Expression and Clinical Significance of Non B Cell-Derived Immunoglobulins in the Urinary System and Male Reproductive System.

The urinary system comprises kidneys, ureters, bladder, and urethra with its primary function being excretion, referring to the physiological process of transporting substances that are harmful or surplus out of the body. The male reproductive system consists of gonads (testis), vas deferens, and accessory glands such as the prostate. According to classical immunology theory, the tissues and organs mentioned above are not thought to produce immunoglobulins (Igs), and any Ig present in the relevant tissues under physiological and pathological conditions is believed to be derived from B cells. For instance, most renal diseases are associated with uncontrolled inflammation caused by pathogenic Ig deposited in the kidney. Generally, these pathological Igs are presumed to be produced by B cells. Recent studies have demonstrated that renal parenchymal cells can produce and secrete Igs, including IgA and IgG. Glomerular mesangial cells can express and secrete IgA, which is associated with cell survival and adhesion. Likewise, human podocytes demonstrate the ability to produce and secrete IgG, which is related to cell survival and adhesion. Furthermore, renal tubular epithelial cells also express IgG, potentially involved in the epithelial-mesenchymal transition (EMT). More significantly, renal cell carcinoma, bladder cancer, and prostate cancer have been revealed to express high levels of IgG, which promotes tumour progression. Given the widespread Ig expression in the urinary and male reproductive systems, continued efforts to elucidate the roles of Igs in renal physiological and pathological processes are necessary.

Their last will and testament: dying immune cells protect the urinary system with extracellular DNA traps.

Like most epithelial organs, the bladder and kidney can be directly accessed by bacteria evolved for invasion. Epithelia and immune cells attempt to stymie this infection with biophysical and chemical mechanisms. Goldspink et al. connected the Na+ gradient in the kidney medulla with an immune defense mounted by dead cells (namely, the explosive death of neutrophils and macrophages), resulting in extracellular DNA traps. The pathway from Na+ concentration to immune death is depicted.

Distribution pattern of local immune cells within the lower urinary tract of male sheep lambs.

The local immunity of the lower urinary tract (LUT) is often presumed to influence the development of ascending infections and local inflammation. Due to small ruminants being at a higher risk of developing obstructive urolithiasis after early castration, a relationship is expected to exist between disturbed local immunity, castration and disease. However, the underlying pathophysiology and histological correlation of this assumption are unknown. This study examines the local cellular immunity of the LUT in male lambs with respect to castration status or a recent history of obstructive urolithiasis. Various tissue samples were taken and examined. The sample consisted of 34 male lambs, aged six months (n = 11 early and n = 11 late castration; n = 12 intact) and eight rams that had undergone necropsy due to fatal outcome after obstructive urolithiasis. Immunohistochemical stainings for CD3-T-cells, CD79α-B-cells and MAC 387-macrophages were performed and compared among the groups. Whereas no global group differences were evident, significant differences were found for the localizations (P = 0.002) with a significant interaction between group and localization (P = 0.004). The immunohistochemical results suggest that castration did not affect the cell number, but did have an effect on the distribution pattern of local T-cells within the urethra. In the urolithiasis cases, a reduction of CD3-positive cells along the middle part of the urethra was noticeable.

Expanding Phenotype of Schimke Immuno-Osseous Dysplasia: Congenital Anomalies of the Kidneys and of the Urinary Tract and Alteration of NK Cells.

Schimke immuno-osseous dysplasia (SIOD) is a rare multisystemic disorder with a variable clinical expressivity caused by biallelic variants in SMARCAL1. A phenotype-genotype correlation has been attempted and variable expressivity of biallelic SMARCAL1 variants may be associated with environmental and genetic disturbances of gene expression. We describe two siblings born from consanguineous parents with a diagnosis of SIOD revealed by whole exome sequencing (WES). Results: A homozygous missense variant in the SMARCAL1 gene (c.1682G>A; p.Arg561His) was identified in both patients. Despite carrying the same variant, the two patients showed substantial renal and immunological phenotypic differences. We describe features not previously associated with SIOD-both patients had congenital anomalies of the kidneys and of the urinary tract and one of them succumbed to a classical type congenital mesoblastic nephroma. We performed an extensive characterization of the immunophenotype showing combined immunodeficiency characterized by a profound lymphopenia, lack of thymic output, defective IL-7Rα expression, and disturbed B plasma cells differentiation and immunoglobulin production in addition to an altered NK-cell phenotype and function. Conclusions: Overall, our results contribute to extending the phenotypic spectrum of features associated with SMARCAL1 mutations and to better characterizing the underlying immunologic disorder with critical implications for therapeutic and management strategies.

Analysis of inflammatory cytokine expression in the urinary tract of BALB/c mice infected with Proteus (P.) mirabilis and enteroaggregative Escherichia (E.) coli (EAEC) strains.

This study aimed to analyze the proinflammatory cytokine mRNA expression in the urinary tract of BALB/c mice infected with bacterial strains with uropathogenic potential. Groups of four 6-week-old female BALB/c mice were intraurethrally inoculated with 5 × 107 colony-forming units (CFU) of P. mirabilis ATCC29906, EAEC O42, P. mirabilis RTX339, or sterile saline (control group) and then sacrificed at 0, 2, 4, 7, or 10 days post-infection (p.i.). Samples were cultured to determine the CFU/mL in urine or CFU/g in the bladders and kidneys. Cytokine expression (tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, -6, and -8) was evaluated in the target organs using real-time PCR and immunohistochemistry; histology was examined with hematoxylin and eosin staining. The results are presented as the means and standard deviations and were compared using one-way ANOVA, with p < 0.05 indicating significant differences. Bacteriuria was not detected in the infected groups; bacterial colonization occurred in the target organs at all time points, but was higher in mice infected with EAEC O42 or P. mirabilis RTX339 at 7 days p.i. The expression of all cytokine mRNAs was seen, but only the levels of the IL-8 protein increased in situ at 7 days p.i. in the P. mirabilis RTX339 and EAEC O42 groups in both organs. Morphological alterations, observed in all of the infected groups, were more prominent in the EAEC O42 and P. mirabilis RTX339 groups. The findings provide insights into the uropathogenicity and inflammatory cytokine expression in the urinary tract of mice infected with three previously untested bacterial strains.

A rare association of Mycobacterium tuberculosis infection of kidney and urinary tract with immunoglobulin A nephropathy.

Mycobacterium tuberculosis(MTB)-related secondary immunoglobulin A (IgA) nephropathy is reported in a 72-year-old male patient. The patient was diagnosed to have MTB infection of the kidney and genitourinary tract which was diagnosed by the demonstration of the organism by GeneXpert Ultra and culture. Concurrent kidney biopsy showed IgA nephropathy. The patient responded to urethral double-J stenting and four-drug antituberculous therapy with improvement of kidney function and resolution of MTB. IgA nephropathy can present as primary glomerulonephritis or secondary to MTB infection.

Host-Derived Nitric Oxide and Its Antibacterial Effects in the Urinary Tract.

Urinary tract infection (UTI) is one of the most common bacterial infections in humans, and the majority are caused by uropathogenic Escherichia coli (UPEC). The rising antibiotic resistance among UPEC and the frequent failure of antibiotics to effectively treat recurrent UTI and catheter-associated UTI motivate research on alternative ways of managing UTI. Abundant evidence indicates that the toxic radical nitric oxide (NO), formed by activation of the inducible nitric oxide synthase, plays an important role in host defence to bacterial infections, including UTI. The major source of NO production during UTI is from inflammatory cells, especially neutrophils, and from the uroepithelial cells that are known to orchestrate the innate immune response during UTI. NO and reactive nitrogen species have a wide range of antibacterial targets, including DNA, heme proteins, iron-sulfur clusters, and protein thiol groups. However, UPEC have acquired a variety of defence mechanisms for protection against NO, such as the NO-detoxifying enzyme flavohemoglobin and the NO-tolerant cytochrome bd-I respiratory oxidase. The cytotoxicity of NO-derived intermediates is nonspecific and may be detrimental to host cells, and a balanced NO production is crucial to maintain the tissue integrity of the urinary tract. In this review, we will give an overview of how NO production from host cells in the urinary tract is activated and regulated, the effect of NO on UPEC growth and colonization, and the ability of UPEC to protect themselves against NO. We also discuss the attempts that have been made to develop NO-based therapeutics for UTI treatment.

Infecciones del tracto urinario, inmunidad y vacunación / Urinary tract infections, immunity, and vaccination

Resumen Las infecciones del tracto urinario (ITU) se consideran como una de las principales causas de morbilidad en el mundo, y Escherichia coli uropatogénica (UPEC, por sus siglas en inglés) es el agente causal asociado a estas infecciones. La alta morbilidad generada por las ITU y la limitación de tratamientos debido al aumento de la resistencia bacteriana a los diversos antibióticos inducen la búsqueda de nuevas alternativas contra estas infecciones. El conocimiento que se ha generado acerca de la respuesta inmunitaria en el tracto urinario (TU) es importante para el desarrollo de estrategias efectivas en la prevención, el tratamiento y el control de las ITU. Los avances en las herramientas de biología molecular y bioinformática han permitido generar proteínas de fusión consideradas como biomoléculas potenciales para el desarrollo de una vacuna viable contra las ITU. Las adhesinas fimbriales (FimH, CsgA y PapG) de UPEC son factores de virulencia que contribuyen a la adherencia, la invasión y la formación de comunidades bacterianas intracelulares. Pocos estudios in vivo e in vitro han mostrado que las proteínas de fusión promueven una respuesta inmunitaria eficiente y de protección contra las ITU causadas por UPEC. Adicionalmente, la vía de inmunización intranasal con moléculas inmunogénicas ha generado una respuesta en la mucosa del TU en comparación contra otras vías de inmunización. El objetivo de esta revisión fue proponer un diseño de vacuna contra las ITU causadas por UPEC, describiendo el panorama general de la infección, el mecanismo de patogenicidad de la bacteria y la respuesta inmunitaria del huésped.

Abstract Urinary tract infections (UTI) are considered one of the main causes of morbidity worldwide, and uropathogenic Escherichia coli (UPEC) is the etiological agent associated with these infections. The high morbidity produced by the UTI and the limitation of antibiotic treatments promotes the search for new alternatives against these infections. The knowledge that has been generated regarding the immune response in the urinary tract is important for the development of effective strategies in the UTI prevention, treatment, and control. Molecular biology and bioinformatic tools have allowed the construction of fusion proteins as biomolecules for the development of a viable vaccine against UTI. The fimbrial adhesins (FimH, CsgA, and PapG) of UPEC are virulence factors that contribute to the adhesion, invasion, and formation of intracellular bacterial communities. The generation of recombinant proteins from fimbrial adhesins as a single molecule is obtained by fusion technology. A few in vivo and in vitro studies have shown that fusion proteins provide an efficient immune response and protection against UTI produced by UPEC. Intranasal immunization of immunogenic molecules has generated a response in the urinary tract mucosa compared with other routes of immunization. The objective of this review was to propose a vaccine designed against UTI caused by UPEC, describing the general scenario of the infection, the mechanism of pathogenicity of bacteria, and the immune response of the host.

Immune analysis of expression of IL-17 relative ligands and their receptors in bladder cancer: comparison with polyp and cystitis.

BACKGROUND: Bladder cancer, cystitis and bladder polyp are the most common urinary system diseases all over the world. Our former research results show that IL-17A and IL-17 F contribute to the pathogenesis of benign prostatic hyperplasia (BPH) and prostate cancer (Pca) while IL-17E interacting with IL-17RB might have an anti-tumor effect. RESULTS: Using imunohistochemistry, we systemically compared immunoreactivity of ligands (IL-17A, E and F) and receptors (IL-17RA, IL-17RB and IL-17RC) of IL-17 family, infiltration of inflammatory cells and changes of structural cells (fibroblast cells, smooth muscle and vascular endothelial cells) in sections of bladder tissues from subjects with bladder cancer, cystitis and bladder polyp. Compared with subjects with cystitis, immunoreactivity for IL-17A, IL-17 F and IL-17RC was significantly elevated in the group of bladder cancer (p < 0.01), while immunoreactivity of IL-17E, IL-17RA and IL-17RB, and the infiltrating neutrophils were decreased (p < 0.05). The numbers of infiltrating lymphocytes and phagocytes and CD31+ blood vessels and immunoreactivity of CD90+ fibroblasts were also elevated in patients with bladder cancer compared with those of cystitis. The patterns of IL-17 ligands and receptors, and inflammatory cells and structural cells varied in cystitis, bladder polyp and bladder cancer. In bladder cancer, immunoreactivity of IL-17E and IL-17 F was positively correlated with smooth muscles and lymphocytes, respectively. In addition, immunoreactivity of IL-17A and IL-17E was positively correlated with their receptors IL-17RA and IL-17RB respectively. CONCLUSIONS: The data suggest that changed patterns of expression of the IL-17 cytokine family ligands and receptors might be associated with infiltration of inflammatory cells and structural cells (CD90+ fibroblasts and CD31+ blood vessels), which might also contribute to occurrence and development in bladder cancer.

Urinary Tract Infection: Pathogenesis and Outlook.

The clinical syndromes comprising urinary tract infection (UTI) continue to exert significant impact on millions of patients worldwide, most of whom are otherwise healthy women. Antibiotic therapy for acute cystitis does not prevent recurrences, which plague up to one fourth of women after an initial UTI. Rising antimicrobial resistance among uropathogenic bacteria further complicates therapeutic decisions, necessitating new approaches based on fundamental biological investigation. In this review, we highlight contemporary advances in the field of UTI pathogenesis and how these might inform both our clinical perspective and future scientific priorities.

Inflammasomes in the urinary tract: a disease-based review.

Inflammasomes are supramolecular structures that sense molecular patterns from pathogenic organisms or damaged cells and trigger an innate immune response, most commonly through production of the proinflammatory cytokines IL-1ß and IL-18, but also through less understood mechanisms independent of these cytokines. Great strides have been made in understanding these structures and their dysfunction in various inflammatory diseases, lending new insights into urological and renal problems. From a clinical perspective, benign urinary pathology almost universally involves the inflammatory process, and understanding how inflammasomes translate etiological conditions (diabetes, obstruction, stones, urinary tract infections, etc.) into acute and chronic inflammatory responses is critical to understanding these diseases at a molecular level. To date, inflammasome components have been found in the bladder, prostate, and kidney and have been shown to be activated in response to several infectious and noninfectious insults. In this review, we summarize what is known regarding inflammasomes in both the upper and lower urinary tract and describe several common disease states where they potentially play critical roles.

Association of O-Antigen Serotype with the Magnitude of Initial Systemic Cytokine Responses and Persistence in the Urinary Tract.

UNLABELLED: Urinary tract infection (UTI) is one of the most common ailments requiring both short-term and prophylactic antibiotic therapies. Progression of infection from the bladder to the kidney is associated with more severe clinical symptoms (e.g., fever and vomiting) as well as with dangerous disease sequelae (e.g., renal scaring and sepsis). Host-pathogen interactions that promote bacterial ascent to the kidney are not completely understood. Prior studies indicate that the magnitude of proinflammatory cytokine elicitation in vitro by clinical isolates of uropathogenic Escherichia coli (UPEC) inversely correlates with the severity of clinical disease. Therefore, we hypothesize that the magnitude of initial proinflammatory responses during infection defines the course and severity of disease. Clinical UPEC isolates obtained from patients with a nonfebrile UTI elicited high systemic proinflammatory responses early during experimental UTI in a murine model and were attenuated in bladder and kidney persistence. Conversely, UPEC isolates obtained from patients with febrile UTI elicited low systemic proinflammatory responses early during experimental UTI and exhibited prolonged persistence in the bladder and kidney. Soluble factors in the supernatant from saturated cultures as well as the lipopolysaccharide (LPS) serotype correlated with the magnitude of proinflammatory responses in vitro. Our data suggest that the structure of the O-antigen sugar moiety of the LPS may determine the strength of cytokine induction by epithelial cells. Moreover, the course and severity of disease appear to be the consequence of the magnitude of initial cytokines produced by the bladder epithelium during infection. IMPORTANCE: The specific host-pathogen interactions that determine the extent and course of disease are not completely understood. Our studies demonstrate that modest changes in the magnitude of cytokine production observed using in vitro models of infection translate into significant ramifications for bacterial persistence and disease severity. While many studies have demonstrated that modifications of the LPS lipid A moiety modulate the extent of Toll-like receptor 4 (TLR4) activation, our studies implicate the O-antigen sugar moiety as another potential rheostat for the modulation of proinflammatory cytokine production.

Extracellular ATP and P2Y receptor activation induce a proinflammatory host response in the human urinary tract.

Extracellular ATP can be released by many cell types under conditions of cellular stress and signals through activation of purinergic receptors. Bladder uroepithelial cells grown in vitro have previously been shown to release ATP in response to stretch. In the present study, we investigated ATP release from uroepithelial cells infected with bacteria and the effect of ATP on the host cell proinflammatory interleukin 8 (IL-8) response. The human kidney epithelial cell line A498 and the human uroepithelial cell line UROtsa were grown in culture and stimulated by the uropathogenic Escherichia coli (UPEC) IA2 strain or the stable ATP analogue ATP-gamma-S. ATP and IL-8 levels were measured in cell culture medium with a luciferin-luciferase assay and enzyme-linked immunosorbent assay (ELISA), respectively. The results showed that UPEC infection of uroepithelial cells for 1 h significantly increased (P < 0.01) the extracellular ATP levels. ATP-gamma-S (10 and 100 microM) stimulated release of IL-8 from UROtsa and A498 cells after 6 and 24 h. Experiments with different purinoceptor agonists suggested that P2Y receptors, and not P2X receptors, were responsible for the ATP-gamma-S-induced IL-8 release. The potency profile further suggested involvement of P2Y(1), P2Y(2), and/or P2Y(11) receptors, and reverse transcription-PCR (RT-PCR) studies confirmed that the cells expressed these receptors. The amount of IL-8 released increased 12-fold in UPEC-infected cells, and apyrase, an enzyme that degrades ATP, reduced this increase by approximately 50%. The present study suggests that enhanced ATP release and P2Y receptor activation during urinary tract infection may represent a novel, non-TLR4-mediated mechanism for production of proinflammatory IL-8 in human urinary tract epithelial cells.

Urinary CD80 is elevated in minimal change disease but not in focal segmental glomerulosclerosis.

Controversy exists as to whether minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) represent different diseases or are manifestations within the same disease spectrum. Urinary excretion of CD80 (also known as B7.1) is elevated in patients with MCD and hence we tested whether urinary CD80 excretion might distinguish between patients with MCD from those with FSGS. Urinary CD80 was measured in 17 patients with biopsy-proven MCD and 22 with proven FSGS using a commercially available enzyme-linked immunosorbent assay and its molecular size determined by western blot analysis. A significant increase in urinary CD80, normalized to urinary creatinine, was found in patients with MCD in relapse compared to those in remission or those with FSGS. No significant differences were seen when CD80 urinary excretion from MCD patients in remission were compared to those with FSGS. In seven of eight MCD patients in relapse, CD80 was found in glomeruli by immunohistochemical analysis of their biopsy specimen. No CD80 was found in glomeruli of two patients with FSGS and another MCD patient in remission. Thus, our study supports the hypothesis that MCD and FSGS represent two different diseases rather than a continuum of one disease. Urinary CD80 excretion may be a useful marker to differentiate between MCD and FSGS.

Chlamydia muridarum-specific CD4 T-cell clones recognize infected reproductive tract epithelial cells in an interferon-dependent fashion.

During natural infections Chlamydia trachomatis urogenital serovars replicate predominantly in the epithelial cells lining the reproductive tract. This tissue tropism poses a unique challenge to host cellar immunity and future vaccine development. In the experimental mouse model, CD4 T cells are necessary and sufficient to clear Chlamydia muridarum genital tract infections. This implies that resolution of genital tract infection depends on CD4 T-cell interactions with infected epithelial cells. However, no laboratory has shown that Chlamydia-specific CD4 T cells can recognize Chlamydia antigens presented by major histocompatibility complex class II (MHC-I) molecules on epithelial cells. In this report we show that MHC-II-restricted Chlamydia-specific CD4 T-cell clones recognize infected upper reproductive tract epithelial cells as early as 12 h postinfection. The timing of recognition and degree of T-cell activation are dependent on the interferon (IFN) milieu. Beta IFN (IFN-beta) and IFN-gamma have different effects on T-cell activation, with IFN-beta blunting IFN-gamma-induced upregulation of epithelial cell surface MHC-II and T-cell activation. Individual CD4 T-cell clones differed in their degrees of dependence on IFN-gamma-regulated MHC-II for controlling Chlamydia replication in epithelial cells in vitro. We discuss our data as they relate to published studies with IFN knockout mice, proposing a straightforward interpretation of the existing literature based on CD4 T-cell interactions with the infected reproductive tract epithelium.

Perfil de sensibilidade e multirresistência em linhagens de Escherichia coli isoladas de infecção do trato urinário, de piometra e de fezes de cães / Sensitivity profile and multiresistance in Escherichia coli strains isolated from urinary tract infection, pyometra and feces of dogs

Susceptibility profile and multiple drug resistance in 158 E. coli strains isolated from urinary tract infection (UTI), pyometra, and feces of dogs were studied. Norfloxacin, ciprofloxacin, and enrofloxacin were the most-effective drugs (>60 percent) for E. coli strains. High rates of resistance to antimicrobials were observed in 60 percent or more of the isolated strains using sulfametoxazole/trimetoprim. Multiple drug resistance for three or more antimicrobials was observed in two (47.1 percent) strains isolated from UTI, seven (13.5 percent) from pyometra, and four (7.3 percent) from feces. From these, 17 (33.3 percent), one (1.9 percent), and three (5.5 percent), respectively, showed multiple resistance to five or more drugs.

[Investigation of the bactericidal effect of urinary epithelial cells against different doses of Escherichia coli]. / Uriner epitel hücrelerinin farkli antijenik miktarlardaki Escherichia coli'ye karsi bakterisidal etkisinin arastirilmasi.

Epithelial cells take part in the stimulation of immune system during the conversion of nonspecific immune response to the adaptive one in the mucosal immune system. Epithelial cells also have critical roles in designating immune homeostasis towards immune regulation or tolerance. Its response type is determined according to the dose and structure of the antigen and the way it is presented. In this study, we aimed to evaluate the response of human urinary epithelial cells to different doses of Escherichia coli K12 by means of their bactericidal effect. Urine was collected from 16 healthy volunteers and urinary epithelial cells were prepared. The cells (effector) were stimulated with bacteria (target) in microplates for one hour with different effector/target cell ratios. At the end of the incubation period, the bactericidal effects were calculated and compared with microorganism controls. Mann-Whitney U test was used for statistical analysis. Urinary epithelial cells which were stimulated by E. coli K12 showed dose dependent bactericidal effect, calculated mean value for bactericidal effects were 60.7% at the 1/100.000 effector/target cell ratio and 11.3% 1/1.000.000 effector/target cell ratio, indicating that the bactericidal effect was dose dependent.

[Bactericidal effects of human oral and urinary system epithelial cells against different Escherichia coli strains]. / Insan agiz ve uriner sistem epitel hücrelerinin farkli Escherichia coli suslarina karsi bakterisidal etkisinin arastirilmasi.

The functions of epithelial cells are more than a physical selective barrier for protection from mucosal pathogens. The epithelial response regulated by host-microorganism interaction may change due to histological and physiological differences between sterile and nonsterile sites. In this study we examined the presence of a difference between bactericidal capacities of urinary and oral epithelial cells against different strains of Escherichia coli. Oral epithelial cells were collected from unstimulated saliva and uroepithelial cells were collected from urine of eight healthy volunteers. E. coli K12 and O75 strains and epithelial cells were prepared for the experiment, added to microplates and incubated for one hour. The growth of bacteria was detected by the quantitative colony counting method. Antibacterial effects of the oral and urinary epithelial cells against E. coli K12 and O75 strains were 49.8%, 34.7%, 45.7% and 29.2%, respectively. As a result, it was detected that the antibacterial activity of oral epithelial cells to E. coli K12 and O75 were higher than urinary epithelial cells.

Toll-like receptor 4 expression and cytokine responses in the human urinary tract mucosa.

Mucosal pathogens trigger a local innate host response by activating epithelial cells. Bacterial adherence and Toll-like receptor 4 (TLR4) signaling have been implicated as key events in this process. This study addressed the molecular basis of the epithelial response to gram-negative infection in the human urinary tract. Mucosal biopsies were obtained from kidneys, ureters, and bladders of patients undergoing urinary tract surgery, and epithelial TLR4 and CD14 expression was examined by immunohistochemistry. TLR4 was detected in epithelial cells lining the entire urinary tract and in the renal tubular epithelium. CD14, in contrast, was completely absent from the epithelial tissue. The response of the epithelial cells to infection was studied by in vitro challenge of the biopsies with uropathogenic Escherichia coli bacteria. A rapid cytokine response was observed, with production of interleukin-1beta (IL-1beta), IL-6, and IL-8 but not of IL-4 or gamma interferon. Adhering, P- or type 1-fimbriated E. coli activated IL-6 and IL-8 production more efficiently than the nonfimbriated control, as shown by cellular staining and analysis of secreted cytokines. The results demonstrate that human uroepithelial cells possess the molecular machinery needed to respond to uropathogenic E. coli. This includes recognition receptors for fimbriae and TLR4 for transmembrane signaling. We speculate that the lack of membrane-bound CD14 allows the epithelium to regulate its sensitivity to lipopolysaccharide and to discriminate between more-virulent and less-virulent strains.