Elevated urinary IL-36γ in patients with active lupus nephritis and response to treatment.

INTRODUCTION: IL-36 is a new member of the IL-1 family with pro-inflammatory properties. Serum levels of IL-36 are elevated in patients with Systemic Lupus Erythematosus (SLE). However, no data is available on urinary levels of IL-36 in Lupus Nephritis (LN). In psoriasis expression of IL-36 is site specific and expressed in skin. Hence, we studied urinary levels of IL-36 cytokines in SLE patients. METHODS: A total of 196 patients with SLE [97 active LN patients (ALN), 42 inactive LN (ILN) and 57 active lupus patients with no renal involvement (ANR)] and 25 healthy subjects were recruited for the study after obtaining informed consent. Urinary and plasma IL-36α, IL-36γ and IL-36Ra levels were measured by ELISA. RESULTS: Out of 196 patients 178 were females. Urinary IL-36γ levels in SLE patients [0(14.3) pg/ml] were significantly higher than healthy controls [0(0) pg/ml, (P < 0.01)]. Patients with ALN [0(40.6) pg/ml] had significantly higher IL-36γ when compared to ANR [0(0) pg/ml] as well as ILN [0(0) pg/ml]. Urinary IL-36γ levels in ALN patients had a fair correlation with renal SLEDAI (r = 0.26, P = 0.004).The levels reduced significantly post 3 months in patients with ALN. No inverse relationship was noted between IL-36Ra and IL-36α/IL36γ levels. CONCLUSION: Urinary IL-36γ is produced locally in kidney, correlates with renal disease activity and reduces upon treatment, suggesting that it may have a role in pathogenesis of LN.

[Studies on the level of proinflammatory cytokines IIL-1a, IL-1b, IL-6, TNF-a in pregnant women with acute pyelonephritis].

UNLABELLED: Proinflammatory cytokines (IL-1a, IL-1b, IL-6, TNF-a) are important mediators of acute inflammation. We studied the levels of those cytokines in pregnant women with acute pyelonephritis. MATERIAL AND METHODS. We studied 30 women with clinical and microbiological evidence of acute pyelonephritis and 30 healthy controls Urinary cytokine levels were measured using an ELISA test. RESULTS: The mean urinary cytokine levels of pregnant women with acute pyelonephritis were higher compared with controls. We found evidence for higher clinical microbiological activity in women with acute pyelonephritis compared to controls. CONCLUSIONS. The urinary levels of proinflamatory cytokines can be used as reliable biomarkers for acute pyelonephritis in pregnant women.

Local overexpression of interleukin-1 family, member 6 relates to the development of tubulointerstitial lesions.

Identification of factors that exacerbate a disease is important for the development of biomarkers. In this study, we discovered ectopic overexpression of interleukin-1 family, member-6 (IL-1F6) in several murine renal diseases. IL-1F6 participates in cytokine/chemokine production in the epithelium. In PCR array analysis for inflammatory mediators, Il1f6 showed the highest expression in the kidney of the B6.MRLc1 glomerulonephritis model. IL-1F6 was localized in the epithelium from the DCTs to CCDs, which showed tubular dilations or epithelial deciduations. Ultrastructual examination of the epithelial cells revealed that IL-1F6 was localized on the cytoplasmic ribosome, vesicles, and nucleus. In and around these tubules, we found infiltrations of CD3-positive T-cells and nestin- or alpha-smooth-muscle actin-positive mesenchymal cells. Expression of the IL-1F6 protein and Il1f6 mRNA in the kidney was increased by the development of TILs in the B6.MRLc1 model and in lupus (BXSB, NZB/WF1, and MRL/lpr), nephrotic syndrome (ICGN), and streptozotocin-induced diabetic models. IL-1F6 was also detected in the epithelia having squamous or deciduous contours in other organs such as the skin, esophagus, thymus, or uterus. In vitro analysis using M-1 cells from the murine collecting duct revealed that Il1f6 mRNA induction was related to the upregulation of IL-6, TGF-beta receptor-1, and mesenchymal markers and to the downregulation of epithelial markers and changes in the squamous cells of the epithelium. Interestingly, urine Il1f6 mRNA expression was detected earlier than renal dysfunctions in these mouse models. Ectopic overexpression of IL-1F6 in kidneys is associated with TILs and especially with cell infiltrations and changes in epithelial morphology. We propose that local overexpression of IL-1F6 is related to the development of TILs.

Pentoxifylline ameliorates proteinuria through suppression of renal monocyte chemoattractant protein-1 in patients with proteinuric primary glomerular diseases.

Proteinuria (albuminuria) reflects dysfunction of the glomerular permeability barrier in which inflammatory cytokines play a key role. Pentoxifylline (PTX) is a phosphodiesterase inhibitor that possesses potent anti-inflammatory and immunomudulatory effects. This study evaluated the effectiveness of PTX to reduce proteinuria and inflammatory mediators in patients with proteinuric primary glomerular diseases. Seventeen patients with primary glomerular diseases, a persistent spot proteinuria exceeding 1.5 g/g creatinine (Cr) and a glomerular filtration rate between 24 and 115 ml/min/1.73 m(2) were treated with PTX 400 mg twice daily for 6 months. Before and after the treatment, serum Cr, plasma renin activity and aldosterone concentrations, plasma and urinary tumor necrosis factor (TNF)-alpha, interleukin-1beta and monocyte chemoattractant protein (MCP)-1, as well as urinary protein and Cr were measured. PTX significantly reduced urinary protein excretion, along with an increase of serum albumin. A significant correlation existed between the basal urinary protein/Cr and the basal urinary MCP-1/Cr ratios. PTX lowered the urinary MCP-1/Cr ratio, and the percent reduction of urinary protein/Cr ratio correlated directly with the precent decrease of urinary MCP-1/Cr ratio after PTX treatment. There was no significant change in blood pressure, renal function, biochemical parameters, plasma renin activity and aldosterone concentrations, or plasma TNF-alpha and MCP-1 levels during the study. In conclusion, administration of PTX 800 mg per day is safe and effective for reducing proteinuria in patients with proteinuric primary glomerular diseases. This beneficial effect occurs in close association with a reduction of urinary MCP-1 excretion.

Strikingly higher interleukin (IL)-1alpha, IL-1beta and soluble interleukin-1 receptor antagonist (sIL-1RA) but similar IL-2, sIL-2R, IL-3, IL-4, IL-6, sIL-6R, IL-10, tumour necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta and interferon IFN-gamma urine levels in healthy females compared to healthy males: protection against urinary tract injury?

The aim of this prospective study was to examine gender-related differences of cytokines in the plasma and urine of healthy individuals that might provide a clue concerning the lower rate of chronic renal diseases in females. Soluble interleukin-1 receptor antagonist (sIL-1RA), interleukin (IL)-1alpha, IL-1beta, IL-2, sIL-2R, IL-3, IL-4, IL-6, sIL-6R, IL-10, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta(2) and interferon (IFN)-gamma were determined using standard enzyme-linked immunosorbent assay (ELISA). Cytokine levels were determined in simultaneously obtained plasma and urine samples of 18 male and 28 female healthy members of our laboratory staff. Urine cytokine levels were studied three times at 1-month intervals. All individuals had a negative urine nitrite test and showed no symptoms of urinary tract infection (UTI). Plasma levels of all studied cytokines were similar in males and females (P = n.s.). However, females had significantly higher urine IL-1alpha (P < 0.0001; P < 0.0001; P < 0.0001) and sIL-1RA (P = 0.0001; P = 0.0003; P = 0.0002) than males at three and higher IL-1beta at one of the three investigations (P = 0.098; P = 0.003; P = 0.073). Urine levels of the other cytokines were similar in males and females. Higher urine levels of IL-1alpha, IL-1beta and sIL-1RA in females may result from stimulation of cells in the urinary tract. Increased sIL-1RA might block T lymphocyte activation. The elevated cytokines may play a role in the protection of the female urinary tract from certain renal diseases, such as pyelonephritis and other inflammatory and sclerotic kidney diseases.

[Urinary concentration of proinflammatory cytokines with regard to infected urinary tract region]. / Stezenie cytokin prozapalnych w moczu w zaleznosci od umiejscowienia zakazenia w drogach moczowych.

UNLABELLED: 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. MATERIAL: 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). METHOD: 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. CONCLUSIONS: 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.

Study of cytokine induced neuropathology by high resolution proton NMR spectroscopy of rat urine.

Multiple sclerosis is a major cause of non-traumatic neurological disability. The identification of markers that differentiate disease progression is critical to effective therapy. A combination of NMR spectroscopic metabolic profiling of urine and statistical pattern recognition was used to detect focal inflammatory central nervous system (CNS) lesions induced by microinjection of a replication-deficient recombinant adenovirus expressing TNF-alpha or IL1-beta cDNA into the brains of Wistar rats. These animals were compared with a group of naïve rats and a group of animals injected with an equivalent null adenovirus. Urine samples were collected 7 days after adenovirus injection, when the inflammatory lesion is maximally active. Principal components analysis and Partial Least Squares-Discriminate analysis of the urine (1)H NMR spectra revealed significant differences between each of the cytokine adenovirus groups and the control groups; for the TNF-alpha group the main differences lay in citrate and succinate, while for the IL-1beta group the predominant changes occurred in leucine, isoleucine, valine and myo-inositol. Thus, we can identify urinary metabolic vectors that not only separate rats with inflammatory lesions in the brain from control animals, but also distinguish between different types of CNS inflammatory lesions.

Interleukin-1beta elevation during the postpartum period.

During the postpartum period, women frequently report increased fatigue, which, if severe, may interfere with maternal-child bonding, delay a new mother's return to her activities of daily living, and contribute to depression. Several studies have sought to determine psychosocial contributions to fatigue during the postpartum period, but few evaluate any physiological changes that may contribute to fatigue during this time. The following study was designed to test whether the potent, pro-inflammatory cytokine interleukin-1beta (IL-1beta), known to be a physiological mediator of fatigue in several clinical and experimental conditions, is elevated in women during the postpartum period and whether it might be related to symptoms of fatigue. Levels of fatigue and the urinary excretion of IL-1beta were measured in 26 women over 4 weeks postpartum. Correlations between fatigue and activation of the inflammatory response were investigated. Results demonstrated a significant elevation in IL-1beta during the postpartum period compared to control participants (p < .05) and a significant, although delayed, correlation between IL-1beta elevation and fatigue (p < .05). These results suggest that activation of the inflammatory response, as reflected by elevation in urinary IL-1beta, occurs in association with postpartum fatigue. Studies to explore further this association and to identify specific mechanisms of action are needed.

Elevation of urinary IL-1beta levels during transplant associated nephropathy in rat model of the nephrotic syndrome.

A recurrence of nephrotic syndrome is a well-known phenomenon in patients who receive kidney transplantation. In this study, we attempt to establish a rat model of recurrent nephrotic change after renal transplantation using puromycin aminonucleoside (PA) induced nephrotic rats. We then examine the mechanism leading to recurrence. Female Sprague-Dawley rats (8 weeks) were divided into four groups: group A, allogenic renal transplantation of a normal kidney to PA-induced nephrotic rats; group B, PA injection only as a nephrotic control; group C, allogenic transplantation of a normal kidney to rats receiving a saline injection; group D, rats receiving only a saline injection. The serum and urinary levels of protein, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-2 and interferon (IFN)-gamma were measured. The cytokine levels were assessed by performing enzyme-linked immunosorbent assays. Six days after renal transplantation, the kidneys were excised, tissue sections were stained with hematoxylin-eosin and the specimens were studied for pathological alterations. The urinary protein levels and the histological results of protein casts in renal tubules of the autologous kidneys of the nephrotic rats and the transplanted kidneys confirmed the recurrence of nephrotic syndrome in the transplanted kidney. After renal transplantation, urinary protein and IL-1beta levels were significantly elevated in recurrent transplanted kidney groups compared with those in the control groups, while the TNF-alpha, IL-2, and IFN-gamma levels were not elevated. In addition, serum levels of TNFalpha and IL-1beta were not elevated. These results suggested that IL-1beta may relate to the recurrent nephropathy in the transplanted kidney in the nephrotic rat.

Plasma and urinary cytokine homeostasis and renal function during cardiac surgery without cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) significantly contributes to the plasma pro-inflammatory cytokine response at cardiac surgery. Complementary plasma and urinary anti-inflammatory cytokine responses have been described. The pro-inflammatory cytokines interleukin 8 (IL-8), tumour necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta) have lower molecular weights than the anti-inflammatory cytokines interleukin 10 (IL-10), interleukin 1 receptor antagonist (IL-1ra) and TNF soluble receptor 2 (TNFsr2) and thus undergo glomerular filtration more readily. In vitro work suggests that proximal tubular cells are vulnerable to pro-inflammatory cytokine mediated injury. Accordingly, this study investigated the hypothesis that cardiac surgery without CPB would not have significant changes in plasma and urinary cytokines and proximal renal dysfunction. Eight patients undergoing coronary artery bypass grafting (CABG) without CPB were studied. Blood and urine samples were analysed for pro- and anti-inflammatory cytokines. Proximal tubular dysfunction was measured using urinary Nu-acetyl-beta-D-glucosaminidase (NAG)/creatinine and alpha(1)-microglobulin/creatinine ratios. Plasma IL-8, IL-10, IL-1ra and TNFsr2 were significantly elevated compared with baseline. Urinary IL-1ra and TNFsr2 were significantly elevated, as were urinary NAG/creatinine and alpha(1)-microglobulin/creatinine ratios. Two hours following revascularization, urinary IL-1ra correlated with urinary alpha(1)-microglobulin/creatinine ratios (P<0.05). As previously reported in CABG surgery with CPB, we now report that non-CPB cardiac surgery also has significant changes in plasma and urinary cytokine homeostasis and early proximal tubular injury. The correlation between urinary IL-1ra and alpha(1)-microglobulin/creatinine ratios is consistent with earlier suggestions of a mechanistic link between cytokine changes and proximal tubular dysfunction. The relative roles of CPB and non-CPB processes in producing inflammation still require definition.

Cytokine profiles of pediatric patients treated with antibiotics for pyelonephritis: potential therapeutic impact.

Urinary tract infections are common in infants and children. Pyelonephritis may result in serious complications, such as renal scarring, hypertension, and renal failure. Identification of the timing of release of inflammatory cytokines in relation to pyelonephritis and its treatment is essential for designing interventions that would minimize tissue damage. To this end, we measured urinary cytokine concentrations of interleukin-1 beta (IL-1 beta), IL-6, and IL-8 in infants and children with pyelonephritis and in healthy children. Children that presented to our institution with presumed urinary tract infection were given the diagnosis of pyelonephritis if they had a positive urine culture, pyuria, and one or more of the following indicators of systemic involvement: fever, elevated peripheral white blood cell count, or elevated C-reactive protein. Urine samples were obtained at the time of presentation prior to the administration of antibiotics, immediately after completion of the first dose of antibiotics, and at follow up 12 to 24 h after presentation. IL-1 beta, IL-6, and IL-8 concentrations were measured by enzyme-linked immunosorbent assay. Creatinine concentrations were also determined, and cytokine/creatinine ratios were calculated to standardize samples. Differences between pre-antibiotic and follow-up cytokine/creatinine ratios were significant for IL-1 beta, IL-6, and IL-8 (P < 0.01). Differences between pre-antibiotic and control cytokine/creatinine ratios were also significant for IL-1 beta, IL-6, and IL-8 (P < 0.01). Our study revealed that the urinary tract cytokine response to infection is intense but dissipates shortly after the initiation of antibiotic treatment. This suggests that renal damage due to inflammation begins early in infection, underscoring the need for rapid diagnosis and intervention.

[Interleukin-1 beta in patients with primary immunocomplex glomerulonephritis]. / Interleukin-1 beta kod bolesnika sa primarnim imunokompleksnim glomerulonefritisom.

Interleukin-1 is one of the most important pro-inflammatory cytokines whose role in the pathogenesis of glomerulonephritic process was proved in numerous studies. The aim of this study was to determine the urinary level of this cytokine in patients with primary immunocomplex glomerulonephritis and its significance in diagnosis of this disease. This prospective study comprised a total of 96 patients (84 males and 12 females) with primary immunocomplex glomerulonephritis. The elevated urinary IL-1 beta level was noticed in 43 (49.4%) patients with different histological forms of glomerulonephritis. The mean concentration was significantly higher in patient's group (57.7 +/- 120.7 pg/mg creatinine) (range 1.1-731) compared to control group (10.2 +/- 5.96 pg/mg creatinine) (range 1.6-25.4) (p < 0.05). There was no significant difference in the frequency of elevated urinary IL-1 beta concentration in different patients group based on histological type of glomerulonephritis (chi 2 = 6.377, p > 0.05). On the basis of our results we concluded that the elevated concentration of IL-1 beta in majority of patients with primary immunocomplex glomerulonephritis had suggested its role in the pathogenesis of glomerulonephritic process. The urinary level of IL-1 beta represents a novel, non-invasive parameter in the diagnosis of this disease, but its measurement is not useful in predicting the histological type of primary immunocomplex glomerulonephritis. The results of our study suggest the possibility that urinary IL-1 beta level reflects the activity of glomerulonephritic process and it could be useful in non-invasive monitoring of the disease progression.

Deficiency of tumor necrosis factor alpha in a subclass of menstrual migraineurs.

OBJECTIVE: The objective of this study was to determine whether differences in urinary proinflammatory cytokines, interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha), exist between migraineurs and nonheadache control subjects, and between nonhormonal migraine and menstrual migraine. Any differences noted would expand and clarify a neuroimmune hypothesis of migraine pathogenesis and lead to future diagnostic markers or therapeutic options or both for the disorder. BACKGROUND: Current theories of migraine pathogenesis focus on biochemical abnormalities in the central nervous system resulting in sterile inflammation of meningeal blood vessels. Vasoactive substances involved in this process may include substance P, calcitonin gene-related peptide, neurokinin A, serotonin, and nitric oxide. Immune cell products, such as histamine, leukotrienes, and cytokines, also have vascular inflammatory properties. METHODS: A study of proinflammatory cytokines, IL-1beta, IL-6, and TNF-alpha, was undertaken in menstrual migraineurs. During and outside of menses, 24-hour urine samples of 19 women with migraine were taken during a menstrual migraine, a nonmenstrual migraine, and a headache-free day, and compared with 24-hour urine samples taken of 10 nonheadache controls during and outside of menses. RESULTS: A neuroimmune mechanism for migraine was tested with expected increases in proinflammatory cytokines tested during a migraine. This hypothesis was not validated. Mean IL-6 levels were increased in all three samples of migraineurs versus controls, but did not achieve statistical significance. No differences were found in IL-1beta levels between samples. Interestingly, marked differences were found in TNF-alpha values in menstrual migraineurs. Twelve (63%) of 19 migraineurs had at least one urine sample with undetectable TNF-alpha levels, whereas none of the 20 samples given by the 10 nonheadache controls in this study had undetectable levels. Thirty-two samples from men with cluster headache and nonheadache control subjects in prior studies had detectable levels. CONCLUSIONS: This deficiency of TNF-alpha levels in women with migraine may signal a disordered neuroimmune communication network and predisposition to migraine.

Intrarenal handling of recombinant human interleukin-1alpha in rats: mechanism for proximal tubular protein reabsorption.

The intrarenal distribution of recombinant human interleukin (IL)-la was studied in Sprague-Dawley male rats by immunohistochemical staining. The effects of the concurrent administration of various proteins or synthetic polypeptides on the urinary excretion of IL-1alpha were also studied to clarify the mechanism(s) for the reabsorption of IL-la in the renal tubules. Microscopic immunohistochemistry showed that IL-1alpha distributed to early proximal convoluted tubules but not to glomeruli, Henle's loops, distal tubules, or collecting ducts. Electron microscopic immunohistochemistry showed that IL-la was taken up into the endocytic vesicle located close to the apical membrane of the proximal tubular epithelial cells, then accumulated in lysosomes. Urinary excretion of intravenous IL-la at 500 microg/kg was extremely low, accounting for only 0.014% of the dose administered. The coadministration of intravenous human serum albumin did not affect the urinary excretion of IL-1alpha, whereas trypsinogen, myoglobin, and trypsin inhibitor dose-dependently produced an increase in the excretion of IL-la, the potency of which was greatest in that order. Poly-L-lysine, but not poly-L-glutamic acid dose-dependently increased the urinary excretion of IL-1alpha. These results indicate that most of the glomerular filtrated IL-1alpha could be easily reabsorbed into the proximal tubular cells via endocytosis, and the reabsorption was inhibited by coadministered low molecular weight proteins, particularly basic proteins. This result suggests that scavengers with a negative charge and broad binding ability for glomerular filtered proteins exist on the surface of the apical membrane of proximal tubular cells and play an important role in the reabsorption of filtered proteins.

Production of platelet-activating factor in patients with sepsis-associated acute renal failure.

BACKGROUND: Studies in experimental animals have suggested that platelet-activating factor (PAF) is a mediator of sepsis-associated acute renal failure (ARF). In the present study we have evaluated whether an increased concentration of PAF within circulation or urine of septic patients correlated with the worsening of renal function. METHODS: The concentration of PAF and selected cytokines (TNF, IL-1, IL-6, IL-8) was evaluated in blood and urine of 12 patients with septic shock and ARF for 4 consecutive days. RESULTS: The data obtained indicate that blood and urinary concentrations of PAF and of IL-1, IL-6 and IL-8 were significantly higher in septic patients than in controls subjects and in patients with chronic renal failure. The concentration of TNF was significantly increased only in urine. A significantly positive correlation was found among blood concentration of PAF and heart rate (r = 0.4193, P < 0.017), serum creatinine (r = 0.3671, P < 0.038), serum IL-6 (r = 0.5475, P < 0.005) and urine excretion of IL-8 (r = 0.3984, P < 0.044), whereas a negative correlation was present with the number of circulating platelets (r = -0.4285, P < 0.018). Moreover, a positive correlation among the concentration of PAF in urine and the serum concentration of IL-6 (r = 0.5654, P < 0.006) and urine excretion of IL-6 (r = 0.6589, P < 0.0008) and IL-8 (r = 0.6371, P < 0.0004) were found. CONCLUSIONS: These results demonstrate in humans during ARF associated with septic shock the production of PAF, a mediator that has been previously implicated in the pathogenesis of experimental endotoxin-induced shock and renal injury. The observation that blood and urinary concentrations of PAF correlated with some of the clinical and laboratory parameters related to the severity of ARF and sepsis suggests that PAF may contribute to the development of renal injury in septic patients.

Systemic immune response after intravesical instillation of bacille Calmette-Guérin (BCG) for superficial bladder cancer.

The mechanism of anti-tumour activity by BCG is not known clearly. However, many studies suggest that immunological response is related to effectiveness of intravesical instillation of BCG in the therapy for superficial bladder carcinoma. Peripheral blood mononuclear cells (PBMC), urine and serum were obtained from patients with superficial carcinoma at various times during the course of BCG instillation. Urine of patients showed increased levels of IL-1beta, IL-2, IL-6, tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and macrophage colony-stimulating factor (M-CSF) after BCG instillation. Levels of IL-2 and IFN-gamma in the serum also increased after BCG instillation, but IL-1beta, IL-6, TNF-alpha and M-CSF were not detectable. Maximal levels of IL-2 and IFN-gamma in the urine or serum were shown after the fourth instillation. BCG-induced killer cell activity in PBMC increased significantly after the third BCG instillation. These results suggest that BCG instillation involved not only local immunological efforts but also systemic immune responses. Tumour-free patients produced higher BCG-induced killer cell activity than tumour recurrence patients. BCG-induced killer cell activity may be useful for monitoring the effectiveness of intravesical BCG instillation.

Urinary IL-6 is elevated in patients with urolithiasis.

PURPOSE: To evaluate the possible role of cytokines interleukin (IL)-1beta, IL-1alpha and IL-6 in patients with urolithiasis. MATERIALS AND METHODS: Fifty-six patients currently with stone disease, 63 patients with bacterial cystitis, and 66 normal individuals were evaluated for urinary IL-1alpha, IL-1beta and IL-6. Clean catch urine samples were obtained and evaluated for cytokine levels using enzyme immunoassays for the respective cytokines. Statistical analysis of the results was carried out using the Kruskal-Wallis test followed by Newman-Keuls test and the chi-squared test. RESULTS: The patients with stone disease had significant elevations in IL-6 (p value< 10(-7)) relative to normal subjects. The levels of IL-6 in stone patients were lower than those of patients with bacterial cystitis. Neither IL-1beta nor IL-1alpha was elevated in stone patients relative to normals. By contrast, bacterial cystitis patients showed significant elevations in all three cytokines relative to normal subjects. Chi-squared analysis confirmed that stone patients had elevated IL-6 without elevation in either IL-1alpha or IL-1beta relative to normal subjects. CONCLUSIONS: Stone patients show significant elevations in IL-6 without marked increases in either IL-1beta or alpha relative to normal subjects. This elevation in IL-6 is not from infection as is seen in bacterial cystitis subjects. The elevation in IL-6 may be useful in the understanding of the pathogenesis of urolithiasis or as a potential marker for stone disease and we are currently investigating these possibilities.

Sarcoidosis associated with acute renal failure and increased levels of interleukin-6 in urine.

A 24-year-old man who had uveitis and showed intrathoracic lymph node swelling on a chest X-ray, was admitted to our hospital for further examination. Transbronchial lung biopsy specimens revealed non-caseating granulomas compatible to sarcoidosis. As the renal function became progressively worse, a specimen was obtained by renal biopsy. It showed a granuloma formation, and was diagnosed as renal sarcoidosis. A high level of interleukin (IL)-6 was detected in his urine. After oral administration of prednisolone, the renal function improved, and the urinary IL-6 level was reduced. These findings suggest that in sarcoidosis associated with renal failure, steroid therapy is effective and that IL-6 plays an important role in the pathogenesis of renal involvement of sarcoidosis.

Does increased urinary interleukin-1 receptor antagonist/interleukin-1beta ratio indicate good prognosis in renal transplant recipients?

BACKGROUND: Interleukin-1 (IL-1) is produced by activated monocytes/macrophages; highly increased amounts of IL-1 have been found in renal tissue in acute rejection of renal grafts. The endogenous inhibitor of IL-1, interleukin-1 receptor antagonist (IL-1ra), is produced in many cells in response to the same stimulus as IL-1. There is some evidence that the balance between IL-1 and IL-1ra is important in the regulation of inflammatory responses. In many inflammatory diseases in both humans and animals, a high concentration of endogenous IL-1ra or administration of exogenous IL-1ra has been shown to relate to shorter recovery time or to reduced mortality. METHODS: We measured the urinary excretion of IL-1ra and IL-1beta during the first 3-6 posttransplant weeks in 23 patients with acute rejection (69 24-hr urine samples) and in 17 patients with stable graft function (51 24-hr urine samples) and expressed the results as cytokine/creatinine ratios. RESULTS: Within the follow-up time, patients with rejection had higher urinary IL-1beta/creatinine (ng/mmol) ratios (median 5.0 vs. 2.7; P<0.005), lower IL-1ra/creatinine (ng/mmol) ratios (median 18.1 vs. 34.2; P<0.1), and consequently lower IL-1ra/IL-1beta ratios (median 3.6 vs. 20.3, P<0.005), compared with patients without rejection. In rejecting patients, IL-1ra/creatinine was constantly low and decreased even further during acute rejection, whereas IL-1beta/creatinine ratios increased from a median prerejection value of 3.5 (range not measurable to 9.0) to a median value of 8.1 (P<0.0005) (range 1.6 to 18.3) during rejection. CONCLUSION: These results suggest that patients who produce high amounts of IL-1ra in relation to IL-1beta are less prone to acute allograft rejection than patients with low IL-1ra/IL-1beta ratios.