Nuclear Factor Kappa B Mediates Lipopolysaccharide-Induced Inflammation in the Urinary Bladder

Wang, Xiaochun; SABAN, RICADO; Kaysen, James H.; Saban, Marcia R.; Allen, Patricia; Benes, Edmund; HAMMOND, TIMMOTHY G.

doi:10.1016/s0022-5347(05)67870-6

Cited by 37 publications

(35 citation statements)

References 32 publications

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“…15 The present results indicate that NF-B is a pathway commonly up-regulated as the bladder responds to other pro-inflammatory stimuli such as antigen and SP stimulation. In contrast to NF-B that was up-regulated by all three stimuli, LPS was the only stimulus to induce the transcription factor AP-1 and transcription factor E2F3.…”

Section: Signal Transduction Pathwaysmentioning

confidence: 51%

“…11 We also reported that intravesical inoculation of mice with LPS induced up-regulation of peptide receptors such as bradykinin-1 (BK1) 14 and NK1. 15 Moreover, we observed that LPS-induced cystitis was associated with activation of nuclear transcription factor B (NF-B). 15 Inhibition of NF-B with lactacystin blocked LPSinduced inflammation and NK1 receptor up-regulation.…”

mentioning

confidence: 99%

“…15 Moreover, we observed that LPS-induced cystitis was associated with activation of nuclear transcription factor B (NF-B). 15 Inhibition of NF-B with lactacystin blocked LPSinduced inflammation and NK1 receptor up-regulation. 15 It is not clear from available data which responses of the urinary bladder are inflammatory stimulus-specific, and/or whether there are some central universal patterns of response.…”

mentioning

confidence: 99%

“…15 Inhibition of NF-B with lactacystin blocked LPSinduced inflammation and NK1 receptor up-regulation. 15 It is not clear from available data which responses of the urinary bladder are inflammatory stimulus-specific, and/or whether there are some central universal patterns of response. Defining the universal and stimulus-specific patterns of response to inflammatory stimuli is critical to begin to understand why some acute inflammatory responses resolve and some transition to the chronic inflammatory process.…”

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confidence: 99%

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Gene Expression Profiling of Mouse Bladder Inflammatory Responses to LPS, Substance P, and Antigen-Stimulation

Saban

Nguyen

Hammond

et al. 2002

The American Journal of Pathology

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110

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Inflammatory bladder disorders such as interstitial cystitis (IC) deserve attention since a major problem of the disease is diagnosis. IC affects millions of women and isClinical and animal models of acute and chronic urinary bladder inflammation have provided several lines of evidence suggesting a central role of mast cells, sensory nerves, and neurokinin (NK)-1 receptors. Fundamental work regarding the participation of sensory nerves and mast cells in cystitis provides indirect evidence, such as increased numbers of mast cells in the detrusor and submucosa, and morphological evidence of mast cell activation and degranulation. [1][2][3][4] In addition, the extensive tissue remodeling seen in some clinical forms of bladder inflammation such as interstitial cystitis, 4 along with increased urinary levels of histamine and tryptase 5 suggest a role for mast cells. Because both mast cells 6 -8 and NK-1 receptors are increased in bladder biopsies of interstitial cystitis (IC) patients, 9,10 it is tempting to propose a role for sensory peptides-mast cell communication in the pathogenesis of this disorder.Experimentally, we have used classical morphometric analysis and microarray technology to determine the role of mast cells, NK-1 receptors, and bacterial toxins in animal models of cystitis. Time-course experiments indicated early and late genes involved in bladder inflammatory responses. 11 The availability of mice genetically deficient in neurokinin-1 receptor (NK-1R Ϫ/Ϫ ) allowed us to propose a mandatory role of SP receptors in cystitis. 12 We also determined genes that depend on the presence of tissue mast cells for their expression by comparing inflammatory responses in mast cell-deficient (Kit W /

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Section: Signal Transduction Pathwaysmentioning

confidence: 51%

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confidence: 99%

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confidence: 99%

mentioning

confidence: 99%

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Gene Expression Profiling of Mouse Bladder Inflammatory Responses to LPS, Substance P, and Antigen-Stimulation

Saban

Nguyen

Hammond

et al. 2002

The American Journal of Pathology

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110

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“…It is of interest that proteasomes have previously been shown to be involved in LPS-induced degradation of IB (42)(43)(44)(45)(46). Current understanding of this pathway suggests that, after LPS activation of macrophages, a cascade of adaptors and kinases interacts with the intracytoplasmic domain of TLR4, leading to the phosphorylation and ubiquitination of IB, which is then degraded by the proteasome.…”

Section: Figurementioning

confidence: 99%

The Proteasome as a Lipopolysaccharide-Binding Protein in Macrophages: Differential Effects of Proteasome Inhibition on Lipopolysaccharide-Induced Signaling Events

Qureshi

Perera

Shen

et al. 2003

The Journal of Immunology

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We have developed a novel LPS probe using a highly purified and homogenous preparation of [3H] Escherichia coli LPS from the deep rough mutant, which contains a covalently linked, photoactivable 4-p-(azidosalicylamido)-butylamine group. This cross-linker was used to identify the LPS-binding proteins in membranes of the murine-macrophage-like cell line RAW 264.7. The α-subunit (PSMA1 C2, 29.5 kDa) and the β-subunit (PSMB4 N3, 24.36 kDa) of the 20S proteasome complex were identified as LPS-binding proteins. This is the first report demonstrating LPS binding to enzymes such as the proteasome subunits. Functionally, LPS enhanced the chymotrypsin-like activity of the proteasome to degrade synthetic peptides in vitro and, conversely, the proteasome inhibitor lactacystin completely blocked the LPS-induced proteasome’s chymotrypsin activity as well as macrophage TNF-α secretion and the expression of multiple inflammatory mediator genes. Lactacystin also completely blocked the LPS-induced expression of Toll-like receptor 2 mRNA. In addition, lactacystin dysregulated mitogen-activated protein kinase phosphorylation in LPS-stimulated macrophages, but failed to inhibit IL-1 receptor-associated kinase-1 activity. Importantly, lactacystin also prevented LPS-induced shock in mice. These data strongly suggest that the proteasome complex regulates the LPS-induced signal transduction and that it may be an important therapeutic target in Gram-negative sepsis.

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Role of NFκB in antigen presentation and development of regulatory T cells elucidated by treatment of dendritic cells with the proteasome inhibitor PSI

et al. 2001

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Dendritic cells (DC) are the most potent antigen‐presenting cells for naive T cells, due to their high expression of MHC and costimulatory molecules, but relatively little is known about the biochemical pathways that regulate this function. We used the proteasome inhibitor N‐benzyloxycarbonyl‐Ile‐Glu(O‐tert‐butyl)‐Ala‐leucinal (PSI) to demonstrate that DC antigen presentation is NFκB dependent. As PSI is not a specific inhibitor of NFκB, we reproduced this finding using a very specific approach, namely adenoviral gene transfer of IκBα, the naturally occurring inhibitor of NFκB. The mechanism for this inhibition of DC antigen presentation involves at least three aspects of antigen presenting function: down‐regulation of HLA class II, down‐regulationof CD86, and inhibition of the immunostimulatory cytokines IL‐12 and TNF‐α. In the light of the marked down‐regulation of antigen‐presentation cell function, it was of interest to investigate what effects exposure to PSI‐treated DC might have on T cell function. It was found that immunological tolerance was induced, as challenge of T cells previously exposed to PSI‐treated DC, with normal DC from the same donor did not restore their response, despite the presence of viable T cells. There were also changes in T cell surface markers, with down‐regulation of CD3 and CD25 expression, and inhibition of the production of Th1 cytokines like IL‐2 and IFN‐γ. These results demonstrates that NFκB is an effective target for blocking DC antigen presentation and inhibiting T cell‐dependent immune responses, and this has implications for the development of therapeutic agents for use in multiple conditions, including transplantation, allergy and autoimmune diseases.

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Nuclear Factor Kappa B Mediates Lipopolysaccharide-Induced Inflammation in the Urinary Bladder

Abstract: NF-kappaB mediates many features of urinary bladder inflammation induced by LPS. The NF-kappaB cascade is an important target for anti-inflammatory management of cystitis.

Cited by 37 publications

References 32 publications

Gene Expression Profiling of Mouse Bladder Inflammatory Responses to LPS, Substance P, and Antigen-Stimulation

Gene Expression Profiling of Mouse Bladder Inflammatory Responses to LPS, Substance P, and Antigen-Stimulation

The Proteasome as a Lipopolysaccharide-Binding Protein in Macrophages: Differential Effects of Proteasome Inhibition on Lipopolysaccharide-Induced Signaling Events

Role of NFκB in antigen presentation and development of regulatory T cells elucidated by treatment of dendritic cells with the proteasome inhibitor PSI

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