The nuclear factor-kappa B (NF-κB) transcription factor is a critical regulatory factor involved in the pathogenesis of many inflammatory diseases, including pulmonary diseases such as cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease (COPD). Despite recent advances in treatment, managing the inflammatory components of these diseases remains suboptimal. A20, an endogenous negative regulator of NF-κB signaling, has been widely described in various autoimmune and inflammatory diseases and has recently been reported in chronic lung diseases.
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The Inflammatory Role of NF-κB
NF-κB is a transcription factor expressed in various cell types, capable of rapid activation in response to multiple stimuli such as cellular stress, and bacterial and viral infections. Upon activation, NF-κB translocates to the nucleus, regulating the expression of numerous inflammatory factors, including cytokines, chemokines, and adhesion molecules. The overexpression and secretion of these factors lead to the persistence and amplification of inflammatory responses, which is a core mechanism in the pathogenesis of many chronic inflammatory diseases.
In lung diseases, the persistent activation of NF-κB is closely associated with the severity and progression of the diseases. For example, in CF patients, NF-κB activation promotes the infiltration of a large number of neutrophils into the lungs, leading to chronic inflammation and tissue damage. Similarly, in asthma patients, NF-κB activation is associated with airway inflammation and allergic reactions. In COPD, NF-κB promotes the expression of inflammatory factors, exacerbating airway and lung tissue destruction.
The Inflammatory Regulatory Role of A20
A20, also known as TNFAIP3, is a key negative regulator of the NF-κB signaling pathway. A20 regulates the ubiquitination state of multiple signaling molecules through its deubiquitinating enzyme activity and E3 ubiquitin ligase activity, thereby inhibiting NF-κB activation. The deficiency or dysfunction of A20 is closely related to the occurrence and development of various inflammatory diseases.
In pulmonary inflammation, A20 regulates the expression of inflammatory factors and the inflammatory response by inhibiting NF-κB signaling. For example, in CF and COPD patients, A20 expression levels are significantly reduced, leading to hyperactivation of the NF-κB signaling pathway and promoting sustained inflammatory responses. Nevertheless, the role of A20 in asthma has not been fully studied, requiring further exploration of its regulatory mechanisms in airway inflammation.
The Regulatory Role of DREAM
DREAM (downstream regulatory element antagonist modulator) is a multifunctional protein that plays a crucial role in the regulation of various cellular processes, including gene expression, cell cycle, and apoptosis. It serves as a key transcriptional regulator, influencing the expression of multiple genes involved in inflammation. DREAM operates through different mechanisms in the nucleus and cytoplasm, which underscores its versatility in cellular regulation.
Fig. 1 Physiological effects of downstream regulatory elements antagonist modulator (DREAM) during inflammation (Momtazi G., et al. 2019).
In the nucleus, DREAM acts by binding to specific DNA sequences known as downstream regulatory elements (DREs). This binding inhibits the transcription of target genes, effectively downregulating the expression of genes involved in inflammatory responses. By controlling the transcriptional activity of these genes, DREAM helps maintain cellular homeostasis and prevents excessive inflammation, which is critical in preventing chronic inflammatory diseases.
In the cytoplasm, DREAM interacts with various signaling molecules, modulating their activity and stability. These interactions can affect numerous signaling pathways, including those involved in the NF-κB signaling cascade. By regulating the stability and activity of these molecules, DREAM indirectly influences the inflammatory response. For instance, it can modulate the activation of kinases and other proteins that play pivotal roles in the transduction of inflammatory signals.
Research has demonstrated that alterations in DREAM expression and function are associated with the pathogenesis of several inflammatory diseases. In the context of pulmonary inflammation, changes in DREAM levels can significantly impact disease severity and progression. For example, reduced expression of DREAM has been linked to heightened inflammatory responses in chronic lung diseases like cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease (COPD).
Moreover, DREAM's regulatory functions extend to the modulation of immune responses. By influencing the expression of cytokines and other immune mediators, DREAM helps orchestrate the body's defense mechanisms against pathogens. However, dysregulation of DREAM can lead to an imbalanced immune response, contributing to the chronic inflammation observed in various pulmonary diseases.
The Role of the A20-DREAM Axis in Pulmonary Inflammation
The A20-DREAM axis plays a crucial regulatory role in pulmonary inflammation, acting as a significant modulator of the NF-κB signaling pathway. A20 and DREAM, both recognized as negative regulators of NF-κB signaling, interact to control the inflammatory response within the lungs. A20, through its deubiquitinating enzyme activity and E3 ubiquitin ligase activity, modulates the ubiquitination state of various signaling molecules, including DREAM. This regulation affects DREAM's functions in both the nucleus and cytoplasm. In the nucleus, DREAM can bind to specific DNA sequences to inhibit the transcription of target genes involved in inflammation, while in the cytoplasm, DREAM influences the activity and stability of signaling molecules, further impacting the inflammatory process.
In chronic lung diseases such as cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), and asthma, the A20-DREAM axis is often dysregulated. Reduced expression or dysfunction of A20 can lead to an imbalance in DREAM regulation, resulting in the hyperactivation of NF-κB signaling and sustained inflammatory responses. For instance, in CF patients, the imbalance in the A20-DREAM axis contributes to the continuous infiltration of neutrophils and the overexpression of pro-inflammatory cytokines, causing persistent inflammation and tissue damage. Similarly, in COPD, the dysregulation of this axis exacerbates airway and lung tissue destruction, contributing to disease progression and severity.
Research indicates that targeting the A20-DREAM axis could offer new therapeutic avenues for managing chronic pulmonary inflammation. By restoring the balance and function of A20 and DREAM, it may be possible to mitigate the overactive NF-κB signaling pathway and its associated inflammatory responses. Potential therapeutic strategies could involve gene therapy to enhance A20 expression or the development of small molecule drugs to modulate DREAM activity. Such approaches aim to reduce inflammation, improve lung function, and slow the progression of chronic pulmonary diseases. Therefore, understanding the intricate mechanisms of the A20-DREAM axis is vital for developing effective treatments for these debilitating conditions.
Conclusion
The A20-DREAM axis has significant regulatory effects on airway inflammatory responses, and its dysregulation may lead to the progression of chronic lung diseases. Future research should further explore the regulatory mechanisms of the A20-DREAM axis and develop therapeutic strategies based on its regulation to effectively manage and treat the inflammatory responses in chronic lung diseases.
References
- Verstrepen L., et al. Expression, biological activities and mechanisms of action of A20 (TNFAIP3). Biochemical Pharmacology. 2010, 80 (12): 2009-20.
- Momtazi G., et al. Regulators of A20 (TNFAIP3): new drug-able targets in inflammation. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2019, 316 (3): L456-69.
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