interleukin-8 and Glomerulonephritis

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Glomerulonephritis; In Vitro Techniques; Interleukin-8; Kidney; Neutrophils

We reported a case of a 22-year old female with a microscopic form of polyarteritis nodosa (PN) who initially manifested Behçet's disease-like symptoms, such as fever, arthralgia, oral aphtha and erythema nodosum, and rapidly progressive glomerulonephritis (RPGN). On admission, her urinalysis showed active nephritic syndrome and her renal function rapidly deteriorated; serum creatinine levels elevated from 1.2 to 3.9 mg/dl within 2 weeks. Skin biopsy specimens from erythema showed panniculitis. Accordingly, she was treated with daily 30 mg of oral prednisolone and three-day intravenous pulse therapy of 1000 mg of methylprednisolone twice. After treatment, skin eruption and oral aphtha disappeared, and the serum creatinine level improved to 1.2 mg/dl. Percutaneous renal biopsy performed on the 28th day showed focal necrotizing glomerulonephritis and hyalinosis of small arteries. Immunofluorescence studies showed only trace stainings for IgG, IgA and beta lc. Electron microscopic findings revealed fusion of the foot process and swelling of endothelial cells, but no dense deposits. Anti-neutrophil cytoplasmic antibody (ANCA) was positive for IgG class with a 40-fold titer by indirect immunofluorescence test and showed a cytoplasmic pattern combined with high urinary IL-8 level (280.1 pg/ml). We diagnosed this case as a microscopic form of PN. ANCA titer and urinary IL-8 correlated positively with the disease activity, and were finally below 8-fold and 58.6 pg/ml, respectively after resolution of RPGN for 42 months. In this case, ANCA was useful not only for differential diagnosis of the patients with systemic vasculitis and crescentic glomerulonephritis, but also for evaluation of the disease activity.

Topics: Adult; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Behcet Syndrome; Disease Progression; Erythema Nodosum; Female; Glomerulonephritis; Humans; Interleukin-8; Polyarteritis Nodosa; Stomatitis, Aphthous

Neutrophil infiltration into inflammatory sites is one of the hallmarks of acute inflammation. Locally produced chemotactic factors are presumed to mediate the sequence of events leading to the infiltration at inflammatory sites. Interleukin-8 (IL-8), a novel leukocyte chemotactic activating cytokine (chemokine), is produced by various types of cells upon stimulation with inflammatory stimuli and exerts a variety of functions on leukocytes, particularly, neutrophils in vitro. However, no definitive evidence has been presented on its role in recruiting and activating neutrophils in the lesions of various types of inflammatory reactions. We administered a highly specific neutralizing antibody against IL-8 in several types of acute inflammatory reactions, including lipopolysaccharide (LPS)-induced dermatitis, LPS/IL-1-induced arthritis, lung reperfusion injury, and acute immune complex-type glomerulonephritis. Anti-IL-8 treatment prevented neutrophil-dependent tissue damage as well as neutrophil infiltration in these conditions. These results suggest that IL-8 plays a causative role in acute inflammation by recruiting and activating neutrophils.

Topics: Animals; Antibodies; Antigen-Antibody Complex; Arthritis; Cross Reactions; Dermatitis; Glomerulonephritis; Inflammation; Inflammation Mediators; Interleukin-1; Interleukin-8; Lipopolysaccharides; Lung Diseases; Neutrophil Activation; Neutrophils; Rabbits; Reperfusion Injury

A total of 105 patients participated in this study, including 10 with chronic glomerulonephritis with normal renal function (CGN patients), 36 uraemic patients (CRF patients), 19 continuous ambulatory peritoneal dialysis patients (CAPD) without peritonitis, three CAPD patients with peritonitis, 37 patients undergoing chronic haemodialysis (HD) divided into short-term HD, 15 patients; medium-term HD, 12 patients; and long-term HD, 10 patients. IL-8 and two other proinflammatory cytokines, IL-6 and TNF alpha were tested using a specific immunoassay. IL-8, IL-6, and TNF alpha serum levels were significantly increased in patients with chronic renal failure compared to their levels in normal individuals (P < 0.0001, P < 0.05 and P < 0.0001 respectively). The most pronounced increment in IL-8, IL-6 and TNF alpha serum levels was observed in CAPD patients (P < 0.0001). CAPD patients without peritonitis showed relatively low levels of IL-8 or IL-6 in peritoneal dialysate effluents (PDE), whereas PDE-TNF alpha were not detectable in almost all patients tested. Patients with peritonitis showed very high serum and PDE levels of IL-8, IL-6 and TNF alpha. The clinical recovery from peritonitis was characterized by a rapid fall in IL-8, IL-6 and TNF alpha in serum and dialysate. HD patients showed a significant increase in serum levels of IL-8 and also IL-6 and TNF alpha compared to normal individuals (P < 0.05, P < 0.05 and P < 0.01 respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Chronic Disease; Female; Glomerulonephritis; Humans; Interleukin-6; Interleukin-8; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Peritonitis; Renal Dialysis; Renal Replacement Therapy; Tumor Necrosis Factor-alpha; Uremia

ANCA vasculitis encompasses several autoimmune conditions characterised by destruction of small vessels, inflammation of the respiratory tract and glomerulonephritis. Most patients harbour autoantibodies to myeloperoxidase (MPO) or proteinase 3 (PR3). Clinical and experimental data suggest that pathogenesis is driven by ANCA-mediated activation of neutrophils and monocytes. We investigated a potential role for distinct monocyte subsets. We found that the relative proportion of intermediate monocytes is increased in patients versus control individuals, and both MPO and PR3 are preferentially expressed on these cells. We demonstrate that MPO and PR3 are expressed independently of each other on monocytes and that PR3 is not associated with CD177. MPO expression correlates with that of Fc receptor CD16 on intermediate monocytes. Monocyte subsets respond differently to antibodies directed against MPO and PR3, with anti-MPO but not anti-PR3 leading to increased IL-1β, IL-6 and IL-8 production. In concordance with the observed higher surface expression of MPO on intermediate monocytes, this subset produces the highest quantity of IL-1β in response to anti-MPO stimulation. These data suggest that monocytes, specifically, the intermediate subset, may play a role in ANCA vasculitis, and also indicate that substantial differences exist between the effect of anti-MPO and anti-PR3 antibodies on these cells.

Topics: Adolescent; Adult; Aged; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal; Autoantigens; Disease Progression; Female; Flow Cytometry; Glomerulonephritis; GPI-Linked Proteins; Humans; Interleukin-1beta; Interleukin-6; Interleukin-8; Isoantigens; Male; Middle Aged; Monocytes; Myeloblastin; Neutrophils; Peroxidase; Receptors, Cell Surface; Receptors, Fc; Receptors, IgG; Vasculitis; Young Adult

Many studies have indicated a role for cytokines in chronic kidney disease (CKD). The aim of this study was to evaluate plasma and urinary levels of monocyte chemoattractant protein-1 (MCP-1/CCL2), transforming growth factor-beta1 (TGF-β1), and interleukin-8 (IL-8/CXCL8) in pediatric patients with CKD stages 2-4.. Cytokines were measured in 37 healthy controls and in 42 CKD patients by enzyme-linked immunoassay. Patients were divided into groups according to CKD etiology: glomerular disease (group 1, n = 11) and congenital anomalies of the kidney and urinary tract (group 2, n = 31). Urinary cytokine measurements were standardized for creatinine.. Plasma and urinary levels of MCP-1/CCL2 were significantly higher in both CKD groups compared to the control group. Between the two CKD groups, only urinary MCP-1/CCL2 levels were significantly different, with MCP-1/CCL2 levels higher in group 1 patients. Plasma and urinary levels of IL-8/CXCL8 and TGF-β1 were undetectable in the control group but comparable between the two CKD groups. In group 1 patients, urinary MCP-1/CCL2 levels were negatively correlated to serum albumin levels and positively correlated to the levels of total cholesterol and triglycerides. In group 2 patients, urinary levels of IL-8/CXCL8 were negatively correlated with the estimated glomerular filtration rate and positively correlated with body mass index.. Differences in cytokine profiles may be related to CKD etiology and other disease-associated alterations.

Topics: Adolescent; Biomarkers; Case-Control Studies; Chemokine CCL2; Child; Cholesterol; Creatinine; Cross-Sectional Studies; Dyslipidemias; Enzyme-Linked Immunosorbent Assay; Female; Glomerulonephritis; Humans; Inflammation Mediators; Interleukin-8; Male; Renal Insufficiency, Chronic; Transforming Growth Factor beta1; Triglycerides; Urogenital Abnormalities; Vesico-Ureteral Reflux

Topics: Animals; Antibodies; Antibodies, Antineutrophil Cytoplasmic; Disease Models, Animal; Glomerulonephritis; Interleukin-17; Interleukin-8; Mice; Mice, Knockout; Neutrophils; Peroxidase; T-Lymphocyte Subsets

Antimyeloperoxidase antibodies can cause crescentic glomerulonephritis and pulmonary hemorrhage. Toll-like receptors (TLRs) respond to infectious agents activating host defenses, whereas infections potentially initiate disease and provoke relapses. Neutrophils were found to be key effector cells of injury in experimental models, as disease does not occur in their absence and injury is enhanced by lipopolysaccharide (LPS). In this study, highly purified LPS (a pure TLR4 ligand) acted with antimyeloperoxidase antibodies to synergistically increase kidney and lung neutrophil recruitment and functional injury; effects abrogated in TLR4-deficient mice. Increased kidney TLR4 expression after stimulation predominantly occurred in glomerular endothelial cells. Enhanced glomerular neutrophil recruitment correlated with increased kidney mRNA expression of CXCL1 and CXCL2 (homologs of human CXCL8), whereas their preemptive neutralization decreased neutrophil recruitment. Disease induction in bone marrow chimeric mice showed that TLR4 in both bone marrow and renal parenchymal cells is required for maximal neutrophil recruitment and glomerular injury. Further studies in human glomerular cell lines stimulated with LPS found that glomerular endothelial cells were the prominent sources of CXCL8. Thus, our results define a role for TLR4 expression in bone marrow-derived and glomerular endothelial cells in neutrophil recruitment and subsequent functional and histological renal injury in experimental antimyeloperoxidase glomerulonephritis.

Topics: Animals; Antibodies, Anti-Idiotypic; Antibodies, Antineutrophil Cytoplasmic; Cell Line; Chemokine CXCL1; Chemokine CXCL2; Disease Models, Animal; Glomerulonephritis; Humans; Interleukin-8; Kidney; Kidney Glomerulus; Leukocytes; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peroxidase; Toll-Like Receptor 4

Interleukin-8 (IL-8) is considered a deleterious chemokine involved in renal injury in glomerulonephritis (GN). IL-8 may be released as a 77-amino acid (AA) peptide or 72-AA protein.. We evaluated gene and protein expression of IL-8 in 53 renal biopsy specimens from patients with GN and 9 control kidneys. Nonradioactive in situ hybridization and reverse-transcriptase polymerase chain reaction (RT-PCR) were applied to detect IL-8 messenger RNA (mRNA). In immunohistochemistry, a double-staining technique with the use of antibodies against the 77-AA and 72-AA forms of IL-8, as well as glomerular cell antigens, was used.. By in situ hybridization, IL-8 mRNA was detected in normal glomerular, tubular, and some interstitial cells. The RT-PCR study showed that IL-8 mRNA expression in control kidneys significantly exceeds that in specimens with GN (0.89 +/- 0.82 versus 0.21 +/- 0.20; P < 0.003). In control kidneys, major sources of 77-AA IL-8 were podocytes and endothelial cells of interstitial vessels, whereas tubular epithelial cells expressed minute amounts of 72-AA IL-8. In GN specimens, podocyte expression of 72-AA IL-8 varied notably, with the greatest level found in minimal change disease and the lowest level found in acute endocapillary GN. Conversely, increased glomerular expression of the 72-AA form of IL-8 was a general feature of GN, with its level significantly exceeding that of the 77-AA form in acute endocapillary GN (P < 0.01).. Our results suggest that intrinsic glomerular cell production of IL-8, in particular the 77-AA form, may be relevant for preservation of the glomerular architecture.

Topics: Anti-Glomerular Basement Membrane Disease; Biopsy; Gene Expression Regulation; Glomerulonephritis; Glomerulonephritis, IGA; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Humans; Immunohistochemistry; In Situ Hybridization; Interleukin-8; Kidney Glomerulus; Lupus Nephritis; RNA, Messenger

The infiltration of leukocytes into the glomeruli is a major factor in inflammatory glomerular damage in acute poststreptococcal glomerulonephritis (APSGN). Chemokines participate in leukocyte infiltration. The aim of the present study was to investigate the role of monocyte chemoattractant protein-1 (CCL2/MCP-1) and interleukin-8 (CXL8/IL-8) in APSGN with special emphasis on their role in the clinical course of renal disease. Twenty-one children with APSGN were studied. Serum and urinary CCL2/MCP-1 and CXL8/IL-8 levels were measured by ELISA. The relationships between urinary chemokines and the degree of proteinuria were investigated. Serum and urinary CCL2/MCP-1 levels were significantly higher in the acute phase than in the resolution phase and in controls ( P<0.05). Urinary CCL2/MCP-1 levels in the control group were significantly lower than in both the acute and resolution phases ( P=0.01 and P =0.001, respectively). In the acute phase, urinary CCL2/MCP-1 correlated with the extent of proteinuria ( r=0.58, P =0.006) but not with serum CCL2/MCP-1 levels ( r=0.21, P =0.36). Urinary and serum CXL8/IL-8 levels were significantly elevated in the acute phase compared with the resolution phase and controls ( P<0.05). A consistent increase in urinary CCL2/MCP-1 was found in the acute phase of patients with APSGN, and this correlates with the degree of proteinuria. Our results emphasize the important role of locally produced chemokines in immune-mediated glomerular injury.

Topics: Acute Disease; Adolescent; Chemokine CCL2; Child; Child, Preschool; Female; Glomerulonephritis; Humans; Interleukin-8; Male; Streptococcal Infections

A sequential model involving chemokines has been proposed for leukocyte extravasation into areas of inflammation; however, site-specific aspects remain to be elucidated. Hence, we studied the role of chemokines produced by mesangial (MC) or glomerular endothelial cells (GEC) and their receptors in glomerular recruitment of monocytes. Stimulation of MC with TNF-alpha up-regulated mRNA and protein of CC and CXC chemokines but not constitutive expression of the CX(3)C chemokine fractalkine. While growth-related activity (GRO)-alpha was immobilized to MC proteoglycans, monocyte chemotactic protein (MCP)-1 was secreted into the soluble phase. Firm adhesion and sequestration of monocytes on activated MC was supported by the GRO-alpha receptor CXCR2 and to a lesser extent by CX(3)CR, whereas the MCP-1 receptor CCR2 contributed to their transendothelial chemotaxis toward activated MC. In contrast, fractalkine mRNA and protein was induced by TNF-alpha in transformed rat GEC, and both CXCR2 and CX(3)CR mediated monocyte arrest on GEC in shear flow. The relevance of these mechanisms was confirmed in a rat nephrotoxic nephritis model where acute glomerular macrophage recruitment was profoundly inhibited by blocking CXCR2 or CCR2. In conclusion, our results epitomize a combinatorial model in which chemokines play specialized roles in driving glomerular monocyte recruitment and emphasize an important role for CXCR2 in macrophage infiltration during early phases of nephrotoxic nephritis.

Topics: Animals; Cell Adhesion; Cell Line; Cell Membrane; Cell Migration Inhibition; Cell Movement; Cells, Cultured; Chemokine CCL2; Chemokine CX3CL1; Chemokine CXCL1; Chemokines, CX3C; Chemokines, CXC; Chemotactic Factors; Chemotaxis, Leukocyte; Diffusion Chambers, Culture; Disease Models, Animal; Endothelium, Vascular; Glomerular Mesangium; Glomerulonephritis; Growth Substances; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-8; Kidney Glomerulus; Male; Membrane Proteins; Monocytes; Rats; Rats, Sprague-Dawley; Receptors, CCR2; Receptors, Chemokine; Receptors, Interleukin-8B; RNA, Messenger; Tumor Necrosis Factor-alpha; Up-Regulation

In neutrophil trafficking, the role of interleukin-8 (IL-8) is location dependent. Tissue IL-8 directs transmigration, whereas intravascular IL-8 frustrates this process. The bystander damage of glomerular endothelium by antineutrophil cytoplasmic autoantibody (ANCA)-activated neutrophils is believed to be an early event in the pathogenesis of ANCA-associated glomerulonephritis. We have studied the role of IL-8 in this process.. Intraglomerular expression of IL-8 in patients with ANCA-associated glomerulonephritis was studied by in situ hybridization and immunohistochemistry and location of neutrophils by serial section immunohistochemistry. In vitro, we analyzed ANCA-stimulated neutrophil IL-8 production by enzyme-linked immunosorbent assay, and the IL-8 attributable effect of ANCA-stimulated neutrophil supernatant by chemotactic and transendothelial assays.. There was intraglomerular expression of IL-8 at segmental, crescentic, and parietal epithelial sites. IL-8 protein expression colocalized to intraglomerular neutrophils; many localized within glomerular capillary loops, suggesting failed trafficking to tissue IL-8. ANCAs differentially stimulated time- and dose-dependent neutrophil IL-8 production, and ANCA-stimulated neutrophil supernatant demonstrated potent IL-8-dependent chemotactic activity and inhibited transendothelial migration of normal human neutrophils toward an IL-8 gradient.. Despite heavy tissue expression of IL-8 in ANCA-associated GN, the production of IL-8 by ANCA-stimulated neutrophils within the intravascular compartment may frustrate neutrophil transmigration, encourage intravascular stasis, and contribute to bystander damage of glomerular endothelial cells.

Topics: Antibodies, Antineutrophil Cytoplasmic; Chemotaxis, Leukocyte; Endothelium, Vascular; Gene Expression; Glomerulonephritis; Humans; Immunohistochemistry; In Situ Hybridization; In Vitro Techniques; Interleukin-8; Neutrophils; RNA, Messenger

The study of interleukine-8 (IL-8) and defensines contribution to pathogenesis of chronic glomerulonephritis (CGN) and pyelonephritis (PN).. 122 patients were assigned to three groups: 42 CGN patients with isolated urinary syndrome (group 1); 60 patients with chronic pyelonephritis (CP) with normal nitrogen-excretory function (group 2); 20 patients with CGN and chronic renal failure (CRF) (group 3). 24 healthy volunteers served control. IL-8 and defensines were measured in urine and plasm of all the patients and controls using enzyme immunoassay.. IL-8 in urine and plasm of controls was not found, in plasm of patients was found in 45%, the differences between the groups being insignificant. The highest IL-8 urine concentration was found in group 2. It was significantly higher than in group 1 and 3 (p < 0.001). Mean IL-8 urine concentration in patients with secondary pyelonephritis was significantly higher than in those with primary pyelonephritis (p < 0.05). In primary pyelonephritis, urinary IL-8 was higher than in patients of groups 1 and 3 (p < 0.001). Mean urinary IL-8 was significantly higher in patients of group 3 than 1 (p < 0.005). IL-8 urinary concentrations of group 3 patients tended to an increase with growing severity of renal failure. Plasm defensines were present in 46.5% of patients without marked differences between the groups. Urine defensines were the highest in group 2 being significantly higher than in group 1, 3 and controls (p < 0.001). Urine defensines in group 1 were slightly higher than in controls and significantly reduced vs group 3 (p < 0.005). Urine defensines concentrations rose with CGN stage. A strong positive correlation was established between IL-8 and defensines in urine (r = 0.62), leukocyturia and IL-8 in urine (r = 0.52). A weak positive correlation (r = 0.38) existed between proteinuria and urine IL-8 only in group 3 patients. A week later concentrations of IL-8 and defensines were low in group 2. In group 1 they rose, fell or remained unchanged.. IL-8 and defensines may be of the same pathogenetic importance both in infectious and non-infectious inflammation in the kidneys. Cytotoxic action of defensines can be related to location of the inflammation in the kidney. IL-8 urine tests can be used in monitoring of inflammation activity and diagnosis of latent glomerulonephritis and pyelonephritis.

Topics: Adolescent; Adult; Aged; Biomarkers; Blood Proteins; Chronic Disease; Defensins; Female; Glomerulonephritis; Humans; Immunoenzyme Techniques; Interleukin-8; Male; Middle Aged; Proteins; Pyelonephritis; Severity of Illness Index

Interleukin-8 (IL-8) is a cytokine, which possesses both chemotactic and activating properties for neutrophils, lymphocytes and basophils. Various evidence has indicated IL-8 to be implicated in the pathophysiology of immune-mediated renal diseases. We thus examined the expression of IL-8 in renal diseases. We detected the expression of IL-8 both in mRNA and the protein levels in renal biopsy specimens obtained from patients with IgA nephropathy and lupus nephritis. A significant correlation was found between the expression of IL-8 mRNA and the number of neutrophils in the glomerulus. We also found a negative correlation between the expression of IL-8 mRNA and creatinine clearance. Our study thus suggested IL-8 to be involved in the pathophysiology of proliferative glomerulonephritis.

Topics: Adolescent; Adult; Aged; Child; Female; Glomerulonephritis; Humans; Interleukin-8; Kidney; Male; Middle Aged; Organ Specificity; RNA, Messenger

Acute poststreptococcal glomerulonephritis (APSGN) is characterized by diffuse glomerular hypercellularity, primarily as a result of accumulation of neutrophils (exudative glomerulonephritis), increase in intrinsic glomerular cells, and transient pathological mesangial matrix expansion. Cytokines and growth factors are supposed to play an important role as mediators of inflammation and as progression factors in various renal disorders. Interleukin-8 is a recently described cytokine, defined as a selective activator and chemoattractant of polymorphonuclear leukocytes (PMNL) and transforming growth factor (TGF)-beta plays a central role in the accumulation of pathological extracellular matrix in glomerulonephritis. This study analyzed the biopsies of ten patients with APSGN, using immunohistochemistry (avidin-biotin complex/horseradish peroxidase method) using monoclonal antibodies anti-IL-8, anti-TGF-beta 1, beta 2, beta 3. Controls consisted of non-immune mouse serum, or anti-TGF-beta preabsorbed with human recombinant TGF-beta. Compared with normal renal tissue, and minimal change disease, an increased glomerular IL-8 and TGF-beta staining was observed in all of the biopsies. Furthermore, in one patient, we observed a weak deposit of TGF-beta in tubulointerstitium. Immunoreactive IL-8 and TGF-beta in glomeruli was correlated with light microscopic and clinical features. There was a significant association (P < 0.05), between IL-8 glomerular immunoreactivity and neutrophil infiltration and between TGF-beta glomerular staining and mesangial matrix expansion. Otherwise, there was no correlation with the mesangial cellularity. It was concluded that increased protein expression of IL-8 and TGF-beta are observed in APSGN and may play a role in the acute glomerular inflammation.

Topics: Adolescent; Adult; Animals; Child; Female; Glomerulonephritis; Humans; Immunohistochemistry; Interleukin-8; Kidney Glomerulus; Male; Mice; Middle Aged; Streptococcal Infections; Transforming Growth Factor beta

Interleukin-8 (IL-8) plays a crucial role in the recruitment and activation of polymorphonucleated leukocytes (PMN) in the site of inflammation. Defensins are specific cationic proteins from azurophil PMN granules which exert antimicrobial, cytotoxic and proinflammatory activities.. Urine and plasma levels of IL-8 and defensins were studied using specific enzyme-linked immunosorbent assays. IL-8 was determined in 107 patients, including 45 with chronic glomerulonephritis (GN) and 62 with chronic pyelonephritis (PN). Urine and plasma levels of defensins were studied simultaneously in 29 patients with GN and 29 with PN. None of the patients examined showed any evidence of renal insufficiency. A group of 24 healthy volunteers was used as a control.. Urinary IL-8 was significantly increased in all groups of patients comparing with healthy control (< 30 pg/ml). The level of IL-8 in the urine of patients with PN (477 +/- 114 pg/ml, mean +/- SEM) was significantly (P < 0.001) higher than in patients with GN (53 +/- 7 pg/ml). The concentration of defensins in urine of patients with GN was slightly increased in comparison with the normal level (21 +/- 3.5 ng/ml versus 15.7 +/- 2.8 ng/ml). Urinary defensins were significantly elevated in patients with PN (134 +/- 118 ng/ml, P < 0.001), and were significantly higher than in the GN group (P < 0.001). A close correlation was observed between IL-8 and defensin concentrations in urine (r = 0.62), and between the urinary leukocyte count and IL-8 level (r = 0.72). The highest levels of IL-8 were observed in patients with PN, associated with nephrolithiasis (14 patients, 822 +/- 219 pg/ml versus 367 +/- 72 pg/ml in patients with PN alone, P < 0.05). IL-8 and defensin levels increased in older patients with PN, but not in older patients with GN.. The levels of IL-8 and defensins in urine were 6-10-fold higher in patients with PN than in patients with GN. Thus, there is a significant difference in IL-8 production between septic and aseptic chronic inflammatory processes in kidney. It is possible to speculate that the timing and progression of kidney inflammation is mediated by an IL-8 dependent mechanism at least in the case of PN.

Topics: Adolescent; Adult; Aged; Blood Proteins; Defensins; Female; Glomerulonephritis; Humans; Immunoenzyme Techniques; Interleukin-8; Male; Middle Aged; Pyelonephritis; Reference Values

Chemokines such as monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 have been implicated in recruiting leukocytes to the glomerulus during immune renal injury. To detect the expression of MCP-1 in human glomerular disease, we measured urinary MCP-1 levels in patients with a variety of glomerulopathies. These data demonstrated that MCP-1 was present in the urine of patients with glomerular disease and that patients with inflammatory glomerulopathies had higher levels of urinary MCP-1. Urinary MCP-1 correlated with the extent of proteinuria (r = 0.71, P < 0.0001), but not with serum MCP-1 levels (r = 0.14, P > 0.3). The MCP-1 present in urine was biologically active, increasing monocyte migration in a microchemotaxis assay. This activity was attenuated by the addition of anti-MCP-1 antibody to the samples. Enumerating glomerular macrophages demonstrated that glomerular inflammation was correlated with urinary MCP-1 levels (r = 0.53, P < 0.02). Individuals with light microscopic evidence of severe glomerular injury (ie, crescents, necrosis, endocapillary proliferation) had significantly higher levels of MCP-1 in their urine than patients with less severe glomerular changes (1,962 +/- 612 pg MCP-1/mg creatinine v 314 +/- 45 pg MCP-1/mg creatinine; P < 0.002). Taken together, these results suggest that urinary MCP-1 reflects the extent to which MCP-1 that is produced in the glomerulus participates in the glomerular inflammatory response.

Topics: Chemokine CCL2; Chemotaxis, Leukocyte; Creatinine; Female; Glomerulonephritis; Humans; Interleukin-8; Kidney Glomerulus; Macrophage Activation; Macrophages; Male; Necrosis; Proteinuria

We compared cytokine production from transformed human fibroblast cell lines derived from either a kidney with interstitial fibrosis or a normal kidney to that from primary human foreskin fibroblasts. Fibrosis-derived as well as normal renal fibroblasts, but not skin fibroblasts, spontaneously produced the chemokine, IL-8, and the growth promoting cytokine, IL-6. Spontaneous IL-8 and IL-6 synthesis by renal fibroblasts was dependent on the intrinsic release of IL-1, since blocking IL-1 receptors with IL-1 receptor antagonist (IL-1Ra) partially inhibited the constitutive production of these cytokines. Both kidney cell lines had detectable mRNA and protein for IL-1 alpha and IL-1 beta. Renal and skin fibroblasts stimulated by picomolar concentrations of exogenous IL-1 or TNF-alpha produced large amounts of IL-6 and IL-8, whereas nanomolar concentrations of basic fibroblast growth factor did not. Fibrosis-derived cells expressed less high affinity IL-1 receptors (600 receptors/cell; KD = 0.6 pM) compared to normal renal fibroblasts (1000 receptors/cell). However, fibrosis-derived renal fibroblasts produce three- to fourfold more IL-8 and IL-6 in response to picomolar concentrations of IL-1 beta compared to cells derived from a normal kidney. As this enhanced production is not due to increased numbers of IL-1 receptors, we speculate that post-receptor responsiveness to either endogenous or exogenous IL-1 is greater in fibrosis-derived renal fibroblasts than in cells from normal kidneys.

Topics: Cell Line; Fibroblasts; Fibrosis; Gene Expression; Glomerulonephritis; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-6; Interleukin-8; Radioimmunoassay; Sialoglycoproteins; Skin; Tumor Necrosis Factor-alpha

IL-8 is a chemotactic cytokine with proinflammatory and growth-promoting activities. The release of IL-8 was measured in supernatants of cultured peripheral blood monocytes (PBM) that were obtained from patients with glomerulonephritis (GN) and healthy controls. Spontaneous and lipopolysaccharide (LPS)-induced IL-8 release was significantly higher in PBM isolated from patients with IgA nephropathy (IgAN) and membranous nephropathy (MN) compared with normal controls. These results raise the question of whether IL-8 contributes to the ongoing pathogenesis of GN. We cannot relate IL-8 release to clinical and laboratory parameters in IgAN and MN patients. Thus, disease progression in vivo may not be accompanied by increased or sustained IL-8 release.

Topics: Adolescent; Adult; Aged; Female; Glomerulonephritis; Humans; Interleukin-8; Kidney Diseases; Lipopolysaccharides; Male; Middle Aged; Monocytes; Prospective Studies

The effects of hemodialysis on plasma interleukin 8 (IL-8) levels and the expression of IL-8 mRNA in peripheral blood mononuclear cells (PBMC) were studied in uremic patients undergoing maintenance hemodialysis (HD) using regenerated cellulose dialyzers. The plasma IL-8 levels in the patients after HD sessions were significantly higher than before HD. Comparison of the IL-8 mRNA levels obtained from PBMC before and after HD indicated that the expression of IL-8 mRNA was increased by HD. The enhancement of production of IL-8 in PBMC during HD may be responsible for inflammatory complications and impaired host defense in HD patients.

Topics: Adult; Aged; Base Sequence; Cellulose; Female; Gene Expression Regulation; Glomerulonephritis; Humans; Inflammation; Interleukin-8; Male; Membranes, Artificial; Middle Aged; Molecular Sequence Data; Monocytes; Polymerase Chain Reaction; Renal Dialysis; RNA, Messenger

Topics: Cells, Cultured; Glomerulonephritis; Humans; Interleukin-8; Kidney Glomerulus; Macrophages

To clarify the mechanism of neutrophil infiltration in glomerulonephritis, both urinary and plasma levels of a potent neutrophil chemotactic cytokine, interleukin-8 (IL-8), were measured in 40 healthy volunteers and 96 patients with various renal diseases. The plasma IL-8 levels were less than 16 pg/ml. The urinary IL-8 levels were elevated in several renal diseases including IgA nephropathy (17 of 43), acute glomerulonephritis (4 of 6), lupus nephritis (11 of 15), purpura nephritis (2 of 4), membranoproliferative glomerulonephritis (1 of 1), and cryoglobulinemia (2 of 2). IL-8 was detected immunohistochemically in diseased glomeruli, suggesting its local production. Elevated urinary IL-8 levels during the acute phase or exacerbations were found to be decreased during spontaneous or steroid pulse therapy-induced convalescence in all patients examined. The urinary IL-8 levels were higher in patients with glomerular leukocyte infiltration than in those without infiltration. Collectively, local production of IL-8 in diseased glomeruli might be involved in the pathogenesis of the glomerular diseases and measurement of IL-8 in the urine might be useful for monitoring the glomerular diseases.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Cryoglobulinemia; Female; Glomerulonephritis; Humans; Immunoenzyme Techniques; Interleukin-8; Kidney Glomerulus; Male; Methylprednisolone; Middle Aged

Chemokines are a family of cytokines whose participation in inflammation in vivo remains to be established. Using the rat model of anti-glomerular basement membrane (GBM) nephritis, we found that mRNA for the chemokine CINC (cytokine-induced neutrophil chemoattractant) was induced in the kidney, and the corresponding protein was elaborated by isolated inflamed glomeruli. Production of CINC by glomeruli was unaffected by complement- or leukocyte-depletion prior to disease induction. Cytokines which induce CINC expression in renal cells (TNF-alpha and IL-1 beta) were also expressed in the kidney during glomerular inflammation. TNF-alpha production, unlike CINC, was complement and leukocyte dependent. In vivo administration of anti-CINC, but not anti-human IL-8, IgG selectively attenuated the influx of PMNs into the glomerulus and commensurately diminished proteinuria. The participation of CINC was not tissue-specific: anti-CINC IgG also diminished the influx of PMNs in dermal immune complex inflammation. In sum, we propose that glomerular immune complex deposition/complement activation leads to cytokine production which results in CINC expression by endogenous glomerular cells. The CINC produced plays a contributory role in the influx of PMNs into the glomerulus in the context of the activation of other inflammatory mediators. These results suggest a potential role for CINC homologues, IL-8 and the GRO family of chemokines, in human immune complex-mediated disease.

Topics: Animals; Antigen-Antibody Complex; Base Sequence; Chemotactic Factors; Cytokines; Glomerulonephritis; Immunoglobulin G; Interleukin-1; Interleukin-8; Molecular Sequence Data; Neutrophils; Rabbits; Rats; Rats, Inbred Lew; Tumor Necrosis Factor-alpha

Glomerular infiltration by neutrophils is a hallmark of acute glomerulonephritis. The pathophysiological role of interleukin 8 (IL-8), a potent neutrophil chemotactic cytokine (chemokine), was explored in an animal model of acute immune complex-mediated glomerulonephritis by administering a neutralizing antibody against IL-8. Repeated injection of bovine serum albumin (BSA) into rabbits caused the deposition of immune complexes consisting of BSA and rabbit IgG in glomeruli. Histological analyses revealed a small but significant number of neutrophils in glomeruli and the fusion of epithelial cell foot processes. Concomitantly, urinary levels of protein and albumin increased markedly (3.20 +/- 0.97 and 1.39 +/- 0.53 mg/h, respectively) compared with those of untreated animals (0.77 +/- 0.21 and 0.01 +/- 0.01 mg/h, respectively). Anti-IL-8 antibody treatment decreased the number of neutrophils in glomeruli by 40% and dramatically prevented the fusion of epithelial cell foot process. Furthermore, treatment with anti-IL-8 antibody completely normalized the urinary levels of protein and albumin (0.89 +/- 0.15 and 0.02 +/- 0.01 mg/h, respectively). These results indicated that IL-8 participated in the impairment of renal functions in experimental acute immune complex-mediated glomerulonephritis through activating as well as recruiting neutrophils.

Topics: Acute Disease; Albuminuria; Animals; Antibodies, Monoclonal; Antigen-Antibody Complex; Glomerulonephritis; Interleukin-8; Kidney Glomerulus; Male; Mice; Proteinuria; Rabbits

We studied the interleukin 8 (IL-8) gene expression by peripheral blood mononuclear cells (PBMC) and the IL-8 serum concentration in patients with idiopathic minimal lesion nephrotic syndrome (IMLNS) and other glomerulopathies. PBMC from eight of the nine (IMLNS) patients in relapse demonstrated the presence of IL-8 mRNA. All three IMLNS patients in remission (P = 0.0026 when compared to patients in relapse) and the two patients with nephrotic syndrome with other glomerulopathies failed to elicit an IL-8 mRNA response. Eleven of the 12 IMLNS patients in relapse showed IL-8 serum concentration above the level of detection. Only one of the seven patients in remission had detectable serum levels of IL-8 (P = 0.0033 when compared to levels from IMLNS patients in relapse). IL-8 serum levels were not detectable in three patients with nephrotic syndrome and other glomerulopathies. Supernatants of PBMC cultures from IMLNS patients in relapse increased the 35sulfate uptake by rat GBM. This effect was abolished by the addition of anti-IL-8 neutralizing antibody to the culture media and reproduced by the addition to the media of IL-8 in concentrations found in the serum of IMLNS patients in relapse. Finally, the effect of IL-8 on the 35sulfate turnover of the glomerular basement membrane (GBM) sulfated compounds was evaluated in vitro. A significant decrease in the percentage of residual 35sulfate incorporated in the GBM (41 +/- 5, mean +/- SEM) was observed in cultures treated with IL-8 as compared to those that were not treated with IL-8 (58 +/- 8, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Animals; Basement Membrane; Child; Child, Preschool; Female; Gene Expression; Glomerulonephritis; Humans; Interleukin-8; Kidney Glomerulus; Leukocytes, Mononuclear; Male; Nephrosis, Lipoid; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Recurrence; RNA, Messenger; Sulfates