Nuclear factor-kappa-B signaling in lung development and disease: one pathway, numerous functions

Abstract

In contrast to other organs, the lung completes a significant portion of its development after term birth. During this stage of alveolarization, division of the alveolar ducts into alveolar sacs by secondary septation, and expansion of the pulmonary vasculature by means of angiogenesis markedly increase the gas exchange surface area of the lung. However, postnatal completion of growth renders the lung highly susceptible to environmental insults such as inflammation that disrupt this developmental program. This is particularly evident in the setting of preterm birth, where impairment of alveolarization causes bronchopulmonary dysplasia, a chronic lung disease associated with significant morbidity. The nuclear factor κ-B (NFκB) family of transcription factors are ubiquitously expressed, and function to regulate diverse cellular processes including proliferation, survival, and immunity. Extensive evidence suggests that activation of NFκB is important in the regulation of inflammation and in the control of angiogenesis. Therefore, NFκB-mediated downstream effects likely influence the lung response to injury and may also mediate normal alveolar development. This review summarizes the main biologic functions of NFκB, and highlights the regulatory mechanisms that allow for diversity and specificity in downstream gene activation. This is followed by a description of the pro and anti-inflammatory functions of NFκB in the lung, and of NFκB-mediated angiogenic effects. Finally, this review summarizes the clinical and experimental data that support a role for NFκB in mediating postnatal angiogenesis and alveolarization, and discusses the challenges that remain in developing therapies that can selectively block the detrimental functions of NFκB yet preserve the beneficial effects.

Keywords: angiogenesis; bronchopulmonary dysplasia; endothelial cells; inflammation; mouse models.

FIGURE 1

Pathways Leading to Activation of NFκB. A: In the canonical pathway of activation, the IKK kinase complex, consisting of kinases IKKα and IKKβ, and the regulatory subunit IKKγ, phosphorylate IκBα on serines 32 and 36. This results in the rapid ubiquitination and degradation of IκBα, which unmasks nuclear localization sequences present on the NFκB subunits, resulting in the rapid translocation of active NFκB complexes into the nucleus, where they bind to κB binding sites in the promoters of target genes and promote gene expression or repression. B: In the noncanonical pathway, IKKα is activated by the NFκB-inducing kinase (NIK), resulting in the processing of p100 to p52, and the nuclear translocation of RelBp52 dimers, which bind to unique κB elements. C: IKK-independent atypical activation of NFκB (observed in response to hypoxia/reoxygenation, or H₂O₂ stimulation) can occur by means of tyrosine kinase-mediated phosphorylation of IκBα on tyrosine 42, and subsequent dissociation or degradation of IκBα.

FIGURE 2

NFκB Dependent and Independent Actions of the IKKs. Both IKKα and -β phosphorylate IκB leading to NFκB mediated gene regulation. IKKβ can promote cell proliferation by inhibiting the anti-proliferative effects of FOXO3a, and activating the pro-proliferative MAP kinase pathway. IKKβ can also enhance gene transcription in an NFκB dependent manner by stabilizing mRNA transcripts containing AU-rich element (ARE) motifs. IKKα can either promote proliferation by increasing β-catenin-mediated transcription of cyclin D1, or inhibit proliferation by increasing cyclin D1 degradation. IKKα can also broadly affect gene transcription, independent of NFκB, by regulating chromatin remodeling.