Resolution of inflammation: Intracellular feedback loops in the endothelium

Winsauer, Gabriele; Martin, Rainer de

doi:10.1160/th06-08-0473

Cited by 31 publications

(21 citation statements)

References 35 publications

(35 reference statements)

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“…However, it should be noted that MEKK2 expression only appeared enhanced in LT-cotreated cells and was not detectable in cells treated with LT alone. Besides pathways that stimulate IKK, another possibility that warrants further investigation is whether LT may inhibit endogenous endothelial mechanisms that are activated for resolution of the NF-B response (49). Potential targets include the COX-2 produced cyclopentenone prostaglandins, anti-inflammatory molecules that are exclusively synthesized late in the inflammatory response and have been shown to inhibit IKK activity (50).…”

Section: Discussionmentioning

confidence: 99%

Anthrax Lethal Toxin Enhances IκB Kinase Activation and Differentially Regulates Pro-inflammatory Genes in Human Endothelium

Warfel

D’Agnillo

2009

Journal of Biological Chemistry

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Anthrax lethal toxin (LT) was previously shown to enhance transcriptional activity of NF-B in tumor necrosis factor-␣-activated primary human endothelial cells. Here we show that this LT-mediated increase in NF-B activation is associated with the enhanced degradation of the inhibitory proteins IB␣ and IB␤ but not IB⑀. Moreover, this was accompanied by enhanced activation of the IB kinase complex (IKK), which is responsible for targeting IB proteins for degradation. Importantly, LT enhancement of IB␣ degradation was completely blocked by a selective IKK␤ inhibitor, whereas IB␤ degradation was attenuated, suggesting a mechanistic link. Consistent with the above data, LT-cotreated cells show elevated phosphorylation of two IKK substrates, IB␣ and p65, both of which were blocked by incubation with the IKK␤ inhibitor. Consistent with NF-B activation, LT increased transcription of the NF-B regulated gene CD40. Conversely, LT inhibited transcription of another NF-B-regulated gene, CCL2. This inhibition was linked to the LT-mediated suppression of another CCL2-regulating transcription factor, AP-1 (activator protein-1). These data suggest that LT-mediated enhancement of NF-B is IKKdependent, but importantly, the net effect of LT on the transcription of proinflammatory genes is driven by the cumulative effect of LT on the particular set of transcription factors that regulate a given promoter. Together, these findings provide new mechanistic insight on how LT may disrupt the host response to anthrax.

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Section: Discussionmentioning

confidence: 99%

Anthrax Lethal Toxin Enhances IκB Kinase Activation and Differentially Regulates Pro-inflammatory Genes in Human Endothelium

Warfel

D’Agnillo

2009

Journal of Biological Chemistry

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“…Inflammatory processes can be controlled by feedback mechanisms [37]. Because ESE-1 mRNA peaked at 2 h in response to cytokines and then rapidly decreased ( Figure 1A), we wanted to determine whether there is a feedback mechanism for this regulation.…”

Section: Ese-1 Induction Is Downregulated By Itselfmentioning

confidence: 99%

Regulation of epithelium-specific Ets-like factors ESE-1 and ESE-3 in airway epithelial cells: potential roles in airway inflammation

Duan

Cao

et al. 2008

Cell Res

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Airway inflammation is the hallmark of many respiratory disorders, such as asthma and cystic fibrosis. Changes in airway gene expression triggered by inflammation play a key role in the pathogenesis of these diseases. Genetic linkage studies suggest that ESE-2 and ESE-3, which encode epithelium-specific Ets-domain-containing transcription factors, are candidate asthma susceptibility genes. We report here that the expression of another member of the Ets family transcription factors ESE-1, as well as ESE-3, is upregulated by the inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in bronchial epithelial cell lines. Treatment of these cells with IL-1β and TNF-α resulted in a dramatic increase in mRNA expression for both ESE-1 and ESE-3. We demonstrate that the induced expression is mediated by activation of the transcription factor NF-κB. We have characterized the ESE-1 and ESE-3 promoters and have identified the NF-κB binding sequences that are required for the cytokine-induced expression. In addition, we also demonstrate that ESE-1 upregulates ESE-3 expression and downregulates its own induction by cytokines. Finally, we have shown that in Elf3 (homologous to human ESE-1) knockout mice, the expression of the inflammatory cytokine interleukin-6 (IL-6) is downregulated. Our findings suggest that ESE-1 and ESE-3 play an important role in airway inflammation.

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“…It is therefore not surprising that mechanisms aimed at rapid and specific initiation of proinflammatory reactions have co-evolved with mechanisms that provide timely termination of such processes. From a systems biology perspective, such "switchability" can be achieved by intracellular feedback loops that permit ligand-induced desensitization and resensitization of proinflammatory signaling cascades (2).…”

mentioning

confidence: 99%

“…In this regard, recent studies have shown that nuclear factor-B (NF-B) 4 signaling plays a critical role in both initiation and resolution of inflammation (2,3). The transcription factor NF-B is a key regulator of innate and adaptive immune responses as well as a mediator of cell survival and proliferation (4).…”

mentioning

confidence: 99%

Identification of a Ligand-induced Transient Refractory Period in Nuclear Factor-κB Signaling

Moss

Gross

Gammon

et al. 2008

Journal of Biological Chemistry

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In response to a variety of extracellular ligands, nuclear factor-B (NF-B) signaling regulates inflammation, cell proliferation, and apoptosis. It is likely that cells are not continuously exposed to stimulating ligands in vivo but rather experience transient pulses. To study the temporal regulation of NF-B and its major regulator, inhibitor of NF-B␣ (IB␣), in real time, we utilized a novel transcriptionally coupled IB␣-firefly luciferase fusion reporter and characterized the dynamics and responsiveness of IB␣ processing upon a short 30-s pulse of tumor necrosis factor ␣ (TNF␣) or a continuous challenge of TNF␣ following a 30-s preconditioning pulse. Strikingly, a 30-s pulse of TNF␣ robustly activated inhibitor of NF-B kinase (IKK), leading to IB␣ degradation, NF-B nuclear translocation, and strong transcriptional up-regulation of IB␣. Furthermore, we identified a transient refractory period (lasting up to 120 min) following preconditioning, during which the cells were not able to fully degrade IB␣ upon a second TNF␣ challenge. Kinase assays of IKK activity revealed that regulation of IKK activity correlated in part with this transient refractory period. In contrast, experiments involving sequential exposure to TNF␣ and interleukin-1␤ indicated that receptor dynamics could not explain this phenomenon. Utilizing a well accepted computational model of NF-B dynamics, we further identified an additional layer of regulation, downstream of IKK, that may govern the temporal capacity of cells to respond to a second proinflammatory insult. Overall, the data suggested that nuclear export of NF-B⅐IB␣ complexes represented another rate-limiting step that may impact this refractory period, thereby providing an additional regulatory mechanism.Adequate resolution of an inflammatory reaction is as equally important as initiation. Persistent or fulminant responses can cause detrimental consequences both locally and systemically (1), and resolution of inflammation is important for both termination of an acute response as well as for prevention of destructive chronic responses. It is therefore not surprising that mechanisms aimed at rapid and specific initiation of proinflammatory reactions have co-evolved with mechanisms that provide timely termination of such processes. From a systems biology perspective, such "switchability" can be achieved by intracellular feedback loops that permit ligand-induced desensitization and resensitization of proinflammatory signaling cascades (2).In this regard, recent studies have shown that nuclear factor-B (NF-B) 4 signaling plays a critical role in both initiation and resolution of inflammation (2, 3). The transcription factor NF-B is a key regulator of innate and adaptive immune responses as well as a mediator of cell survival and proliferation (4). Improper regulation of NF-B contributes to induction and progression of a wide range of human disorders, including a variety of pathological inflammatory conditions, neurodegenerative diseases as well as many types of cancer (5, 6). In resting cells...

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Resolution of inflammation: Intracellular feedback loops in the endothelium

Cited by 31 publications

References 35 publications

Anthrax Lethal Toxin Enhances IκB Kinase Activation and Differentially Regulates Pro-inflammatory Genes in Human Endothelium

Anthrax Lethal Toxin Enhances IκB Kinase Activation and Differentially Regulates Pro-inflammatory Genes in Human Endothelium

Regulation of epithelium-specific Ets-like factors ESE-1 and ESE-3 in airway epithelial cells: potential roles in airway inflammation

Identification of a Ligand-induced Transient Refractory Period in Nuclear Factor-κB Signaling

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