Lung-Targeted Overexpression of the NF-κB Member RelB Inhibits Cigarette Smoke–Induced Inflammation

McMillan, David H.; Baglole, Carolyn J.; Thatcher, Thomas H.; Maggirwar, Sanjay B.; Sime, Patricia J.; Phipps, Richard P.

doi:10.1016/j.ajpath.2011.03.030

Cited by 52 publications

(53 citation statements)

References 66 publications

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“…Aryl hydrocarbon receptor-deficient fibroblasts exposed to cigarette smoke showed increased expression of cyclooxygenase-2 and prostaglandins, in association with a loss of RelB (41). Indeed, an anti-inflammatory role for RelB in cigarette smoke-induced inflammation was recently demonstrated, as evidenced by decreased neutrophilic infiltration and the diminished content of proinflammatory mediators after the adenovirus-mediated transduction of RelB (42). In response to LPS, RelB 2/2 fibroblasts showed prolonged increases in proinflammatory cytokines compared with wild-type controls, suggesting a role for RelB in the resolution of inflammatory responses (43).…”

Section: Discussionmentioning

confidence: 99%

Cooperation between Classical and Alternative NF-κB Pathways Regulates Proinflammatory Responses in Epithelial Cells

Tully

Nolin²,

Guala³

et al. 2012

Am J Respir Cell Mol Biol

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The transcription factor NF-kB has been causally linked to inflammatory lung diseases. Recent studies have unraveled the complexity of NF-kB activation by identifying two parallel activation pathways: the classical NF-kB pathway, which is controlled by IkB kinase complex-b (IKKb) and RelA/p50, and the alternative pathway, which is controlled by IKKa and RelB/p52. The alternative pathway regulates adaptive immune responses and lymphoid development, yet its role in the regulation of innate immune responses remains largely unknown. In this study, we determined the relevance of the alternative NF-kB pathway in proinflammatory responses in lung epithelial cells. The exposure of C10 murine alveolar lung epithelial cells to diverse stimuli, or primary murine tracheal epithelial cells to LPS, resulted in the activation of both NF-kB pathways, based on the nuclear translocation of RelA, p50, RelB, and p52. Increases in the nuclear content of RelA occurred rapidly, but transiently, whereas increases in nuclear RelB content were protracted. The small interfering (si) RNAmediated knockdown of IKKa, RelA, or RelB resulted in decreases of multiple LPS-induced proinflammatory cytokines. Surprisingly, the siRNA ablation of IKKa or RelB led to marked increases in the production of IL-6 in response to LPS. The simultaneous expression of constitutively active (CA)-IKKa and CA-IKKb caused synergistic increases in proinflammatory mediators. Lastly, the disruption of the IKK signalsome inhibited the activation of both NF-kB pathways. These results demonstrate that the coordinated activation of both NF-kB pathways regulates the magnitude and nature of proinflammatory responses in lung epithelial cells.Keywords: lung; IkB kinase-b; IkB kinase-a; RelA; RelB NF-kB is a transcription factor that plays a cardinal role in multiple cellular processes, including survival, proliferation, and inflammation. In unstimulated cells, NF-kB dimers RelA and p50 are sequestered in the cytosol by the inhibitor of kB (IkBa). The IkB kinase complex (IKK) consists of two catalytic subunits, IKKb and IKKa, and the regulatory protein, IKKg (also known as NF-kB essential modulator). Upon ligation by a variety of stimuli such as TNF-a or Toll-like receptor agonists, IKKb is phosphorylated and in turn phosphorylates IkBa, leading to its subsequent ubiquitination and degradation by the 26S proteasome (1, 2). The processing of IkBa promotes the nuclear translocation of RelA/p50, leading to the transcriptional activation of NF-kB-dependent genes. NF-kB activates the transcription of many proinflammatory cytokine and chemokine genes that initiate and propagate innate immune responses (1, 2).The airway epithelium, classically regarded as the first line of defense against inhaled agents, toxic factors, and physical trauma, is now recognized as a key component of the innate immune system, and plays an active role in the orchestration of acute inflammatory and adaptive immune responses (3, 4). Upon stimulation, epithelial cells secrete proinflammatory mediators such as...

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Section: Discussionmentioning

confidence: 99%

Cooperation between Classical and Alternative NF-κB Pathways Regulates Proinflammatory Responses in Epithelial Cells

Tully

Nolin²,

Guala³

et al. 2012

Am J Respir Cell Mol Biol

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“…Adult female C57BL/6J mice were purchased from The Jackson Laboratory (Bar Harbor, ME) and housed in the Inhalation Core Facility at the University of Rochester. Mainstream CS exposures were as previously described (35,61,62). Mice were placed in individual compartments of a wire cage that was placed inside a closed plastic box connected to the smoke source.…”

Section: Methodsmentioning

confidence: 99%

“…CS contains high levels of free radicals and other reactive oxygen species (ROS) that contribute to proinflammatory activation of lung cells via NF-B and other redox-sensitive transcription factors (10,35,52,53). Additional ROS, including superoxide, H 2 O 2 , and hypochlorus acid, are released by inflammatory macrophages and neutrophils via the action of enzymes, including xanthine/xanthine oxidase, myeloperoxidase (MPO), and NADPH oxidase (30,69).…”

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confidence: 99%

Neu-164 and Neu-107, two novel antioxidant and anti-myeloperoxidase compounds, inhibit acute cigarette smoke-induced lung inflammation

Thatcher

Hsiao

Pinner

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Recently, studies have reported that RelB diminished cigarette smoke-induced COX-2 protein expression in lung fibroblasts, attenuating inflammation (46). The overexpression of RelB suppressed the inflammatory response and protected against lung injury (47). Therefore, we screened p65, p50, and RelB to clarify the role of NF-kB in the inflammation-resolving activity of COX-2.…”

Section: Figurementioning

confidence: 99%

Resolvin D1 Improves the Resolution of Inflammation via Activating NF-κB p50/p50–Mediated Cyclooxygenase-2 Expression in Acute Respiratory Distress Syndrome

Gao

Zhang

Luo

et al. 2017

The Journal of Immunology

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Acute respiratory distress syndrome (ARDS) is a severe illness characterized by uncontrolled inflammation. The resolution of inflammation is a tightly regulated event controlled by endogenous mediators, such as resolvin D1 (RvD1). Cyclooxygenase-2 (COX-2) has been reported to promote inflammation, along with PGE2, in the initiation of inflammation, as well as in prompting resolution, with PGD2 acting in the later phase of inflammation. Our previous work demonstrated that RvD1 enhanced COX-2 and PGD2 expression to resolve inflammation. In this study, we investigated mechanisms underlying the effect of RvD1 in modulating proresolving COX-2 expression. In a self-limited ARDS model, an LPS challenge induced the biphasic activation of COX-2, and RvD1 promoted COX-2 expression during the resolution phase. However, it was significantly blocked by treatment of a NF-κB inhibitor. In pulmonary fibroblasts, NF-κB p50/p50 was shown to be responsible for the proresolving activity of COX-2. Additionally, RvD1 potently promoted p50 homodimer nuclear translocation and robustly triggered DNA-binding activity, upregulating COX-2 expression via lipoxin A4 receptor/formyl peptide receptor 2. Finally, the absence of p50 in knockout mice prevented RvD1 from promoting COX-2 and PGD2 expression and resulted in excessive pulmonary inflammation. In conclusion, RvD1 expedites the resolution of inflammation through activation of lipoxin A4 receptor/formyl peptide receptor 2 receptor and NF-κB p50/p50–COX-2 signaling pathways, indicating that RvD1 might have therapeutic potential in the management of ARDS.

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Lung-Targeted Overexpression of the NF-κB Member RelB Inhibits Cigarette Smoke–Induced Inflammation

Cited by 52 publications

References 66 publications

Cooperation between Classical and Alternative NF-κB Pathways Regulates Proinflammatory Responses in Epithelial Cells

Cooperation between Classical and Alternative NF-κB Pathways Regulates Proinflammatory Responses in Epithelial Cells

Neu-164 and Neu-107, two novel antioxidant and anti-myeloperoxidase compounds, inhibit acute cigarette smoke-induced lung inflammation

Resolvin D1 Improves the Resolution of Inflammation via Activating NF-κB p50/p50–Mediated Cyclooxygenase-2 Expression in Acute Respiratory Distress Syndrome

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