A Sustained Reduction in IκB-β May Contribute to Persistent NF-κB Activation in Human Endothelial Cells

Johnson, David R.; Douglas, Iris; Jahnke, Andreas; Ghosh, Sankar; Pober, Jordan S.

doi:10.1074/jbc.271.27.16317

Cited by 107 publications

(88 citation statements)

References 39 publications

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“…In this study, we demonstrate for the first time that Candida activates IKK2 resulting in phosphorylation and subsequent degradation of I B␣ as well as NF-B-dependent transcription. However, in sharp contrast to the prototypical activator of endothelial chemokine expression TNF-␣, the kinetics of IKK2 activation by Candida is markedly delayed, which is in line with reports on other stress-like endothelial stimuli such as PMA, LPS, or nickel chloride (21,36,37). Delayed and persistent activation imply a different mode of activation.…”

Section: Discussionsupporting

confidence: 87%

Candida albicans Triggers Activation of Distinct Signaling Pathways to Establish a Proinflammatory Gene Expression Program in Primary Human Endothelial Cells

Müller

Viemann²,

Schmidt

et al. 2007

The Journal of Immunology

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Endothelial cells (EC) actively participate in the innate defense against microbial pathogens. Under unfavorable conditions, defense reactions can turn life threatening resulting in sepsis. We therefore studied the so far largely unknown EC reaction patterns to the fungal pathogen Candida albicans, which is a major cause of lethality in septic patients. Using oligonucleotide microarray analysis, we identified 56 genes that were transcriptionally up-regulated and 69 genes that were suppressed upon exposure of ECs to C. albicans. The most significantly up-regulated transcripts were found in gene ontology groups comprising the following categories: chemotaxis/migration; cell death and proliferation; signaling; transcriptional regulation; and cell-cell contacts/intercellular signaling. Further examination of candidate signaling cascades established a central role of the proinflammatory NF-κB pathway in the regulation of the Candida-modulated transcriptome of ECs. As a second major regulatory pathway we identified the stress-activated p38 MAPK pathway, which critically contributes to the regulation of selected Candida target genes such as CXCL8/IL-8. Depletion of MyD88 and IL-1R-associated kinase-1 by RNA interference demonstrates that Candida-induced NF-κB activation is mediated by pattern recognition receptor signaling. Additional experiments suggest that C. albicans-induced CXCL8/IL-8 expression is mediated by TLR3 rather than TLR2 and TLR4, which previously have been implicated with MyD88/IκB kinase-2/NF-κB activation by this fungus in other systems. Our study provides the first comprehensive analysis of endothelial gene responses to C. albicans and presents novel insights into the complex signaling patterns triggered by this important pathogen.

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Section: Discussionsupporting

confidence: 87%

Candida albicans Triggers Activation of Distinct Signaling Pathways to Establish a Proinflammatory Gene Expression Program in Primary Human Endothelial Cells

Müller

Viemann²,

Schmidt

et al. 2007

The Journal of Immunology

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“…The specific functions of I B-␤ have not yet been established. In endothelial cells, it was suggested that a transient phase of NF-B activation is mediated through I B-␣, whereas a persistent phase is mediated through I B-␤ [28,56]. Consistent with these data, we observed in THP-1 cells that the level of I B-␣ was quickly restored after stimulation, whereas that of I B-␤ remained low (data not shown).…”

Section: Discussionsupporting

confidence: 81%

“…I B-␤ was recently cloned and a first characterization was performed in endothelial cells [28,56]. The specific functions of I B-␤ have not yet been established.…”

Section: Discussionmentioning

confidence: 99%

Effect of proteasome inhibitors on monocytic IκB-α and -β depletion, NF-κB activation, and cytokine production

Haas

Page

et al. 1998

Journal of Leukocyte Biology

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Abstract:We investigated the effect of proteasome inhibitors on the lipopolysaccharide (LPS)-induced expression of several monocytic cytokines, which may be dependent on the transcription factor, nuclear factor-B (NF-B). Exposure of human monocytic THP-1 cells to ALLN and Mu873 prevented the LPS-induced degradation of I B-␣ and -␤, as did the more potent proteasome inhibitor, PSI, whereas several calpain inhibitors were ineffective. This was accompanied by the inhibition of nuclear NF-B binding activity and NF-B transcriptional activation. At the mRNA level, the inhibitors blocked the expression of tumor necrosis factor (TNF) and interleukin-1␤ (IL-1␤), whereas IL-8 remained unaffected by ALLN and was only partially reduced by the highest dose of PSI. The latter effect appears to be due to an increase in IL-8 mRNA stability in the presence of proteasome inhibitors. Furthermore, the production of TNF was efficiently suppressed by ALLN and PSI, less by Mu873, and not at all by calpain inhibitors. In primary human blood monocytes ALLN also prevented the LPS-induced degradation of I B-␣ and -␤, efficiently blocked the production of TNF and, to a lesser extent, IL-1␤, whereas that of IL-8 was not inhibited. The expression of NF-B-dependent monocytic cytokines may be selectively controlled by the proteasome, offering a potential therapeutic target in inflammatory disease.

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“…To investigate whether the increased expression of VCAM-1 and E-selectin mRNAs induced by MPA in TNFa-activated EC is caused by persistent activation of NF-kB (Johnson et al, 1996), we measured the TNFa-activation of NF-kB in MPA-treated cells by EMSA of DNA-binding proteins (Figure 7). In four separate experiments, TNFa-activation of NF-kB was decreased by MPA-preincubation, on average approximately by 50% at 3h (Figure 7a).…”

Section: Tnfa-activation Of the Transcription Factor Nf-kb Is Not Incmentioning

confidence: 99%

Effect of mycophenolic acid on TNFα‐induced expression of cell adhesion molecules in human venous endothelial cells in vitro

Hauser

Johnson

Thévenod

et al. 1997

British J Pharmacology

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Mycophenolic acid (MPA) is an inhibitor of inosine‐5′‐monophosphate dehydrogenase and therefore interferes with cellular GTP biosynthesis. Recently, MPA has been used as an antiproliferative and immunosuppressive agent. In the present study, the effect of MPA on the expression of the endothelial cell adhesion molecules (CAMs), intercellular (I) CAM‐1, vascular (V) CAM‐1 and endothelial (E)‐selectin, was investigated in tumour necrosis factor‐α (TNFα)‐activated cultured human venous endothelial cells (EC). Surface expression of CAMs was measured by flow cytometry and mRNA expression by Northern blot analysis. Transcriptional activation of CAMs by the nuclear factor NF‐κB was determined by an electromobility shift assay. The function of CAMs was studied by a static adhesion assay with human monocyte‐like undifferentiated U937 cells. Pretreatment of TNFα‐ (5 ng ml−1, 12 h) activated EC with MPA (10 μM, 24 h) increased the binding of U937 cells, which had not been treated with MPA, by ∼amp;2 fold. MPA‐pretreatment of EC did not affect TNFα‐induced surface expression of ICAM‐1. However, VCAM‐1 and E‐selectin were increased 2–3 fold and remained elevated up to 24 h, by which time TNFα‐activated control EC had returned to baseline levels of expression. The effect of MPA on the surface expression of CAMs was half‐maximal at ∼amp;1 μM and required 12 h of pretreatment. Guanosine (0.3 mM), a precursor of GTP, did not prevent the effect of MPA on the expression of CAMs in TNFα‐activated EC. Kinetics of mRNA expression of CAMs mirrored protein expression: mRNA for ICAM‐1 was unaffected, whereas TNFα‐induced mRNA expression for E‐selectin and VCAM‐1 was prolonged and increased by MPA. This effect was not due to increased transcription mediated by the nuclear transcription factor NF‐κB. However, half‐life for E‐selectin mRNA was increased 10 fold by MPA, whereas ICAM‐1 mRNA half‐life was unchanged. The data demonstrate that apart from its antiproliferative effects on lymphocytes, MPA enhances TNFα‐induced VCAM‐1 and E‐selectin surface expression on EC by selectively increasing the mRNA‐stability of these cell adhesion molecules. This effect of MPA on EC appears to be independent from inhibition of inosine‐5′‐monophosphate dehydrogenase.

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A Sustained Reduction in IκB-β May Contribute to Persistent NF-κB Activation in Human Endothelial Cells

Cited by 107 publications

References 39 publications

Candida albicans Triggers Activation of Distinct Signaling Pathways to Establish a Proinflammatory Gene Expression Program in Primary Human Endothelial Cells

Candida albicans Triggers Activation of Distinct Signaling Pathways to Establish a Proinflammatory Gene Expression Program in Primary Human Endothelial Cells

Effect of proteasome inhibitors on monocytic IκB-α and -β depletion, NF-κB activation, and cytokine production

Effect of mycophenolic acid on TNFα‐induced expression of cell adhesion molecules in human venous endothelial cells in vitro

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