Enhanced chemokine response in experimental acute Escherichia coli pyelonephritis in IL‐1β‐deficient mice

Department of Clinical Microbiology, Microbiology and Tumorbiology Center, Karolinska Hospital, Stockholm, Sweden.
Clinical & Experimental Immunology (Impact Factor: 3.04). 03/2003; 131(2):225-33. DOI: 10.1046/j.1365-2249.2003.02076.x
Source: PubMed


The aim of the present study was to investigate the effects of IL-1beta and Escherichia coli on the expression and secretion of MIP-2, the mouse equivalent to human IL-8, MCP-1 and RANTES in the kidneys of mice with acute pyelonephritis. Female Bki NMRI, as well as IL-1beta deficient mice and their wild-type littermates, were transurethrally infected with either E. coli CFT 073 or injected with NaCl 0.9% (w/v) and thereafter obstructed for 6 h. The Bki NMRI mice were killed at 0, 24, 48 h and 6 days and the IL-1beta-deficient mice at 48 h. Chemokine mRNA and protein levels peaked at 24 h for the tested chemokines with the mRNA expression localized in the tubular epithelial cells and for MIP-2 also in neutrophils. Obstruction per se, also induced a chemokine expression similar to E. coli infection although at a lower level. Interestingly, MIP-2 levels were higher in the IL-1beta deficient mice as compared with the wild-type littermates. Likewise, the inflammatory changes were more frequent and, when present, more widespread in the IL-1beta-deficient mice than in the wild-type mice. Stimulation of a human renal tubular epithelial cell line (HREC), A498 and of primary human mesangial cells (HMC) with the same bacterial antigen depicted gene expression of the same chemokines. A rapid release of IL-8 and MCP-1 was observed from both cell types. RANTES response was delayed both in the HREC and the HMC. We conclude that acute E. coli pyelonephritis induces a MIP-2/IL-8, MCP-1 and RANTES expression and secretion localized primarily to the epithelial cells and that this production is confirmed after in vitro stimulation with the same bacterial antigen of human epithelial and mesangial cells. Blockade of induction of chemokine response may thus be an attractive target for possible therapeutic intervention.

Download full-text


Available from: Kjell Tullus,
  • Source
    • "Bacteria that enter the urinary tract cause an activation of the host inflammatory response. In the results of bacterial stimulation, renal epithelial cells have been shown to produce a number of cytokines and chemokines , among other substances [8]. Cytokines, especially interleukin-6 (IL-6), participate in the local inflammatory response to infections [4, 9–11]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Urinary tract infection (UTI) is a common bacterial disease in infants and children, with potentially serious complications, including kidney damage. The aim of this study was to test whether serum and urinary levels of interleukin-6 (IL-6), macrophage inflammatory protein-1a (MIP-1a) and interferon-γ-inducible protein-10 (IP-10) can be used as biomarkers in children with urinary tract infections. The study group consisted of 22 children with UTI and 20 controls. Blood and urine samples were collected in the acute phase and the convalescent phase, on the eighth day after the onset of antibiotic therapy. Serum and urine levels of MIP-1a, IP-10 and IL-6 were measured. In children with UTI in the acute phase, serum MIP-1a and IL-6 levels were significantly higher compared to the controls (p < 0.05 and p < 0.005, respectively). A correlation between the serum levels of the chemokines MIP-1a and IP-10 in the acute phase was found. The findings suggest that the chemokines MIP-1a or IP-10 respond to infection, but they cannot be used as biomarkers for UTI in childhood.
    Advances in Clinical and Experimental Medicine 11/2014; 23(6):933-8. DOI:10.17219/acem/37341 · 1.10 Impact Factor
  • Source
    • "Similarly, many systemic diseases affecting the kidneys are associated with NLRP3 inflammasome/IL-1β/IL-18 axis activation (Table 2). These include UUO [68,76,80,83], I-R injury [43-45,61,66,81], GN [46-48,67,70,90,97,119], sepsis [91,92,94], CKD [80,120], hypoxia [96], glycerol-induced renal failure [93], and crystal nephropathy [121]. Apart from two studies of CKD of various aetiologies [77,80] most of the disorders studied have been acute inflammatory diseases. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The inflammasome is a large, multiprotein complex that drives proinflammatory cytokine production in response to infection and tissue injury. Pattern recognition receptors that are either membrane bound or cytoplasmic trigger inflammasome assembly. These receptors sense danger signals including damage-associated molecular patterns and pathogen-associated molecular patterns (DAMPS and PAMPS respectively). The best-characterized inflammasome is the NLRP3 inflammasome. On assembly of the NLRP3 inflammasome, post-translational processing and secretion of pro-inflammatory cytokines IL-1beta and IL-18 occurs; in addition, cell death may be mediated via caspase-1. Intrinsic renal cells express components of the inflammasome pathway. This is most prominent in tubular epithelial cells and, to a lesser degree, in glomeruli. Several primary renal diseases and systemic diseases affecting the kidney are associated with NLRP3 inflammasome/IL-1beta/IL-18 axis activation. Most of the disorders studied have been acute inflammatory diseases. The disease spectrum includes ureteric obstruction, ischaemia reperfusion injury, glomerulonephritis, sepsis, hypoxia, glycerol-induced renal failure, and crystal nephropathy. In addition to mediating renal disease, the IL-1/ IL-18 axis may also be responsible for development of CKD itself and its related complications, including vascular calcification and sepsis. Experimental models using genetic deletions and/or receptor antagonists/antiserum against the NLRP3 inflammasome pathway have shown decreased severity of disease. As such, the inflammasome is an attractive potential therapeutic target in a variety of renal diseases.
    BMC Nephrology 01/2014; 15(1):21. DOI:10.1186/1471-2369-15-21 · 1.69 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Urinary tract infections (UTI) are common in infants and children and may result in serious complications, such as renal scarring, hypertension, and renal failure. Identification of the new markers in relation to acute pyelonephritis (APN) and its treatment is essential for designing interventions that would minimize tissue damage. This prospective study investigated the first UTI infection in 71 children (age range: 1–24months) in respect to interleukin-6 (IL-6) −174G/C polymorphism and renal scarring. The patients were divided into an APN group and a lower UTI group according to dimercaptosuccinic acid (DMSA). The IL-6 −174G/C genotypes were determined by tetra-primer ARMSPCR. Serum IL-6 was significantly higher in the APN group than in the group with lower UTI (p < 0.05). In both groups, the −174G/C genotype and allele frequencies did not differ significantly from the control group. The highest white blood cell (WBC) count was observed in the CC genotype (p < 0.05). A non-significant trend toward higher serum IL-6 was observed in children with CC genotype. On follow-up DMSA imaging performed 6months later, renal scarring was detected in 36.9% of APN children. We did not find the significant association of IL-6 −174G/C polymorphism with APN and/or postinfectious renal scarring. These results indicate that serum IL-6 concentrations were significantly higher in children with APN than in patients with lower UTI. KeywordsAcute pyelonephritis-IL-6 gene polymorphism-DMSA-Renal scarring-Children
    Pediatric Nephrology 25(10):2099-2106. · 2.86 Impact Factor
Show more