant studies and summarized the data. Analyzed data were reported as standardized mean difference (SMD) with 95% confidence interval (CI).. Data from 23 articles were included in the present study. Analyses showed that IL-6, IL-8, IL 1 beta and IL-1 alpha urinary levels are significantly higher in children with UTI than that of other children. Moreover, serum levels of IL-6 and IL-8 in children with UTI were significantly higher than that of healthy children. However, IL-6 and IL-8 serum levels were not significantly different between children with UTI and non-UTI febrile group. Finally, the area under the curve of urinary IL-6 and IL-8 and serum IL-8 levels in the diagnosis of pediatric UTIs were 0.89 (95% CI: 0.86, 0.92), 0.95 (95% CI: 0.92, 0.96) and 0.80 (95% CI: 0.77, 0.84), respectively.. The findings of the present study showed that the diagnostic utility of ILs 8 and 6 urinary levels is most desirable in the detection of febrile UTIs from other febrile conditions in children and adolescents, in comparison with the diagnostic utility of other ILs' urinary and serum levels in the detection of febrile UTI. However, even after nearly 3 decades of research on these biomarkers, their optimal cut-off points in diagnosing pediatric UTIs are still to be determined in further studies.

Topics: Adolescent; Biomarkers; Child; Fever; Humans; Interleukin-6; Interleukin-8; Interleukins; Urinary Tract Infections

Urinary tract infection (UTI) is common among pediatric population. Pyelonephritis, especially in young infants, is associated with a significant morbidity. Usually, clinical manifestations, laboratory findings, and imaging are used to differentiate between lower and upper UTI. Lack of specific clinical findings and commonly used nonspecific blood indices are important hamper differentiation between lower and upper UTI in early stages. Imaging techniques are neither cost benefit nor safe for detection of UTI. Recent efforts have focused on characterization of novel serum and urinary biomarkers for early detection of acute pyelonephritis in children. It seems that urinary NGAL, NAG, TNF-α and IL-8 may be used as novel markers for early diagnosis of acute pyelonephritis in children.

Topics: Acute Disease; beta-N-Acetyl-Galactosaminidase; Biomarkers; Child; Child, Preschool; Early Diagnosis; Humans; Infant; Interleukin-8; Lipocalin-2; Pyelonephritis; Tumor Necrosis Factor-alpha; Urinary Tract Infections

Topics: Adhesins, Bacterial; Animals; Bacterial Adhesion; Fimbriae, Bacterial; Humans; Interleukin-8; Mannose; Urinary Tract; Urinary Tract Infections; Urine; Urodynamics; Vesico-Ureteral Reflux; Virulence

Acute lower uncomplicated urinary tract infection (uUTI) affects a large proportion of women. Increased antimicrobial resistance has created an urgent need for novel therapeutics and the phytotherapeutic drug BNO 1045 (Canephron® N) has previously been shown to be noninferior to standard antimicrobial stewardship. This sub-analysis from a randomized, double-blind, controlled phase III noninferiority clinical trial using BNO 1045 versus fosfomycin to treat uUTI aimed to determine how urine cytokine levels are altered by the two different treatments.. Urine samples from a predefined subset of women diagnosed with uUTI (18-70 years) and treated with BNO 1045 (n = 58) or fosfomycin (n = 69) were analyzed for urine levels of IL-6 and IL-8, using analyte-to-creatinine ratios.. BNO 1045 treatment showed similar effects to fosfomycin treatment in reducing both urine IL-6 and IL-8 levels. Mean IL-6 and IL-8 levels were markedly reduced in all patients regardless of treatment. BNO 1045 treatment decreased urine IL-8 significantly (p = 0.0142) and showed a trend toward reduction of urine IL-6 (p = 0.0551). Fosfomycin treatment reduced both IL-6 and IL-8 levels significantly (p = 0.0038, <0.0001 respectively).. BNO 1045 is, in addition to reducing symptoms, comparable to fosfomycin treatment in reducing the local inflammatory response associated with uUTI.

Topics: Anti-Bacterial Agents; Female; Fosfomycin; Humans; Interleukin-6; Interleukin-8; Phytotherapy; Urinary Tract Infections

Women with uncomplicated urinary tract infection (UTI) symptoms are commonly treated with empirical antibiotics, resulting in overuse of antibiotics, which promotes antimicrobial resistance. Available diagnostic tools are either not cost-effective or diagnostically sub-optimal. Here, we identified clinical and urinary immunological predictors for UTI diagnosis. We explored 17 clinical and 42 immunological potential predictors for bacterial culture among women with uncomplicated UTI symptoms using random forest or support vector machine coupled with recursive feature elimination. Urine cloudiness was the best performing clinical predictor to rule out (negative likelihood ratio [LR-] = 0.4) and rule in (LR+ = 2.6) UTI. Using a more discriminatory scale to assess cloudiness (turbidity) increased the accuracy of UTI prediction further (LR+ = 4.4). Urinary levels of MMP9, NGAL, CXCL8 and IL-1β together had a higher LR+ (6.1) and similar LR- (0.4), compared to cloudiness. Varying the bacterial count thresholds for urine culture positivity did not alter best clinical predictor selection, but did affect the number of immunological predictors required for reaching an optimal prediction. We conclude that urine cloudiness is particularly helpful in ruling out negative UTI cases. The identified urinary biomarkers could be used to develop a point of care test for UTI but require further validation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Algorithms; Biomarkers; Diagnosis, Computer-Assisted; Female; Humans; Immunologic Factors; Interleukin-1beta; Interleukin-8; Likelihood Functions; Lipocalin-2; Machine Learning; Matrix Metalloproteinase 9; Middle Aged; Nephelometry and Turbidimetry; Point-of-Care Testing; Support Vector Machine; Urinary Tract Infections; Young Adult

Urinary interleukin-6 (UIL-6) and urinary interleukin-8 (UIL-8) concentrations were measured by immunoassay in 39 and 34 patients respectively, hospitalized with febrile urinary tract infection (UTI), and in 37 and 32 age-, race- and sex-matched febrile control children respectively, with negative urine cultures. UIL-6 and UIL-8 concentrations, measured in picograms per milliliter and corrected for creatinine, were compared with clinical and laboratory indicators of inflammation and bacterial virulence factors of Escherichia coli. Median UIL-6 concentrations at the time of admission were 397 pg/ml (range 0-65,789 pg/ml) in the 37 patients compared to 0 pg/ml (range 0-473.8 pg/ml) in the 37 controls (P < 0.0001). Median UIL-8 concentrations at the time of admission were 5809 pg/ml (range 0-347,368 pg/ml) in the 32 patients compared to 0 pg/ml (range 0-2231 pg/ml) in the 32 controls (P < 0.0001). UIL-6 and UIL-8 concentrations were lower (P < 0.0001 for UIL-6 and P = 0.0005 for UIL-8) in follow-up urine samples from UTI patients, obtained 48 h after the initiation of antibiotic therapy. UIL-6 and UIL-8 concentrations were statistically significantly correlated with urine white blood cells (WBC). UIL-8 concentrations were elevated in patients with E. coli organisms producing hemolysin. UIL-6 and UIL-8 are elevated in children with febrile UTI and decrease in response to antibiotic therapy. Magnitude of UIL-8 response is associated with hemolysin production, a bacterial virulence factor of E. coli. UIL-6 and UIL-8 concentrations are statistically correlated with urine WBC. UIL-6 and UIL-8 may be mediators of inflammation in children with febrile UTI.

Topics: Child; Child, Preschool; Creatinine; Escherichia coli Infections; Female; Fever; Humans; Immunoassay; Infant; Infant, Newborn; Interleukin-6; Interleukin-8; Male; Reference Values; Retrospective Studies; Urinary Tract Infections

Neutrophil accumulation in the graft kidney is a feature of cellular rejection and bacterial infection. The cellular infiltration is mediated by the local production of chemoattractant factors. The aim of the study was to analyze levels of IL-8 in renal graft recipients during and after episodes of acute renal rejection and urinary tract infection (UTI). A total of 50 renal graft recipients, including 10 with acute graft rejection (Group I) and 20 with UTI (Group II) were studied. Urine and serum levels of IL-8 were determined in patients of Group I before and after 7 days of antirejection therapy and in patients of Group II before and after 2 weeks of antimicrobial therapy. Results were compared with group of 20 patients with stable renal function and a group of 25 healthy people. IL-8 was determined by ELISA technique. The level of IL-8 in urine (uIL-8) was elevated in patients with acute graft rejection and uIL-8 decreased after antirejection treatment (772 +/- 241 pg/mg cr. vs 140 +/- 50 pg/mg cr.; p < 0.01). In 13 patients UTI was asymptomatic and 6 patients had an acute pyelonephritis. The level of uIL-8 was elevated in all patients with UTI and decreased after antimicrobial therapy. Levels of uIL-8 during acute pyelonephritis were significantly higher (p < 0.01) than in patients with asymptomatic bacteriuria (2582 +/- 950 pg/mg cr. vs 804 +/- 225 pg/mg cr.) Urine levels of IL-8 were lower in patients infected by Gram-positive Cocci as compared to patients infected by Gram-negative organisms. Patients with higher concentrations of serum creatinine during UTI had high urine levels of IL-8. Serum levels of IL-8 in patients of Group I and Group II were comparable with patients with stable graft function although they were higher than in control group. Elevated urinary secretion of IL-8 in acute rejection and UTI suggests a role of IL-8-neutrophiles system in in the pathogenesis in both inflammatory complications after kidney transplantation. Urine level of IL-8 was correlated with clinical symptoms of UTI.

Topics: Adult; Aged; Bacterial Infections; Bacteriuria; Biomarkers; Creatinine; Female; Graft Rejection; Humans; Interleukin-8; Kidney Transplantation; Male; Middle Aged; Neutrophil Activation; Pyelonephritis; Urinary Tract Infections

The clinical significance of differences between antibiotics in endotoxin-liberating potential is unknown. Thirty patients with gram-negative urosepsis were randomized between imipenem and ceftazidime, which have, respectively, a low and a high endotoxin-liberating potential in vitro. In patients treated with ceftazidime, a slower defervescence was noticed. After 4 h of treatment, the blood endotoxin level decreased in all 3 endotoxemic patients receiving imipenem, whereas it increased in 2 of the 4 endotoxemic patients receiving ceftazidime, and in ceftazidime-treated patients, the endotoxin level in urine decreased less than in imipenem-treated subjects. Serum and urine cytokine levels increased 10%-40% after 4 h of ceftazidime treatment compared with no increase in the imipenem-treated patients (P > .05). Endotoxin release during antibiotic killing in vitro, assessed for all microorganisms, was 10-fold higher with ceftazidime (P < .001). These results indicate that differences between antibiotics in endotoxin release may affect the inflammatory response during treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bacteremia; Ceftazidime; Double-Blind Method; Endotoxins; Enterobacter cloacae; Escherichia coli; Gram-Negative Bacterial Infections; Humans; Imipenem; Interleukin-6; Interleukin-8; Klebsiella pneumoniae; Middle Aged; Prospective Studies; Pseudomonas aeruginosa; Tumor Necrosis Factor-alpha; Urinary Tract Infections

Topics: Epithelial Cells; Escherichia coli Infections; Female; Glucose; Humans; Inflammation; Interleukin-6; Interleukin-8; Male; Ribonucleases; Signal Transduction; Toll-Like Receptor 4; Urinary Bladder; Urinary Tract Infections; Uropathogenic Escherichia coli

The sensitivity and specificity of the leukocyte esterase test for the diagnosis of urinary tract infection (UTI) are suboptimal. Recent studies have identified markers that appear to more accurately differentiate children with and without UTI. The objective of this study was to determine the accuracy of these markers, which included CCL3, IL-8, CXCL1, TNF-alpha, IL-6, IFN-gamma, IL-17, IL-9, IL-2, and NGAL, in the diagnosis of UTI.. This was a prospective cross-sectional study to compare inflammatory proteins between urine samples from febrile children with a UTI, matched febrile controls without a UTI, and asymptomatic healthy controls.. We included 192 children (75 with febrile UTI, 69 febrile controls, and 48 asymptomatic healthy controls). Urinary proteins that best discriminated between febrile children with and without UTI were NGAL, a protein that exerts a local bacteriostatic role in the urinary tract through iron chelation; CCL3, a chemokine involved in leukocyte recruitment; and IL-8, a cytokine involved in neutrophil recruitment. Levels of these proteins were generally undetectable in asymptomatic healthy children.. NGAL, CCL3, and IL-8 may be useful in the early diagnosis of UTI.. ClinicalTrials.gov (NCT01391793) A higher resolution version of the Graphical abstract is available as Supplementary information.

Topics: Biomarkers; Case-Control Studies; Chemokine CCL3; Child; Cross-Sectional Studies; Fever; Humans; Interleukin-8; Lipocalin-2; Prospective Studies; Urinary Tract Infections

We compared the effect of commercial vaginal douching products on Lactobacillus crispatus, L. jensenii, L. gasseri, L. iners, E. coli, and immortalized vaginal epithelial cells (VK2). All studied douching products (vinegar, iodine and baking soda based) induced epithelial cell death, and all inhibited growth of E. coli. Co-culture of vaginal epithelial cells with any of the lactobacilli immediately following exposure to douching products resulted in a trend to less human cell death. However, co-culture of epithelial cells with L. iners was associated with higher production of IL6 and IL8, and lower IL1RA regardless of presence or type of douching solution. Co-culture with L. crispatus or L. jensenii decreased IL6 production in the absence of douches, but increased IL6 production after exposure to vinegar. Douching products may be associated with epithelial disruption and inflammation, and may reduce the anti-inflammatory effects of beneficial lactobacilli.

Topics: Acetic Acid; Cell Survival; Coculture Techniques; Cytokines; Epithelium; Escherichia coli; Female; Humans; Hydrogen-Ion Concentration; Immune System; Interleukin-6; Interleukin-8; Iodine; Lactobacillus; Lactobacillus crispatus; Lactobacillus gasseri; Microbial Sensitivity Tests; Risk; Sodium Bicarbonate; Urinary Tract Infections; Vagina; Vaginal Douching

To prevent the onset of urosepsis and reduce mortality, a better understanding of how uropathogenic Escherichia coli (UPEC) manages to infiltrate the bloodstream through the kidneys is needed. The present study elucidates if human renal interstitial fibroblasts are part of the immune response limiting a UPEC infection, or if UPEC has the ability to modulate the fibroblasts for their own gain. Microarray results showed that upregulated genes were associated with an activated immune response. We also found that chemokines released from renal fibroblasts upon a UPEC infection could be mediated by LPS and triacylated lipoproteins activating the TLR2/1, TLR4, MAPK, NF-κB and PKC signaling pathways. Furthermore, UPEC was also shown to be able to adhere and invade renal fibroblasts, mediated by the P-fimbriae. Furthermore, it was found that renal fibroblasts were more immunoreactive than renal epithelial cells upon a UPEC infection. However, both renal fibroblasts and epithelial cells were equally efficient at inducing neutrophil migration. In conclusion, we have found that human renal fibroblasts can sense UPEC and mobilize a host response with neutrophil migration. This suggests that renal fibroblasts are not only structural cells that produce and regulate the extracellular matrix, but also highly immunoreactive cells.

Topics: Escherichia coli Infections; Escherichia coli Proteins; Fibroblasts; Humans; Interleukin-8; Kidney; NF-kappa B; Protein Kinase C; Signal Transduction; Toll-Like Receptor 1; Toll-Like Receptor 2; Toll-Like Receptor 4; Urinary Tract Infections; Uropathogenic Escherichia coli

Objective diagnosis of symptomatic urinary tract infections in patients prone to asymptomatic bacteriuria is compromised by local host responses that are already present and the positive urine culture. We investigated interleukin-6 as a biomarker for nonfebrile urinary tract infection severity and diagnostic thresholds for interleukin-6 and 8, and neutrophils to differentiate between asymptomatic bacteriuria and urinary tract infection.. Patients with residual urine and neurogenic bladders due to spinal lesions included in a long-term Escherichia coli 83972 asymptomatic bacteriuria inoculation trial were monitored for 2 years. Symptom scoring and urine sampling to estimate interleukin-6 and 8, and neutrophils were performed regularly monthly and at urinary tract infection episodes.. Patients were followed in the complete study for a mean of 19 months (range 10 to 27) and those with asymptomatic bacteriuria with E. coli 83972 were followed a mean of 11 months (range 4 to 19). A total of 37 nonfebrile urinary tract infection episodes with complete data on interleukin-6 and 8, neutrophils and symptom scoring were documented. Interleukin-6 was the only marker that persistently increased during urinary tract infection compared to asymptomatic bacteriuria in pooled and paired intra-individual comparisons (p <0.05). Interleukin-6 above the threshold (greater than 25 ng/l) correlated to more severe urinary tract infection symptoms (p <0.05). The sensitivity and specificity of all biomarkers were poor/moderate when differentiating asymptomatic bacteriuria vs all urinary tract infection episodes. However, in urinary tract infections with worse symptoms interleukin-6 and neutrophils demonstrated equal good/excellent outcomes.. Triggered interleukin-6 correlated to urinary tract infection symptom severity and demonstrated a promising differential diagnostic capacity to discriminate urinary tract infection from asymptomatic bacteriuria. Future studies should explore interleukin-6 as a biomarker of urinary tract infection severity and assess the treatment indication in nonfebrile urinary tract infections.

Topics: Bacteriuria; Biomarkers; Cohort Studies; Diagnosis, Differential; Escherichia coli; Humans; Interleukin-6; Interleukin-8; Leukocyte Count; Neutrophils; Sensitivity and Specificity; Severity of Illness Index; Symptom Assessment; Urinary Tract Infections

Cellular and antibody-mediated rejection processes and also interstitial fibrosis/tubular atrophy (IFTA) lead to allograft dysfunction and loss. The search for accurate, specific and non-invasive diagnostic tools is still ongoing and essential for successful treatment of renal transplanted patients. Molecular markers in blood cells and serum may serve as diagnostic tools but studies with high patient numbers and differential groups are rare. We validated the potential value of several markers on mRNA level in blood cells and serum protein level in 166 samples from kidney transplanted patients under standard immunosuppressive therapy (steroids±mycophenolic acid±calcineurin inhibitor) with stable graft function, urinary tract infection (UTI), IFTA, antibody-mediated rejection (ABMR), and T-cell-mediated rejection (TCMR) applying RT-PCR and ELISA. The mRNA expression of RANTES, granulysin, granzyme-B, IP-10, Mic-A and Interferon-γ in blood cells did not distinguish specifically between the different pathologies. We furthermore discovered that the mRNA expression of the chemokine IL-8 is significantly lower in samples from IFTA patients than in samples from patients with stable graft function (p<0.001), ABMR (p<0.001), Borderline (BL) TCMR (p<0.001), tubulo-interstitial TCMR (p<0.001) and vascular TCMR (p<0.01), but not with UTI. Serum protein concentrations of granzyme-B, Interferon-γ and IL-8 did not differ between the patient groups, RANTES concentration was significantly different when comparing UTI and ABMR (p<0.01), whereas granulysin, Mic-A and IP-10 measurement differentiated ongoing rejection or IFTA processes from stable graft function but not from each other. The measurement of IL-8 mRNA in blood cells distinguishes clearly between IFTA and other complication after kidney transplantation and could easily be used as diagnostic tool in the clinic.

Topics: Adult; Aged; Animals; Atrophy; Biomarkers; Blood Cells; Calcineurin Inhibitors; Diagnosis, Differential; Fibrosis; Graft Rejection; Humans; Immune Tolerance; Interleukin-8; Isoantibodies; Kidney; Kidney Transplantation; Mice; Middle Aged; Mycophenolic Acid; Steroids; T-Lymphocytes; Urinary Tract Infections

Proteus mirabilis is a common human pathogen causing recurrent or persistent urinary tract infections (UTIs). The underlying mechanisms for P. mirabilis to establish UTIs are not fully elucidated. In this study, we showed that loss of the sigma factor E (RpoE), mediating extracytoplasmic stress responses, decreased fimbria expression, survival in macrophages, cell invasion, and colonization in mice but increased the interleukin-8 (IL-8) expression of urothelial cells and swarming motility. This is the first study to demonstrate that RpoE modulated expression of MR/P fimbriae by regulating mrpI, a gene encoding a recombinase controlling the orientation of MR/P fimbria promoter. By real-time reverse transcription-PCR, we found that the IL-8 mRNA amount of urothelial cells was induced significantly by lipopolysaccharides extracted from rpoE mutant but not from the wild type. These RpoE-associated virulence factors should be coordinately expressed to enhance the fitness of P. mirabilis in the host, including the avoidance of immune attacks. Accordingly, rpoE mutant-infected mice displayed more immune cell infiltration in bladders and kidneys during early stages of infection, and the rpoE mutant had a dramatically impaired ability of colonization. Moreover, it is noteworthy that urea (the major component in urine) and polymyxin B (a cationic antimicrobial peptide) can induce expression of rpoE by the reporter assay, suggesting that RpoE might be activated in the urinary tract. Altogether, our results indicate that RpoE is important in sensing environmental cues of the urinary tract and subsequently triggering the expression of virulence factors, which are associated with the fitness of P. mirabilis, to build up a UTI.

Topics: Animals; Epithelial Cells; Female; Fimbriae, Bacterial; Gene Expression Regulation, Bacterial; Humans; Interleukin-8; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Mutation; Polymyxin B; Promoter Regions, Genetic; Proteus Infections; Proteus mirabilis; Recombinases; Sigma Factor; Urea; Urinary Tract Infections; Urothelium; Virulence

Febrile urinary tract infection (UTI) is a common bacterial disease that may lead to substantial morbidity and mortality especially among the elderly. Little is known about biomarkers that predict a complicated course. Our aim was to determine the role of certain urinary cytokines or antimicrobial proteins, plasma vitamin D level, and genetic variation in host defense of febrile UTI and its relation with bacteremia.. A case-control study. Out of a cohort of consecutive adults with febrile UTI (n = 787) included in a multi-center observational cohort study, 46 cases with bacteremic E.coli UTI and 45 cases with non-bacteremic E.coli UTI were randomly selected and compared to 46 controls. Urinary IL-6, IL-8, LL37, β-defensin 2 and uromodulin as well as plasma 25-hydroxyvitamin D were measured. In 440 controls and 707 UTI patients polymorphisms were genotyped in the genes CXCR1, DEFA4, DEFB1, IL6, IL8, MYD88, UMOD, TIRAP, TLR1, TLR2, TLR5 and TNF.. IL-6, IL-8, and LL37 are different between controls and UTI patients, although these proteins do not distinguish between patients with and without bacteremia. While uromodulin did not differ between groups, inability to produce uromodulin is more common in patients with bacteremia. Most participants in the study, including the controls, had insufficient vitamin D and, at least in winter, UTI patients have lower vitamin D than controls. Associations were found between the CC genotype of IL6 SNP rs1800795 and occurrence of bacteremia and between TLR5 SNP rs5744168 and protection from UTI. The rare GG genotype of IL6 SNP rs1800795 was associated with higher β-defensin 2 production.. Although no biomarker was able to distinguish between UTI with or without bacteremia, two risk factors for bacteremia were identified. These were inability to produce uromodulin and an IL6 rs1800795 genotype.

Topics: Adult; Aged; Aged, 80 and over; Antimicrobial Cationic Peptides; Bacteremia; beta-Defensins; Case-Control Studies; Cathelicidins; Female; Fever; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Polymorphism, Genetic; Risk Factors; Urinary Tract Infections; Uromodulin; Vitamin D

In this study, we analyzed gene expression levels of apoptotic (Fas, FasL, Bcl-2, Bax) and survival (CXCR1, CXCR2, IL-8) signal pathways of the urine-deprived bladder tissues and the relation of urinary tract infections with these pathways.. We included 37 patients admitted for renal transplantation between December 2009 and December 2012. Bladder mucosal samples were obtained at the time of transplantation and 6-8 weeks posttransplantation, at the time of ureteral catheter removal. RNA extraction and cDNA synthesis were done using guanidium-thiocyanate and colon filter methods. Expression analysis was studied with quantitative real-time polymerase chain reaction optimized with ROX dye and internal control β-actin.. According to our findings Fas, FasL, Bcl-2, and Bax expression was higher in urine-deprived bladder samples than those in the posttransplant samples (P < .05). Although Fas, FasL, Bcl-2, and Bax expression levels increased in pretransplant samples, there was an increase in posttransplant bladder samples; however, this increase was not as marked as those of pretransplant samples. IL-8, CXCR1, and CXCR2 expression was decreased at the pretransplant samples and increased in posttransplant bladder samples.. We have found an upregulated apoptotic process and decreased survival signals at the urine-deprived bladder tissue. After transplantation, bladder tissue survival parameters were increased, demonstrating the importance of urinary flow for bladder tissue.

Topics: Adult; Apoptosis; Apoptosis Regulatory Proteins; Fas Ligand Protein; Female; Humans; Interleukin-8; Kidney Transplantation; Male; Middle Aged; Real-Time Polymerase Chain Reaction; Urinary Tract Infections; Urine; Urothelium

To study the role of outer membrane protein T (OmpT) in the pathogenesis of uropathogenic Escherichia.coli.. In cultured human bladder epithelial cell line 5637, we examined the adhesion ability of wild-type (CFT073), ompT gene knockout (COTD), and revertant (pST) strains of E.coli to the cells and the extracellular matrix (ECM). The expressions of the adhesion gene iha and virulence gene iroN were detected by real-time PCR. Murine models of urinary tract infection with the 3 strains were established to evaluate the bacterial burden of the bladder and kidney tissue and bacterial counts in blood. We also detected the expressions of interleukin-6 (IL-6) and IL-8 in the bladder and kidney tissues of the mice.. The COTD strain showed a significantly lower cell adhesion rate than CFT073 strain [(4.62∓0.39)% vs (8.81∓1.13)%, P<0.05] with also a lower ECM-adhesion rate [(4.95∓0.59)% vs (8.85∓0.79)%, P<0.05]. The mRNA expressions of iha and iroN in CFT073 strain were 2.1 and 3.8 times that of COTD strain. In the mouse model, the mean bacterial load of CFT073 strain in the bladder tissue was 6.36∓0.06, significantly greater than that of COTD (6.01∓0.07) and revertant (6.29∓0.06) strains (P<0.05); the bacterial load of CFT073 strain in the kidney tissue was also significantly higher than that of COTD strain (6.25∓0.05 vs 5.87∓0.06, P<0.05). In mice infected with the wild-type, knockout, and revertant strains, the detection rates of IL-6, which were identical to those of IL-8, in the inflammatory bladder and kidney tissues were 60%, 12.5%, and 50%, respectively.. OmpT may regulate the expression of the adhesion gene iha and the transferrin gene iroN to affect the adhesion of uropathogenic E.coli to host cells.

Topics: Animals; Bacterial Adhesion; Bacterial Load; Bacterial Outer Membrane Proteins; Cell Line, Tumor; Escherichia coli Infections; Escherichia coli Proteins; Gene Knockout Techniques; Humans; Inflammation; Interleukin-6; Interleukin-8; Kidney; Mice; Peptide Hydrolases; Receptors, Cell Surface; Urinary Bladder; Urinary Tract Infections; Uropathogenic Escherichia coli

Interleukins are a group of cytokines responsible for regulating inflammatory and infectious responses. Interleukin-8 plays an important role in chemotaxis and functioning of leukocytes and is locally produced in infected tissues; it is seen in abundance in the urine of individuals with Urinary Tract Infection.. Midstream sterile urine sampling was performed in different patients admitted to the Spinal Cord Injury (SCI) research center. The samples were tested to determine the level of IL-8 through the ELISA method. The commercial kit used for this study was an R & D kit built in Germany.. The mean level of IL-8 was 369.59 pg/ml and 75.42 pg/ml in male and female patients respectively. Among the 97 patients under study, 87 (89.7%) were IL-8 positive (>10 pg/ml) and 10 patients were IL-8 negative (<10 pg/ml). Among the 87 IL-8 positive subjects, 64 patients had no UTI symptoms, while 23 did.. SCI patients should have their urinary IL-8 levels measured on a routine and periodic basis, irrespective of their SCI severity or the presence or absence of UTI symptoms. The timely and effective diagnosis & treatment of UTI can prevent the irreversible complications caused by frequent UTI and resistance to treatment in this group of patients.

Topics: Adult; Asymptomatic Infections; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-8; Male; Spinal Cord Injuries; Urinary Tract Infections; Young Adult

Vesicoureteral reflux (VUR) is a risk factor for kidney scarring, hypertension and declining renal function. Standard diagnostic methods are invasive and can cause exposure to radiation and urinary tract infections (UTIs). We aimed to investigate urine albumin and interleukin-8 levels as markers of ongoing VUR and renal damage in children without UTIs.. Random urine samples were collected from 51 children, including 16 children with VUR (group A), 17 children with resolved VUR (group B) and 18 normal children (group C). The diagnosis of VUR or resolved VUR was confirmed by voiding cystourethrogram (VCUG) or direct radionuclide cystography (DRNC). All children had normal kidney function and had no evidence of UTI in the preceding three months. Random urine specimens were assayed for albumin (Alb), creatinine (Cr) and interleukin-8 (IL-8) and mean values were compared by one way ANOVA.. In groups A and B, the mean age at first UTI was 31.7 ± 2.4 and 27 ± 2.0 months respectively. In group A, the mean duration between VUR diagnosis and study entrance was 30 ± 9.1 months. In group B, the mean duration between VUR diagnosis and recovery was 19.9 ± 1.3 months. Overall, 76.4% of affected children had bilateral VUR and 41.2% had severe VUR. There were no significant differences in urinary Alb, IL-8, Alb/Cr and IL-8/Cr between the three groups.. The current study does not support the hypothesis that microalbuminuria or urinary IL-8 are good indicators of ongoing VUR and renal injury in children.

Topics: Albuminuria; Analysis of Variance; Biomarkers; Case-Control Studies; Child; Child, Preschool; Cross-Sectional Studies; Female; Humans; Interleukin-8; Male; Urinary Tract Infections; Vesico-Ureteral Reflux

We characterized and identified the uroepithelial P2 receptor responsible for adenosine triphosphate mediated release of the cytokines interleukin-8 and 6.. The human renal epithelial cell line A498 (ATCC™) was cultured and stimulated with different purinergic agonists with or without prior inhibition with different antagonists or signaling pathway inhibitors. Supernatant was analyzed for interleukin-8 and 6 by enzyme-linked immunosorbent assay. P2 receptor mRNA expression was assessed by real-time reverse transcriptase-polymerase chain reaction. The candidate receptor was knocked down with siRNA technology. Interleukin-8 and 6 responses were measured after purinergic stimulation of knocked down cells.. ATP and ATP-γ-S (Roche Diagnostics, Mannheim, Germany) were equipotent as inducers of interleukin-8 and 6 release. Agonist profile experiments using different P2 receptor agonists indicated that P2Y(2) was the main contributor to this release, although P2Y(11) and P2X(7) activation could not be excluded. Signaling pathway experiments showed that interleukin-8 release involved phospholipase C and inositol trisphosphate mediated signaling, indicating a P2Y receptor subtype. Antagonist experiments indicated P2Y(2) as the responsible receptor. Gene expression analysis of P2 receptors showed that strong expression of P2Y(2) receptor and subsequent knockdown of P2Y(2) receptor mRNA for 72 and 96 hours abrogated interleukin-8 and 6 release after purinergic stimulation with adenosine triphosphate-γ-S.. Interleukin-8 and 6 release after purinergic stimulation in uroepithelial A498 cells is mediated through P2Y(2) receptor activation.

Topics: Adenosine Triphosphate; Calcium Signaling; Cells, Cultured; Cytokines; Epithelial Cells; Humans; Interleukin-6; Interleukin-8; Receptors, Purinergic P2Y2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Sensitivity and Specificity; Signal Transduction; Urinary Tract Infections; Urothelium

Urinary tract infections (UTIs) are frequently polymicrobial diseases mainly sustained by Escherichia coli in association with other opportunistic pathogens. Cystitis and pyelonephritis are usually accompanied by an inflammatory response, which includes neutrophil recruitment. Uropathogenic E. coli possess the ability to evade host defenses, modulating the innate immune response. The aim of this study was to determine whether particular E. coli strains correlate with polymicrobial bacteriuria and whether escape from the early host defenses and microbial synergy could lead to mixed UTIs. We evaluated 188 E. coli-positive urine samples and assessed the relationships among polymicrobism, neutrophil presence and several traits of E. coli isolates (virulence factors such as hlyA, fimA, papC and their relative products, i.e. hemolysin, type 1 and P fimbriae, and cnf1, their phylogenetic group) and their ability to suppress cytokine response in 5637 bladder epithelial cells. Escherichia coli susceptibility toward quinolones and fluoroquinolones, known to be linked to the pathogenicity of this species, was also considered. We found significant correlations among polymicrobial bacteriuria, absence of pyuria and quinolone/fluoroquinolone susceptibility of E. coli isolates and their enhanced capability to suppress interleukin-8 urothelial production when compared with the patterns induced by the resistant strains.

Topics: Aged; Anti-Bacterial Agents; Bacteriuria; Epithelial Cells; Escherichia coli; Escherichia coli Infections; Female; Humans; Interleukin-8; Male; Microbial Sensitivity Tests; Middle Aged; Opportunistic Infections; Quinolones; Tumor Cells, Cultured; Urinary Bladder; Urinary Tract Infections

Urine IL-8 concentrations are known to be elevated in urinary tract infection (UTI), as well as in vesicoureteral reflux (VUR) even in the absence of infection. In this study we further investigated urine IL-8 in infants with congenital anomalies of the kidneys and urinary tract and with antenatally diagnosed isolated pelvic dilatation. Urine IL-8 was measured in 159 infants aged 1 month to 1 year with acute UTI (group A, n = 26), resolved UTI (group B, n = 16), VUR without recent UTI (group C, n = 44), non-VUR congenital urinary anomalies without recent UTI (group D, n = 30), isolated antenatal pelvic dilatation (group E, n = 14) and in infants without known urinary tract condition (control group F, n = 29). Median values of urine IL-8/creatinine levels were 61.5, 4.64, 15.5, 14.3, 1.06 and 4.19 pg/μmol in groups A, B, C, D, E and F respectively. Compared with the control group, urine IL-8 was elevated in infants with acute UTI, VUR without acute UTI and congenital anomalies without acute UTI (p < 0.0001; p < 0.005; and p = 0.027 respectively), but not in infants with resolved UTI or with antenatal pelvic dilatation. Urine IL-8 levels are elevated in a variety of infectious and non-infectious urinary tract conditions, and hence may serve as a sensitive but not specific screening biomarker of urinary tract diseases.

Topics: Biomarkers; Child, Preschool; Enzyme-Linked Immunosorbent Assay; Humans; Infant; Interleukin-8; Urinary Tract Infections; Urologic Diseases; Vesico-Ureteral Reflux

The innate host defenses at mucosal surfaces are critical in the early stages of urinary tract bacterial infection. Recent studies have shown that uroepithelial cells aid innate immune cells in fighting off infection, although the exact mechanism by which the uroepithilium participates in immunity remains unclear. TLR4 has been implicated to possess antimicrobial activities specific for bladder epithelial cells (BECs). TLR4 promotes secretion of IL-6 and IL-8, mediates inhibition of bladder epithelial cell (BEC) bacterial invasion, and mediates expulsion of uropathogenic Escherichia coli from BECs. In this study, cultured 5637 cells and Balb/C mice were treated with Astragalus polysaccharides (APS) against invading E. coli. To determine the contribution of TLR4 upregulation to immune response, TLR4 expression and bacterial colony numbers were monitored. After 24 h incubation, only 5637 cells treated with 500 microg/ml APS expressed higher levels of TLR4 compared with the untreated group. However, after 48h, all 5637 cells treated by APS showed higher levels of TLR4 expression than the control cells. The TLR4 expression in the bladder and macrophages mice that received APS was higher than that in the controls. Bacterial colonization in 5637 cells and the bladders of mice treated with APS was significantly reduced compared with the controls. These results demonstrate that at certain concentrations, APS can induce increased TLR4 expression in vivo and in vitro. Further, TLR4 expression upregulation can enhance innate immunity during mucosal bacterial infection. The findings establish the use of APS to modulate the innate immune response of the urinary tract through TLR4 expression regulation as an alternative option for UTI treatment.

Topics: Animals; Astragalus Plant; Cell Line; Epithelial Cells; Escherichia coli; Female; Humans; Immunity, Innate; Interleukin-6; Interleukin-8; Mice; Mice, Inbred BALB C; Polysaccharides; RNA, Messenger; Toll-Like Receptor 4; Up-Regulation; Urinary Bladder; Urinary Tract Infections

Bacterial growth in multicellular communities, or biofilms, offers many potential advantages over single-cell growth, including resistance to antimicrobial factors. Here we describe the interaction between the biofilm-promoting components curli fimbriae and cellulose of uropathogenic E. coli and the endogenous antimicrobial defense in the urinary tract. We also demonstrate the impact of this interplay on the pathogenesis of urinary tract infections. Our results suggest that curli and cellulose exhibit differential and complementary functions. Both of these biofilm components were expressed by a high proportion of clinical E. coli isolates. Curli promoted adherence to epithelial cells and resistance against the human antimicrobial peptide LL-37, but also increased the induction of the proinflammatory cytokine IL-8. Cellulose production, on the other hand, reduced immune induction and hence delayed bacterial elimination from the kidneys. Interestingly, LL-37 inhibited curli formation by preventing the polymerization of the major curli subunit, CsgA. Thus, even relatively low concentrations of LL-37 inhibited curli-mediated biofilm formation in vitro. Taken together, our data demonstrate that biofilm components are involved in the pathogenesis of urinary tract infections by E. coli and can be a target of local immune defense mechanisms.

Topics: Adult; Antimicrobial Cationic Peptides; Bacterial Proteins; Biofilms; Cathelicidins; Cell Line; Cellulose; Child; Epithelial Cells; Female; Fimbriae, Bacterial; Humans; Immunity; Interleukin-8; Male; Urinary Tract Infections; Uropathogenic Escherichia coli

Cytokines play a major role in renal scar formation following febrile urinary tract infection (UTI). We investigated the role of dexamethasone combined with antibiotics in diminishing urinary interleukin-6 (UIL-6) and UIL-8 concentrations during the acute phase of pyelonephritis compared with standard antibiotic therapy. UIL-6 and UIL-8 concentrations were determined by enzyme immunoassay in 34 children with pyelonephritis who were treated with ceftriaxone plus dexamethasone (case group) and in 20 patients with the same diagnosis treated with ceftriaxone alone (control group). Urine samples were obtained at the time of presentation prior to drug administration and at follow-up 72 h after initiation of medication. Creatinine concentrations were also determined, and cytokine/creatinine ratios were calculated to standardize samples. Differences between cytokine/creatinine ratios in initial and follow-up urine samples were significant in the case group (P < 0.001) but not for controls. In addition, combined antibiotic and dexamethasone significantly decreased UIL-6 and UIL-8 concentrations compared with antibiotic alone (P < 0.05). We conclude that dexamethasone combined with antibiotics significantly decreases UIL-6 and UIL-8 levels in patients with acute pyelonephritis. This suggests that the clinical use of corticosteroids may prevent scar formation following febrile UTI.

Topics: Acute Disease; Ceftriaxone; Child; Child, Preschool; Cicatrix; Creatinine; Cytokines; Dexamethasone; Female; Humans; Infant; Interleukin-6; Interleukin-8; Leukocyte Count; Male; Pyelonephritis; Urinary Tract Infections; Vesico-Ureteral Reflux

Catheter associated urinary tract infection is the most common type of hospital acquired infection. An understanding of catheter associated urinary tract infection pathogenesis is needed to improve the control and treatment of these infections. We investigated the relationship among catheter material, bacteria and bladder epithelial cell reaction.. Urinary catheter sections and a clinical isolate of Escherichia coli were added to human bladder carcinoma epithelial cells in vitro in combination or independently. The catheters were rotated for 30 seconds over the cells, followed by incubation. The cytokines interleukin-6 and 8 were measured by enzyme-linked immunosorbent assay as indicators of inflammation and cell membrane disruption was assessed using a lactate dehydrogenase assay.. The levels of lactate dehydrogenase release and cytokine production depended on the number of bacteria added. Bacteria grown for 3 days caused greater secretion of cytokines than bacteria grown overnight. Silicone catheter material alone caused immediate damage to cells with increased lactate dehydrogenase in the supernatant but little interleukin-6 or 8 production. Silicone catheters caused significantly less cytokine secretion from bladder cells than latex catheters. Conversely bacteria caused little immediate damage to cells but stimulated cytokine production after 12 hours.. Disruption of bladder epithelial cell membranes in vitro occurred immediately as a result of physical abrasion caused by catheters but delayed inflammation occurred in response to bacterial infection.

Topics: Bacterial Adhesion; Catheterization; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Escherichia coli; Humans; In Vitro Techniques; Interleukin-6; Interleukin-8; L-Lactate Dehydrogenase; Latex; Sensitivity and Specificity; Silicones; Urinary Bladder; Urinary Tract Infections; Urothelium

The defense against mucosal infections relies on chemokines that recruit inflammatory cells to the mucosa. This study examined if the chemokine response to uro-pathogenic Escherichia coli is influenced by fimbrial expression. The CXC (CXCL1, CXCL5, CXCL8, CXCL9, CXCL10) and CC chemokines (CCL2, CCL3, CCL5) were quantified after in vitro infection of uro-epithelial cells with a fimbriated E. coli pyelonephritis isolate, or with P or type 1 fimbriated transformants of an avirulent E. coli K-12 strain. The response profile was shown to vary with the fimbrial type. Type 1 fimbriated E. coli elicited mainly CXCL1 and CXCL8, whereas P fimbriated E. coli stimulated CCL2 and CCL5 and class II were more potent chemokine inducers than class III P fimbriae. Chemokines were also quantified in urine samples from 73 patients with febrile urinary tract infection, and analyzed as a function of disease severity and fimbrial expression by the strain infecting each patient. A complex CXC and CC chemokine response was detected in patient urine, with a significant influence of the fimbrial type. The results show that virulence factors like fimbriae may modify the mucosal chemokine response. This mechanism may allow the host to adjust the inflammatory cell infiltrate to fit the infecting strain.

Topics: Adhesins, Escherichia coli; Adult; Aged; Aged, 80 and over; Cell Line; Chemokines; Escherichia coli; Escherichia coli Infections; Female; Fever; Fimbriae Proteins; Fimbriae, Bacterial; Genotype; Humans; Interleukin-8; Kinetics; Lectins; Male; Middle Aged; Mucous Membrane; RNA, Messenger; Urinary Tract Infections; Urothelium

We performed a case-control study in children diagnosed by the first episode of upper urinary tract infection with or without vesicoureteral reflux to evaluate the association of functional polymorphism of interleukin-8 (-251A>T and +2767A>G), and its receptor CXCR1 (+2607G>C).. Genomic DNA was obtained from 265 children with a clinical and laboratory diagnosis of urinary tract infection who were recruited in northeast Italy. The children were subdivided as 173 who were dimercapto-succinic acid scan positive with positive static renal scintigraphy in acute conditions, consistent with the diagnosis of acute pyelonephritis, and 92 who were dimercapto-succinic acid scan negative. Genetic analysis for the same polymorphisms was also extended to a control population of 106 umbilical cord DNA samples.. Statistical analysis of genotype data showed that 1) the tested populations were in Hardy-Weinberg equilibrium, 2) there were significant differences between the dimercapto-succinic acid scan positive and negative groups (p=0.049), and the dimercapto-succinic acid scan positive group vs controls (p=0.032) in terms of interleukin-8 -251A>T polymorphism frequency, 3) there was also a significant difference in the distribution of IL-8 -251A>T and +2767A>G polymorphisms between dimercapto-succinic acid scan positive and negative children in the subgroup without vesicoureteral reflux (p=0.03 and 0.02, respectively) and 4) no significant differences were found in the frequency of the distribution of CXCR1 +2607G>C polymorphism in all groups.. These data suggest that the gene for the proinflammatory chemokine interleukin-8 is involved in susceptibility to acute pyelonephritis during upper urinary tract infection in children with or without vesicoureteral reflux.

Topics: Acute Disease; Case-Control Studies; Child; Child, Preschool; Female; Genetic Predisposition to Disease; Humans; Infant; Infant, Newborn; Interleukin-8; Male; Polymorphism, Genetic; Pyelonephritis; Receptors, Interleukin-8A; Urinary Tract Infections; Vesico-Ureteral Reflux

Uropathogenic Escherichia coli (UPEC), the most frequent cause of urinary tract infection (UTI), is associated with an inflammatory response which includes the induction of cytokine/chemokine secretion by urothelial cells and neutrophil recruitment to the bladder. Recent studies indicate, however, that UPEC can evade the early activation of urothelial innate immune response in vitro. In this study, we report that infection with the prototypic UPEC strain NU14 suppresses tumor necrosis factor alpha (TNF-alpha)-mediated interleukin-8 (CXCL-8) and interleukin-6 (CXCL-6) secretion from urothelial cell cultures compared to infection with a type 1 piliated E. coli K-12 strain. Furthermore, examination of a panel of clinical E. coli isolates revealed that 15 of 17 strains also possessed the ability to suppress cytokine secretion. In a murine model of UTI, NU14 infection resulted in diminished levels of mRNAs encoding keratinocyte-derived chemokine, macrophage inflammatory peptide 2, and CXCL-6 in the bladder relative to infection with an E. coli K-12 strain. Furthermore, reduced stimulation of inflammatory chemokine production during NU14 infection correlated with decreased levels of bladder and urine myeloperoxidase and increased bacterial colonization. These data indicate that a broad phylogenetic range of clinical E. coli isolates, including UPEC, may evade the activation of innate immune response in the urinary tract, thereby providing a pathogenic advantage.

Topics: Animals; Chemokine CXCL2; Chemokines; Colony Count, Microbial; Escherichia coli; Escherichia coli Infections; Female; Immunity, Innate; Interleukin-6; Interleukin-8; Mice; Mice, Inbred C57BL; Peroxidase; RNA, Messenger; Tumor Necrosis Factor-alpha; Urinary Bladder; Urinary Tract Infections; Urine; Urothelium; Virulence

To determine the serum cytokine profiles of patients with spinal cord injury (SCI) and varying clinical presentations relative to healthy, able-bodied, age-matched control subjects.. Cross-sectional study.. Clinical research unit.. People with SCI (N=56) and different clinical presentations, and healthy, able-bodied, age-matched control subjects (N=35).. Not applicable.. Serum levels of the proinflammatory cytokines interleukin (IL) 1beta, IL-6, tumor necrosis factor alpha (TNF-alpha), the anti-inflammatory cytokines IL-4 and IL-10, the regulatory cytokine IL-2, the IL-1 receptor antagonist (IL-1RA), and autoantibodies against myelin-associated glycoprotein and GM(1) ganglioside (anti-GM(1)) immunoglobulin (IgG and IgM), as determined by enzyme-linked immunosorbent assay. The relationship between elevated serum cytokine levels and clinical variables was also studied.. SCI subjects exhibited serum concentrations of IL-6, TNF-alpha, IL-1RA, and anti-GM(1) (IgG) that were greater (P<.05) than control group values. Elevated cytokine concentrations were not associated with high white blood cell counts, level of injury, or American Spinal Injury Association classification; they were evident in SCI subjects who were asymptomatic for medical complications, but were further elevated in subjects with pain, urinary tract infection (UTI), and pressure ulcers.. Elevated levels of circulating proinflammatory cytokines and autoantibodies are present in the serum of SCI subjects without medical complications, and are further elevated in SCI subjects with neuropathic pain, UTI, or pressure ulcers, relative to healthy, able-bodied control subjects. These findings may be indicative of a protective autoimmunity, simply a consequence of occult or evident infection, or evidence of cytokine dysregulation that may contribute to an immune-mediated impairment of axonal conduction.

Topics: Adult; Autoantibodies; Cervical Vertebrae; Cross-Sectional Studies; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; G(M1) Ganglioside; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-8; Male; Myelin-Associated Glycoprotein; Paraplegia; Pressure Ulcer; Quadriplegia; Reference Values; Spinal Cord Injuries; Thoracic Vertebrae; Tumor Necrosis Factor-alpha; Urinary Tract Infections

Vesicoureteral reflux (VUR) is a common finding in children presenting with urinary tract infection (UTI) and prenatally diagnosed urinary tract dilatation and in relatives of index patients. Children with VUR are at risk for ongoing renal damage with subsequent infections. Detecting VUR and renal scarring currently depends on imaging modalities with associated problems of radiation, invasiveness, and expense. Noninvasive methods would greatly facilitate diagnosis and would also help in identifying relatives of index cases who should be screened. Interleukin-8 (IL-8) is produced by epithelial cells of the renal tract in response to inflammatory stimuli and has been shown to increase during acute UTI. The objective of this study was to assess the urine levels of IL-8 as a noninvasive marker of VUR in infants in the absence of a recent UTI episode.. We evaluated urine concentrations of IL-8 in 59 infants aged 1 month to 2 years. All infants were free of UTI for a minimum of 3 weeks before IL-8 evaluation. Infants were divided into 3 groups: group A, subjects with proven VUR (24 infants aged 0.15-1.95 years, median 0.43); group B, subjects with a history of UTI but negative investigation for VUR (14 infants aged 0.32-1.95 years, median 0.57); and group C, subjects without any history of acute or chronic condition that might impair renal function (21 infants aged 0.08-1.92 years, median 0.33). IL-8 concentrations were determined by a commercially available quantitative enzyme-linked immunosorbent assay. To avoid dilution effects, urinary levels of IL-8 were expressed as the ratio of cytokine-to-urinary creatinine.. Results were presented as medians and ranges. The Kruskal-Wallis test, the Mann-Whitney rank sum U test, and the Spearman rank order correlation test were performed for the univariate analysis. Two-tailed P values were calculated and the conventional level of significance P < .05 was applied in all cases. Infants in groups A and B had been free of UTI for a period of 3 to 52 weeks (median, 5.0 weeks) and 3 to 78 weeks (median, 4.5 weeks), respectively, before IL-8 determination. No significant difference was noted in the length of the UTI-free period between groups A and B (P = .469). Urine creatinine concentrations did not differ among groups A, B, and C (medians 1.15, 2.25, and 1.15 micromol/mL, respectively; P = .080). The median urine IL-8/creatinine concentrations (pg/micromol) were 40.5 (range, 2.04-3874) in group A, 1.91 (range, 0.001-386) in group B, and 2.47 (range, 0.002-55.6) in group C. Urine IL-8/creatinine concentrations were significantly higher in group A than both in group B (P = .0003) and in group C (P < .0001). No significant difference was observed between groups B and C (P = .749). In group A, no significant correlation was shown between IL-8/creatinine concentrations and the presence of renal parenchymal damage (P = .506), reflux grade (P = .770), or time from UTI (P = .155). A receiver-operator characteristic curve was constructed by plotting the sensitivity versus the specificity for different cutoff concentrations of IL-8/creatinine. With a cutoff concentration of urinary IL-8/creatinine at 5 pg/micromol, the sensitivity of this marker in diagnosing VUR was 88%, the specificity 69%, the positive prognostic value 66%, and the negative prognostic value 89%. In higher cutoff concentrations, specificity of the marker increased but sensitivity rapidly decreased.. We present evidence that urine IL-8 concentrations remain elevated in infants with VUR even in the absence of UTI and that a cutoff of 5 pg/micromol IL-8/creatinine is of high sensitivity and adequate specificity for diagnosing VUR. Elevated urine IL-8 levels in VUR and renal scarring have already been reported; however, the present study is, to our knowledge, the first to confirm significant differences between infants with VUR and infants with a history of UTI alone and healthy controls, and to suggest a reliable cutoff concentration for diagnosing VUR. Our findings additionally suggest that inflammatory process in VUR is ongoing even after UTI has resolved, pointing against the currently held belief that sterile reflux cannot harm kidneys. The chronic inflammatory cell infiltrate associated with reflux nephropathy rather than VUR itself might offer an explanation for the secretion of IL-8, which may well be independent of reflux grade. Using urine IL-8 for diagnosing VUR is not free of limitations, because IL-8 may be elevated as a result of urinary tract manipulation or undetected UTI. In addition, this study focused on infants and not in older children with longstanding VUR. Increased urine IL-8 concentrations after UTI has resolved is a promising noninvasive marker for an initial screening for VUR in infancy with high sensitivity and adequate specificity.

Topics: Biomarkers; Creatinine; Humans; Infant; Interleukin-8; Predictive Value of Tests; Sensitivity and Specificity; Urinary Tract Infections; Vesico-Ureteral Reflux

Nitric oxide (NO) is an antibacterial factor that is produced by the enzyme inducible NO synthase (iNOS). Uroepithelial cells express iNOS in experimental models of urinary tract infection but the stimulatory and regulatory mechanisms are still unclear. We investigated the influence of uropathogenic Escherichia coli strains with different fimbrial expression and the effect of proinflammatory cytokines on the host iNOS response.. A498 human kidney epithelial cells were stimulated with different uropathogenic E. coli strains, namely the P and type 1-fimbriated clinical isolate AD110, the recombinant P-fimbriated strain E. coli HB101(pPIL110-75) and the recombinant type 1-fimbriated strain E. coli AAEC191A(pPKL4). NO production was determined as nitrite production in cell culture medium. Studies of nuclear factor-kappaB (NF-kappaB) binding to the iNOS promoter and reverse transcriptase-polymerase chain reaction of iNOS mRNA were performed to investigate iNOS gene activation in response to uropathogenic E. coli. The effect of interleukin (IL)-6, IL-8 and transforming growth factor-beta on NO production was also examined.. E. coli per se failed to induce NO production and iNOS mRNA in A498 cells. However, in combination with interferon-gamma AD110 and the type 1-fimbriated strain caused a small increase in NO production and iNOS mRNA. AD110 stimulated A498 cells demonstrated weak binding of NF-kappaB to a human iNOS promoter sequence. IL-6, IL-8 and transforming growth factor-a did not affect NO production in A498 cells.. Uropathogenic bacteria are weak inducers of human uroepithelial iNOS, which may be related to insufficient binding of NF-kappaB to iNOS promoter. The uroepithelial iNOS response did not appear to be regulated by proinflammatory cytokines.

Topics: Cells, Cultured; Epithelial Cells; Escherichia coli Infections; Humans; Interleukin-6; Interleukin-8; Kidney; Nitric Oxide; Nitric Oxide Synthase; Transforming Growth Factor beta; Urinary Tract Infections; Urothelium

Uropathogenic bacteria stimulate epithelial cells of interstitial tissue and macrophages to secrete proinflammatory cytokines: interleukin I (IL-1beta), interleukin 6 (IL-6) and interleukin 8 (IL-8). The aim of the study was to check: 1) if the concentration of proinflammatory cytokines (IL-1beta, IL-6, IL-8) differs in dependence on region and clinical picture of urinary tract infection, 2) what is the influence of antibacterial treatment on their concentration.. We examined 67 children, aged 1-15 years, who were divided into 3 groups: 27 children with acute pyelonephritis (AP), caused by E. coli (group I), in whom the examination was carried out twice: A - before treatment, B - after 14 days of antibacterial treatment, 10 children with chronic urinary tract infection (UTI) associated with neurogenic bladder (group II) and 30 healthy children (group K).. Urinary concentration of examined cytokines was assessed using ELISA immunoenzymatic method and was expressed in pg/mg creatinine. Results showed that in group I before treatment the urinary concentration of examined cytokines was increased (p<0.05). After antibacterial treatment concentration of IL-1beta was normal and concentration of IL-6 and IL-8 decreased but was still higher than in control group (p<0.05). In group II before treatment the increase in concentration of IL-1beta and IL-8 was not so high (p<0.05) and the urinary concentration of IL-6 was normal (p>0.05). In examination A in children from group I and II a positive correlation between examined cytokines and C reactive protein was shown. We have also found a positive correlation between urinary concentration of IL-1beta a IL-8.. 1. Urinary concentration of examined proinflammatory cytokines is different in children with AP and UTI associated with neurogenic bladder and correlates with concentration of C-reactive protein. 2. In most of children with AP after 14-days of antibacterial treatment the urinary concentration of proinflammatory cytokines has been increased.

Topics: Adolescent; Analysis of Variance; C-Reactive Protein; Case-Control Studies; Child; Child, Preschool; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Humans; Infant; Interleukin-1; Interleukin-6; Interleukin-8; Male; Poland; Pyelonephritis; Risk Factors; Statistics, Nonparametric; Urinary Bladder, Neurogenic; Urinary Tract Infections

Interleukin-8 elevation in urine during urinary tract infections (UTIs) has been documented for different uropathogenic germs in 85 patients. We showed that for 17 different isolates, IL-8 was increased in 92% of UTIs with an average value of 627 pg/ml for infected, as compared to 45 pg/ml for uninfected patients. We suggest that the high negative predictive value of the IL-8 urine assay could be useful to eliminate UTIs in routine screenings.

Topics: Anti-Bacterial Agents; Bacterial Infections; Humans; Interleukin-8; Neutrophils; Predictive Value of Tests; Urinary Tract Infections

Topics: Age Factors; Case-Control Studies; Child, Preschool; Female; Fever; Follow-Up Studies; Humans; Incidence; Inflammation Mediators; Interleukin-6; Interleukin-8; Male; Reference Values; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index; Urinalysis; Urinary Tract Infections

The aim of this study was to assess relations between the clinical course of UTI, IL-6 and IL-8 levels, and the presence of inflammatory changes detected by renal scintigraphy using 99mTc-DMSA (DMSA).. We studied 33 children aged 1-24 months (mean 7.1+/-5.8 months) with first-time UTI. The subjects were divided in two groups: with fever (group I, n=10) and without fever (group II, n=23). Inflammatory markers (ESR, CRP, leukocyte count), urinary IL-6 and IL-8 level, and DMSA scan were evaluated in all children.. Urinary IL-6 and IL-8 levels [IL-6, IL-8/creatinine (pg/mg)] were significantly higher in group I than in group II (Il-6 level: 39.4+/-41.1 vs. 6.3+/-13.7, p<0.01; IL-8 level: 791.1+/-1143.6 vs. 36+/-87.9, p<0.001). We found positive correlation between urinary IL-6 and IL-8 levels and ESR, CRP, and leukocyte count (IL-6: r=0.43, p<0.05; r=0.46, p<0.05; and r=0.59, p<0.001, respectively; IL-8: r=0.55, p<0.05; r=0.72, p<0.0001; and r=0.44, p<0.05, respectively). We found no relation between urinary cytokine levels and the presence of inflammatory changes detected by DMSA scanning, despite slightly higher mean urinary cytokine levels in children with inflammatory changes in DMSA scan.. We found significantly higher IL-6 and IL-8 levels in children with febrile UTI and elevated inflammatory markers. IL-6 and IL-8 levels do not differentiate between acute pyelonephritis and UTI in children to age 24 months.

Topics: Child, Preschool; Creatinine; Female; Humans; Infant; Interleukin-6; Interleukin-8; Kidney; Male; Radionuclide Imaging; Technetium Tc 99m Dimercaptosuccinic Acid; Urinary Tract Infections

This study investigated the role of P fimbriae in colonization of Escherichia coli, host response, and bacterial persistence in humans. Human volunteers were inoculated intravesically with the nonadherent ABU isolate E. coli 83972 and with P fimbriated transformants of the same strain. During the following 24 h all urine samples, and thereafter daily samples, were collected for urine culture, analysis of neutrophil numbers, and cytokine concentrations (IL-6 and IL-8). The P fimbriated transformants showed enhanced bacterial colonization in comparison to E. coli 83972 and lowered the bacterial numbers needed for persistent bacteriuria. The P fimbriated transformants also lowered the bacterial numbers needed for a significant neutrophil and cytokine host response. We conclude that P fimbriae enhance bacterial colonization and trigger the host response in the human urinary tract.

Topics: Adult; Ampicillin Resistance; Bacterial Adhesion; Child, Preschool; Colony Count, Microbial; Escherichia coli; Escherichia coli Infections; Female; Fimbriae, Bacterial; Genotype; Humans; Interleukin-6; Interleukin-8; Kanamycin Resistance; Leukocyte Count; Male; Neutrophils; Pyuria; Receptors, Immunologic; Recombination, Genetic; Urinary Tract Infections; Virulence

Bacterial adherence to mucosal cells is a key virulence trait of pathogenic bacteria. The type 1 fimbriae and the P-fimbriae of Escherichia coli have both been described to be important for the establishment of urinary tract infections. While P-fimbriae recognize kidney glycosphingolipids carrying the Galalpha4Gal determinant, type 1 fimbriae bind to the urothelial mannosylated glycoproteins uroplakin Ia and Ib. The F1C fimbriae are one additional type of fimbria correlated with uropathogenicity. Although it was identified 20 years ago its receptor has remained unidentified. Here we report that F1C-fimbriated bacteria selectively interact with two minor glycosphingolipids isolated from rat, canine, and human urinary tract. Binding-active compounds were isolated and characterized as galactosylceramide, and globotriaosylceramide, both with phytosphingosine and hydroxy fatty acids. Comparison with reference glycosphingolipids revealed that the receptor specificity is dependent on the ceramide composition. Galactosylceramide was present in the bladder, urethers, and kidney while globotriaosylceramide was present only in the kidney. Using a functional assay, we demonstrate that binding of F1C-fimbriated Escherichia coli to renal cells induces interleukin-8 production, thus suggesting a role for F1C-mediated attachment in mucosal defense against bacterial infections.

Topics: Animals; Bacterial Adhesion; Chromatography, Thin Layer; Dogs; Escherichia coli; Escherichia coli Infections; Galactosylceramides; Glycosphingolipids; Humans; Interleukin-8; Magnetic Resonance Spectroscopy; Mucous Membrane; Rats; Receptors, Immunologic; Sphingosine; Trihexosylceramides; Urinary Tract; Urinary Tract Infections

Urinary tract epithelial cells (T 24/83) are able to express interleukin (IL)-6, IL-8, platelet-derived growth factor (PDGF) and tumour necrosis factor-alpha, but not IL-1 beta, IL-2, IL-4 and IL-10 in response to an infection with uropathogenic bacteria. The process of cytokine secretion is time dependent, with a significant increase in the cytokine activity after 60 min. The expression of virulence factors of the bacteria does not seem to play a role. The interaction between bacterial products (e.g. lipopolysaccharide) and/or bacterial adhesion mediated by adhesins and specific receptor molecules of cell surfaces may be responsible for the activity of mediator protein expression in the epithelial cells. The release of PDGF and IL-8 was found to be higher when due to Escherichia coli HB 101 (rough form) than that caused by other bacterial strains. Citrobacter CB 3009 provoked the highest level of IL-6. The PDGF level correlated significantly with IL-6 and IL-8 values (P<0.001). There was a significant correlation between the time-dependent release of IL-6 and IL-8 (P<0.05). In epithelial cytokine response to bacterial infection, the reaction of the epithelial cells may modify themselves (e.g. internalization of bacteria) and the immuno-regulatory processes that are caused by infection and responsible for parenchymal injury.

Topics: Citrobacter; Cytokines; Enterobacteriaceae Infections; Enzyme-Linked Immunosorbent Assay; Escherichia coli; Escherichia coli Infections; Humans; Interleukin-6; Interleukin-8; Platelet-Derived Growth Factor; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha; Urinary Bladder Neoplasms; Urinary Tract Infections; Urogenital System; Urothelium; Virulence

Neutrophil migration to infected mucosal sites involves a series of complex interactions with molecules in the lamina propria and at the epithelial barrier. Much attention has focussed on the vascular compartment and endothelial cells, but less is known about the molecular determinants of neutrophil behavior in the periphery. We have studied urinary tract infections (UTIs) to determine the events that initiate neutrophil recruitment and interactions of the recruited neutrophils with the mucosal barrier. Bacteria activate a chemokine response in uroepithelial cells, and the chemokine repertoire depends on the bacterial virulence factors and on the specific signaling pathways that they activate. In addition, epithelial chemokine receptor expression is enhanced. Interleukin (IL)-8 and CXCR1 direct neutrophil migration across the epithelial barrier into the lumen. Indeed, mIL-8Rh knockout mice showed impaired transepithelial neutrophil migration, with tissue accumulation of neutrophils, and these mice developed renal scarring. They had a defective antibacterial defense and developed acute pyelonephritis with bacteremia. Low CXCR1 expression was also detected in children with acute pyelonephritis. These results demonstrate that chemokines and chemokine receptors are essential to orchestrate a functional antimicrobial defense of the urinary tract mucosa. Mutational inactivation of the IL-8R caused both acute disease and chronic tissue damage.

Topics: Animals; Bacterial Adhesion; Bacteriuria; Chemotaxis, Leukocyte; Child; Disaccharides; Drosophila Proteins; Escherichia coli; Escherichia coli Infections; Fimbriae, Bacterial; Genetic Predisposition to Disease; Glycosphingolipids; Humans; Immunity, Innate; Interleukin-8; Macrophages; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Knockout; Mucous Membrane; Neutrophils; Pyelonephritis; Receptors, Cell Surface; Receptors, Chemokine; Receptors, Interleukin-8A; Recurrence; Toll-Like Receptors; Urinary Tract Infections; Urothelium; Virulence

To assess the implications of detection of interleukin 8 (IL-8) in urine.. IL-8 was measured by immunoassay in all 305 urine samples from children aged 0-18.4 years received by our microbiology laboratory during four weeks, with a retrospective structured case note audit for all those in whom IL-8, white cells, or bacteria were detected. Patients were divided into three groups: urinary tract infection (UTI), at least one sample with >/=5 leucocytes x 10(9)/l and >/=10(5) cultured bacteria/ml; possible UTI, at least one sample with >/=5 leucocytes x 10(9)/l or >/=10(5) cultured bacteria/ml but not both; UTI unlikely, sample(s) with <5 leucocytes x 10(9)/l and <10(5) cultured bacteria/ml. Medical records were sought for all in groups 1 (14/14 found) and 2 (18/21 found) and those in group 3 (41/59 found) in whose urine any leucocytes, cultured bacteria, or IL-8 were detected.. IL-8 was detected in 58/305 samples from 48/264 patients. IL-8 was detected in at least one urine sample from 13/14 patients with confirmed UTI (group 1); in 11/21 patients with possible UTI (group 2), of whom two were treated as UTI; and in 23/228 patients without UTI. Using a cut off of 200 pg/ml, urine IL-8 had a sensitivity of 93% and a specificity of 90% for diagnosing UTI.. Urine IL-8 is a sensitive test for UTI, but is poorly specific as it is also present in a variety of other infectious and inflammatory disorders.

Topics: Adolescent; Bacteriuria; Biomarkers; Child; Child, Preschool; Enzyme-Linked Immunosorbent Assay; Female; Humans; Infant; Infant, Newborn; Interleukin-8; Leukocyte Count; Male; Predictive Value of Tests; Retrospective Studies; ROC Curve; Sensitivity and Specificity; Urinary Tract Infections

Urine of patients with urinary tract infection (UTI) contains high levels of interleukin (IL)-6 and IL-8. However, knowledge of the kinetics of their release in urine is limited. We therefore compared the appearance of IL-6 and IL-8 in urine after uncomplicated surgery and surgery complicated by UTI.. 165 patients undergoing abdominal surgery who received a urinary catheter were studied. Urine IL-6 and IL-8 were prospectively measured in patients who did (n = 10) or did not (n = 20) develop UTI. Statistical analysis was done by one-way ANOVA and the Mann-Whitney test.. Although urine IL-6 increased in the 2 to 4 days preceding the bacteriological documentation of UTI, a similar increase was observed in patients who did not develop UTI. Urine IL-8 was elevated on the day UTI was diagnosed, while remaining low in controls.. In this patient group with postoperative UTI, urine IL-8 was a better marker for the early host response than urine IL-6.

Topics: Abdomen; Aged; Biomarkers; Female; Humans; Interleukin-6; Interleukin-8; Kinetics; Male; Middle Aged; Postoperative Complications; Sensitivity and Specificity; Urinary Catheterization; Urinary Tract Infections

Acute rejection and urinary tract infection (UTI) both increase nitric oxide synthase (NOS) activity in urine from renal transplant patients. Also, with rejection, a regulatory interplay between nitric oxide (NO) and cytokines has been suggested. Thus, measurement of the temporal changes of NOS products and cytokines in urine will provide a strategy for the diagnosis of acute rejection and for its differentiation from UTI.. Soluble interleukins (ILs) and NOS-related products, cyclic GMP (cGMP), nitrate, and nitrite were measured in 192 urine samples consecutively collected from 13 patients within the first three months of transplantation. Sixty-seven additional urine specimens were collected randomly from 24 patients for follow-up analysis of the nitrate test.. Among patients who experienced rejection, the percentage (%) binding of IL-2 increased within the first five days (P = 0.0004) after transplantation and one to five days prior to the clinical diagnosis (dx) of rejection (P = 0.02). Tumor necrosis factor-alpha, IL-6, and IL-8 increased at the time of rejection dx (P < or = 0.01). With UTI, IL-2 (P = 0.01) decreased one to five days prior to dx, and IL-10 (P = 0.003) increased one to five days after dx. Although cGMP and nitrate are dependent variables, cGMP increased (P < or =0.0009) with both rejection and UTI, and nitrate increased (P = 0.0001) with rejection and decreased (P = 0.0001) with UTI. Prior to formal dx (1 to 5 days), urine nitrate clearly differentiated rejection (3004 to 7451 micromol/L) from UTI (90 to 885 micromol/L) and controls (1059 to 3235 micromol/L). The additional 67 urines demonstrated that the sensitivity of the nitrate test for rejection and UTI was 100%.. In renal transplant patients, specific temporal changes in urine cytokine levels do occur with acute rejection and UTI, but urine nitrate levels are the most precise at differentiating rejection from UTI.

Topics: Acute Disease; Adult; Creatinine; Cyclic GMP; Cytokines; Female; Follow-Up Studies; Graft Rejection; Humans; Interleukin-10; Interleukin-2; Interleukin-6; Interleukin-8; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Predictive Value of Tests; Time Factors; Tumor Necrosis Factor-alpha; Urinary Tract Infections

Neutrophil migration across infected mucosal surfaces is chemokine dependent, but the role of chemokine receptors has not been investigated. In this study, chemokine receptors were shown to be expressed by epithelial cells lining the urinary tract, and to play an essential role for neutrophil migration across the mucosal barrier. Uroepithelial CXCR1 and CXCR2 expression was detected in human urinary tract biopsies, and in vitro infection of human uroepithelial cell lines caused a dramatic increase in both receptors. As a consequence, there was higher binding of IL-8 to the cells and the IL-8-dependent neutrophil migration across the infected epithelial cell layers was enhanced. Abs to IL-8 or to the CXCR1 receptor inhibited this increase by 60% (p<0.004), but anti-CXCR2 Abs had no effect, suggesting that CXCR1 was the more essential receptor in this process. Similar observations were made in the mouse urinary tract, where experimental infection stimulated epithelial expression of the murine IL-8 receptor, followed by a rapid flux of neutrophils into the lumen. IL-8 receptor knockout mice, in contrast, failed to express the receptor, their neutrophils were unable to cross the epithelial barrier, and accumulated in massive numbers in the tissues. These results demonstrate that epithelial cells express CXC receptors and that infection increases receptor expression. Furthermore, we show that CXCR1 is required for neutrophil migration across infected epithelial cell layers in vitro, and that the murine IL-8 receptor is needed for neutrophils to cross the infected mucosa of the urinary tract in vivo.

Topics: Animals; Cell Communication; Cell Line; Cell Movement; Epithelial Cells; Escherichia coli Infections; Female; Genetic Predisposition to Disease; Humans; Interleukin-8; Mice; Mice, Inbred BALB C; Mice, Knockout; Neutrophils; Protein Binding; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Urinary Tract Infections; Urothelium

Interleukin (IL)-6 and -8 are important inflammatory cytokines in bacterial infections. Their serum and urine concentrations were measured in 27 neonates with urinary tract infection (UTI) at onset and the second week of therapy, as well as in 23 control neonates. Escherichia coli was isolated in 89% of cases. 99mTc-dimercaptosuccinic acid (99mTc-DMSA) scans were performed between the 10th and 90th days after UTI and showed pyelonephritic changes in 15 neonates (56%). Increased IL-6 and IL-8 concentrations were found in urine but not in serum within the first 24 h after presumptive diagnosis of UTI (P=.036 and.010, respectively), suggesting that the neonatal urinary tract can respond to uropathogens by producing inflammatory cytokines. Urine concentrations of IL-6 correlated with findings of renal changes in 99mTc-DMSA scans (P=.012) and thus may serve as a marker of renal parenchymal outcome. All neonates exhibited undetectable urine cytokine levels during the second week of therapy.

Topics: Female; Follow-Up Studies; Humans; Infant, Newborn; Interleukin-6; Interleukin-8; Kidney; Male; Pyelonephritis; Radionuclide Imaging; Radiopharmaceuticals; Technetium Tc 99m Dimercaptosuccinic Acid; Urinary Tract Infections

Urine and serum interleukin (IL)-6 and IL-8 responses were higher in children with febrile urinary tract infection (n = 61) than in those with asymptomatic bacteriuria (n = 39). By univariate analysis, cytokine levels were related to age, sex, reflux, renal scarring, urine leukocytes, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and bacterial properties (P fimbriae but not hemolysin). Multivariate modeling showed that urine IL-6 responses were higher in girls than boys, increased with age, and were positively associated with CRP, ESR, serum IL-6, and urine leukocyte counts. The urine IL-8 response was not influenced by age, but it was influenced by P fimbriae and was associated with ESR, CRP, urine leukocytes, and female sex. The results show that cytokine responses to urinary tract infection vary with the severity of infection and that cytokine activation is influenced by a variety of host and bacterial variables.

Topics: Bacteriuria; Child, Preschool; Female; Fever; Fimbriae, Bacterial; Humans; Infant; Interleukin-6; Interleukin-8; Male; Sex Factors; Urinary Tract Infections

Interleukin 8 (IL-8) is one of the most widely studied chemoattractants for leukocytes. It belongs to the newly classified CXC family of chemokine which possesses biological activities mainly on neutrophils. The potential role of IL-8 in inflammation is substantiated by the growing evidences of clinical relevance of IL-8 in various diseases such as infection, ischemia and autoimmune disorders. The common characteristic pathological feature of these events is neutrophil infiltration. Although little is known about the mechanism of neutrophil recruitment into the urine, urinary tract infections (UTI) are accompanied by pyuria. Elevated urinary IL-8 levels were found in patients with UTI. Bioactive, multiple forms of IL-8 were produced locally within the urinary tract, and implied that IL-8 participated in the induction of neutrophil migration into the inflammatory site. Similar findings were observed in the peritoneal dialysate of patients on continuous ambulatory peritoneal dialysis with peritonitis. The notion of involvement of IL-8 in local infection was reinforced by the findings obtained on the rabbit UTI model. Finally, the clinical usefulness, as well as the problems of IL-8 level determination in various body fluids are discussed.

Topics: Humans; Interleukin-8; Peritonitis; Urinary Tract Infections

Topics: Cell Line; Cytokines; DNA, Complementary; Epithelial Cells; Epithelium; Gene Expression Regulation; Humans; Interleukin-6; Interleukin-8; Kidney; Organ Specificity; RNA, Messenger; Urinary Bladder; Urinary Tract Infections

1. Uropathogenic E. coli adhere to mucosal sites. 2. In the urinary tract, adherence is followed by inflammation, including a mucosal cytokine response. 3. Bacteria activate epithelial cells to secrete IL-6 and IL-8. IL-6 may cause the fever and acute phase response that accompany systemic urinary tract infections. IL-8 may function as a neutrophil chemoattractant. 4. E. coli up-regulate adhesion molecule expression on epithelial cell lines and neutrophil migration through epithelial cell monolayers. This process is inhibited by antibodies to CD18 and ICAM-1. 5. Cytokines released by nonepithelial cells (T cells and monocytes) modify the epithelial cell cytokine response to bacteria.

Topics: Bacterial Adhesion; Carbohydrate Sequence; Cytokines; Escherichia coli; Escherichia coli Infections; Fimbriae, Bacterial; Glycolipids; Humans; Interleukin-6; Interleukin-8; Molecular Sequence Data; Neutrophils; T-Lymphocytes; Urinary Tract Infections

Urinary tract infections activate a mucosal inflammatory response, which includes cytokine secretion and neutrophil influx. The mechanisms involved in the neutrophil influx have not been identified. Interleukin-8, a potent chemoattractant for neutrophils, is produced by urinary tract epithelial cell lines in vitro. This study analyzed the human IL-8 response to deliberate Escherichia coli infection of the urinary tract. Urine and serum samples were obtained before and after intravesical instillation of E. coli. Neutrophil numbers were determined on uncentrifuged urine, and IL-8 levels were measured by ELISA. A urinary IL-8 response was found in all patients after bacterial instillation, but no serum IL-8 was detected. There was a strong correlation between urinary IL-8 levels and urinary neutrophil numbers. The same E. coli strains used to colonize the patients stimulated IL-8 production in urinary tract epithelial cells. The level of IL-8 secreted by epithelial cell lines was influenced by the fimbrial properties of the E. coli. These results demonstrated that E. coli elicit a mucosal IL-8 response in humans, and suggested that IL-8 is involved in the onset of pyuria. Epithelial cells may be an important source of IL-8 during urinary tract infection.

Topics: Cell Line; Enzyme-Linked Immunosorbent Assay; Epithelium; Escherichia coli Infections; Female; Humans; Immunohistochemistry; Interleukin-8; Neutrophils; Urinary Tract; Urinary Tract Infections

Pyuria is one of the main features of urinary tract infections (UTI). Nevertheless, the mechanism of polymorphonuclear leukocyte (PMN) recruitment into the urine remains to be investigated. We examined whether interleukin-8 (IL-8), a potent neutrophil chemoattractant and activator, was involved in pyuria seen in UTI. Of 113 patients, 112 had elevated levels of IL-8 in their urine (1,078.0 +/- 181.5 pg/ml), regardless of whether they had an upper or lower UTI; this was in contrast to undetectable levels (less than 16 pg/ml) in the urine of all of the 20 normal individuals and 74 control patients without UTI. A concomitant study revealed increases in urine IL-6, but not IL-1 beta, and tumor necrosis factor alpha levels in patients with UTI. In addition to gram-negative bacteria, a wide spectrum of microorganisms was capable of inducing IL-8 production in urine. Local production of IL-8 in the urinary tract was suggested by a urine IL-8 level that was higher than the paired serum IL-8 level. The urine IL-8 level correlated with the number of PMN in the urine, and an average of half of the chemotactic activity in urine from patients with UTI could be abrogated by anti-IL-8 antibody treatment in vitro. Furthermore, urine IL-8 purified from patients was bioactive and showed multiple forms on immunoblotting analysis. This is the first documentation of IL-8 in the urine of patients with UTI, and these results imply that IL-8 is involved in inducing PMN migration into the urinary tract.

Topics: Adolescent; Adult; Aged; Chemotaxis, Leukocyte; Child; Child, Preschool; Female; Humans; Infant; Interleukin-1; Interleukin-6; Interleukin-8; Male; Middle Aged; Neutrophils; Tumor Necrosis Factor-alpha; Urinary Tract Infections