Circulating IL-17A Levels in Postmenopausal Women with Primary Hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (PHPT) is a common cause of secondary osteoporosis in postmenopausal women. Th17 lymphocytes and the released cytokine IL-17A play an important role in bone metabolism. Th17 cells have been shown to be activated by PTH, and peripheral blood T cells from patients affected with PHPT express higher levels of IL-17A mRNA than controls. AIM: To investigate circulating levels of IL-17A and the ratio RANKL/OPG, as markers of osteoclastogenesis, in 50 postmenopausal PHPT women compared with postmenopausal osteoporotic non-PHPT women (n = 20). RESULTS: Circulating levels of IL-17A were similarly detectable in most PHPT and non-PHPT osteoporotic women (12.9 (8.4-23.1) vs. 11.3 (8.3-14.3) pg/ml, median (range interquartile), P = 0.759), at variance with premenopausal women where IL-17A was undetectable. In PHPT women, any significant correlations could be detected between circulating IL-17A levels and PTH levels. Nonetheless, significant negative correlations between circulating IL-17A and ionized calcium levels (r = -0.294, P = 0.047) and urine calcium excretions (r = -0.300, P = 0.045) were found. Moreover, PHPT women were characterized by positive correlations between IL-17A levels and femur neck (r = 0.364, P = 0.021) and total hip (r = 0.353, P = 0.015) T-scores. Circulating IL-17A levels did not show any significant correlation with sRANKL, OPG, and sRANKL/OPG ratio in PHPT women. CONCLUSIONS: In postmenopausal PHPT women, circulating IL-17A levels were similar to those detected in postmenopausal non-PHPT women, showing a disruption of the relationship observed in postmenopausal osteoporosis among circulating PTH, sRANKL, OPG, IL-17A, and bone demineralization in postmenopausal PHPT women. The data support an osteogenic effect of IL-17A in postmenopausal PHPT women.

Serum and urine interleukin-17A levels as biomarkers of disease activity in systemic lupus erythematosus.

OBJECTIVES: This study examined the correlations of both serum and urine interleukin-17A (IL-17A) levels with disease activity in systemic lupus erythematosus (SLE). This study was also aimed at determining their sensitivity and specificity as biomarkers of disease activity in SLE. METHODS: A cross-sectional study was performed involving SLE patients (n = 120 patients) from Universiti Kebangsaan Malaysia Medical Centre (UKMMC). Serum and urinary IL-17A levels were determined by immunoassay while disease activity was assessed using Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) and British Isles Lupus Assessment Group's 2004 index (BILAG 2004) scores. The correlations between serum and urinary IL-17A levels with total SLEDAI-2K and BILAG 2004 scores were determined using bivariate correlation analyses. Receiver operating characteristic curves were calculated to determine their sensitivity and specificity as disease activity biomarkers. RESULTS: Both serum and urinary IL-17A levels correlated with total scores of BILAG 2004, BILAG renal, BILAG mucocutaneous, and SLEDAI-2K (P < 0.05). Urine IL-17A levels correlated positively with urine protein : creatinine index while serum IL-17 level correlated with the BILAG hematology score (all P < 0.05). The area under curve of serum IL-17A and urine IL-17A with BILAG and SLEDAI scores were low (<0.75). CONCLUSION: Despite positive correlations between serum and urine IL-17A with SLE disease activity, both were neither sensitive nor specific as biomarkers to predict active disease. Hence, IL-17 measurement has no role in SLE disease activity assessments and future studies are needed to search for other reliable activity biomarkers.

Increased Urine Interleukin-17 and Interleukin-22 Levels in Patients With Candidal Urinary Tract Infection.

INTRODUCTION: Candiduria is common in the hospitalized patients. This study aimed to quantify interleukin (IL)-17 and IL-22 levels in urine of candiduric patients. MATERIALS AND METHODS: A case-control study was conducted on inpatients at Hashemi Nejad Kidney Center. Thirty-four patients were identified with Candida species in their urine samples (> 103 colony-forming units per milliliter and presence of Candida species only). Urine samples with concomitant infections were excluded. Thirty-four patients with negative direct examination and culture were included as the control patients. Interleulin-17 and IL-22 levels were measured in the lyophilized and nonlyophilized urine. The relevant cytokine titers of the two groups were compared, and the association of cytokine elevation and candiduria was investigated. RESULTS: The majority of the candiduric patients were from the intensive care and urology units of women. Only 4 patients (11.7%) manifested fever and dysuria. Massive leukocyturia was observed in 4 patients. Candida glabrata was the most commonly isolated species (44%). Levels of the urine IL-17 and IL-22 were significantly elevated in the candiduric patients, when compared to the noncandiduric controls. While an increased IL-17 level was significantly associated with candiduria (odds ratio, 1.09; 95% confidence interval, 1.003 to 1.17; P = .04), an increased IL-22 level was not. The results showed that lyophilized urine samples maximized the detection power of urinary cytokines. CONCLUSIONS: Our results indicated that direct examination, fungal urine culture, and investigation of urine IL-17 and IL-22 levels are useful tools for diagnosis of Candida urinary tract infection.

T helper (Th)-cytokines in the urine of patients with primary glomerulonephritis treated with immunosuppressive drugs: Can they predict outcome?

BACKGROUND: Glomerulonephritides (GNs) represent common causes of chronic kidney disease associated with a wide spectrum of clinical and histological features. Various factors that activate the inflammatory cascade are involved in the development of kidney injury. The aim of this study was to estimate the urinary excretion of pro-inflammatory (IL-2, INF-γ, TNF-α, IL-6, IL-17) and anti-inflammatory (IL-4, IL-10, TGF-ß1) cytokines, as well as the chemokine MCP-1 in patients with various types of GN treated by immunosuppressive drugs and to identify any prognostic value of excreted cytokines for future renal function. PATIENTS AND METHODS: Ninety-seven patients (62 M/35 F, age 53.1 ± 15.6 years) with primary glomerulonephritis and 32 healthy controls were studied. The original diagnoses were membranous nephropathy (MN, n=36), IgA nephropathy (IgAN, n=31) and minimal changes disease or focal segmental glomerulosclerosis (MCD/FSGS, n=30). All patients had been treated with immunosuppressive drugs and, at the time of measurement of urinary cytokine excretion, were either in clinical remission or still had active disease with persistent proteinuria. RESULTS: GN patients had significantly higher levels of all cytokines and MCP-1 compared to healthy controls. A strong positive correlation between TGF-ß1 and MCP-1 concentrations was observed in all GN patients. Increased urinary excretion of all tested cytokines apart from TNF-α and TGF-ß1 was observed even in patients with clinical remission. The main difference between patients with proteinuria and those in clinical remission was the level of MCP-1 urinary excretion. The urinary excretion of MCP-1 and TGF-ß1 was significantly higher in patients with MN who showed deterioration of renal function over a follow-up period of five years. CONCLUSIONS: Increased levels of cytokines are observed in the urine of patients with different types of glomerulonephritis, even after the achievement of clinical remission with the administration of immunosuppressive drugs. Urinary excretion of MCP-1 and TGF-ß1 indicates the ongoing inflammatory and fibrotic processes in the kidney and is probably related to unfavourable outcomes.

Evaluation of Th17 pathway in the diagnosis of autosomal dominant polycystic kidney disease.

INTRODUCTION: Current assessment tools of autosomal dominant polycystic kidney disease (ADPKD) diagnosis are challenging. This study evaluated the possible application of assessment of interleukin (IL)-17-related cytokines and the circulatory T helper 17 cells in the diagnosis of ADPKD. MATERIALS AND METHODS: Enrolling 54 ADPKD patients and 54 healthy individuals, we measured serum and urine levels of IL-6, IL-17, IL-23, and transforming growth factor-ß and the peripheral blood frequency of T helper 17 cells through flowcytometry. We computed sensitivity and specificity of each inflammatory marker as well as their different combinations using the receiver operating characteristic curve and discriminant function analysis. RESULTS: The mean serum and urine levels of IL-17 and IL-23 as well as urine levels of IL-6 were higher in ADPKD patients compared to the healthy controls (P < .001). There was no significant difference in the number of T helper 17 cells between the two groups. Among different combinations of the inflammatory markers, the serum IL-17 was the best factor in the diagnosis of ADPKD with a sensitivity as well as specificity of 100%. CONCLUSIONS: It is likely that T helper 17 pathway is involved in the pathogenesis of ADPKD; therefore, it may be beneficial if such a pathway be considered in its diagnosis.

IL-17, neutrophil activation and muscle damage following endurance exercise.

The T-cell subset Th17 is induced partly by interleukin (IL)-6 and activated by IL-23, and produces a proinflammatory cytokine IL-17. Since IL-6 increases dramatically following long-lasting endurance exercise, this response may also stimulate the induction of IL-17 and IL-23 after exercise. The aim of this study was to clarify the dynamics of IL-17 in association with endurance exercise-induced muscle damage and inflammatory responses. Fourteen male triathletes participated in a duathlon race consisting of 5 km of running, 40 km of cycling and 5 km of running. Venous blood and urine samples were collected before, immediately after 1.5 h and 3 h after the race. Plasma and urine were analyzed using enzyme-linked immunosorbent assays (ELISA). Haematological and biochemical variables such as neutrophil activation marker (myeloperoxidase: MPO), muscle damage marker (myoglobin: Mb) and soluble receptor activator of nuclear factor (NF)-KB ligand (sRANKL) were also determined to estimate the biological and pathological significance. Plasma concentrations oflL-6 (+26.0x), MPO (+3.2x) and Mb (+4.9x) increased significantly immediately after the race and IL-17 and IL-23 tended to increase. Furthermore, plasma concentrations of IL-12p40 and sRANKL increased significantly after the race. The measured parameters related to Thl 7 cytokines in the urinary output were closely correlated with each other and muscle damage marker. These findings suggest that IL-17 induced by IL-6 and activated by IL-23 or other IL-17 producing-cells and IL-23 might promote neutrophil activation and muscle damage following prolonged endurance exercise.

Discriminators of mouse bladder response to intravesical Bacillus Calmette-Guerin (BCG).

BACKGROUND: Intravesical Bacillus Calmette-Guerin (BCG) is an effective treatment for bladder superficial carcinoma and it is being tested in interstitial cystitis patients, but its precise mechanism of action remains poorly understood. It is not clear whether BCG induces the release of a unique set of cytokines apart from its pro-inflammatory effects. Therefore, we quantified bladder inflammatory responses and alterations in urinary cytokine protein induced by intravesical BCG and compared the results to non-specific pro-inflammatory stimuli (LPS and TNF-alpha). We went further to determine whether BCG treatment alters cytokine gene expression in the urinary bladder. METHODS: C57BL/6 female mice received four weekly instillations of BCG, LPS, or TNF-alpha. Morphometric analyses were conducted in bladders isolated from all groups and urine was collected for multiplex analysis of 18 cytokines. In addition, chromatin immune precipitation combined with real-time polymerase chain reaction assay (CHIP/Q-PCR) was used to test whether intravesical BCG would alter bladder cytokine gene expression. RESULTS: Acute BCG instillation induced edema which was progressively replaced by an inflammatory infiltrate, composed primarily of neutrophils, in response to weekly administrations. Our morphological analysis suggests that these polymorphonuclear neutrophils are of prime importance for the bladder responses to BCG. Overall, the inflammation induced by BCG was higher than LPS or TNF-alpha treatment but the major difference observed was the unique granuloma formation in response to BCG. Among the cytokines measured, this study highlighted the importance of IL-1beta, IL-2, IL-3, IL-4, IL-6, IL-10, IL-17, GM-CSF, KC, and Rantes as discriminators between generalized inflammation and BCG-specific inflammatory responses. CHIP/Q-PCR indicates that acute BCG instillation induced an up-regulation of IL-17A, IL-17B, and IL-17RA, whereas chronic BCG induced IL-17B, IL-17RA, and IL-17RB. CONCLUSION: To the best of our knowledge, the present work is the first to report that BCG induces an increase in the IL-17 family genes. In addition, BCG induces a unique type of persisting bladder inflammation different from TNF-alpha, LPS, and, most likely, other classical pro-inflammatory stimuli.

[Interleukin-17 concentration in serum and urine of children with idiopathic nephrotic syndrome]. / Stezenie interleukiny-17 w surowicy i w moczu dzieci z idiopatycznym zespolem nerczycowym.

UNLABELLED: T-cells and their cytokines play an important role in the pathogenesis of idiopathic nephrotic syndrome (INS) in children. IL-17 secreted by activated CD4+ Tcells induces production of proinflammatory mediators, enhances T-cell-mediated immune responses and Th1 type reactions. The aim of the study was to evaluate IL-17 concentrations in serum and urine of children with INS and determine the possible role of this cytokine in the course of disease. PATIENTS AND METHODS: 67 children with INS, aged 3 to 16 years (mean 9 +/- 4) and 15 normal controls were included in the study. The patients were divided into 2 groups according to activity of the disease: I (n=37)--INS in relapse, II (n=30)--INS in remission. Serum (s) and urinary (u) IL-17 were determined by immunoenzymatic method. In children with INS serum biochemical parameters, clearance of endogene creatinine and 24 hour proteinuria were measured. RESULTS: sIL-17 and uIL-17 concentrations (51.66 +/- 8.38 pg/mg and 56.29 +/-14.24 pg/mg creatinine (cr), respectively) were significantly higher (p<0.001) in group I compared with group II (35.7 +/- 10.18 pg/ml and 17.47 +/- 3.46 pg/mg cr) and normal controls (27.17 +/- 1.87 pg/ml and 13.91 +/- 1.22 pg/mg cr). UIL-17 correlated positively with sIL-17 (r=0.783, p<0.0001). A positive correlations between uIL-17 and sIL-17 and urinary protein excretion were found (r=0.58, r=0.42, respectively; p<0.05). IN CONCLUSION: elevated serum and urinary IL-17 levels in children with relapse of nephrotic syndrome suggest the role of IL-17 in the pathophysiology of INS. IL-17 concentrations in serum and urine may reflect the disease activity of INS.

Increased urinary excretion of interleukin-17 in nephrotic patients.

BACKGROUND/AIM: Interleukin (IL)-17 is a newly discovered cytokine that is secreted by activated memory CD4+ T cells and modulated the early stage of immune response. To elucidate the pathophysiology of minimal-change nephrotic syndrome (MCNS), we focused on IL-17, which is one of the key factors in regulating an inflammatory response, and thus determined the daily excretion of IL-17 in urine. METHODS: For this purpose, excretion levels of IL-17 were measured in the urine of patients with MCNS during relapse and remission using a highly sensitive sandwich enzyme-linked immunosorbent assay. The data obtained were compared with levels of daily urinary excretion of IL-17 in patients with IgA nephropathy (IgAN). A group of healthy subjects served as control. In both experimental groups urine levels of IL-17 excretion were plotted against their daily urinary protein excretion. RESULTS: We demonstrated increased levels of IL-17 excretion in the urine of patients with MCNS and IgAN as compared to the non-nephrotic and healthy controls. In MCNS the daily urinary IL-17 (uIL-17) excretion was increased and returned to baseline with remission of the nephrotic syndrome (NS). We also demonstrated a positive correlation between urinary protein excretion and daily uIL-17 excretion. CONCLUSION: Taken together, these data indicate that uIL-17 excretion is increased during the NS, suggesting the possibility that daily uIL-17 excretion may reflect the disease activity of NS.