Nuclear factor-κB: a key regulator in health and disease of lungs

Abstract

Rel/NF-κB transcription factors play a key role in modulating the response of immunoregulatory genes including cytokines and chemokines, cell adhesion molecules, acute phase proteins, and anti-microbial peptides. Furthermore, an array of genes important for angiogenesis, tumor invasion and metastasis is also regulated by nuclear factor-κB (NF-κB). Close association of NF-κB with inflammation and tumorigenesis makes it an attractive target for basic research as well as for pharmaceutical industries. Studies involving various animal and cellular models have revealed the importance of NF-κB in pathobiology of lung diseases. This review (a) describes structures, activities, and regulation of NF-κB family members; (b) provides information which implicates NF-κB in pathogenesis of pulmonary inflammation and cancer; and (c) discusses information about available synthetic and natural compounds which target NF-κB or specific components of NF-κB signal transduction pathway and which may provide the foundation for development of effective therapy for lung inflammation and bronchogenic carcinomas.

Fig. 1

Activation of NF-κB through different signaling pathways. The classical pathway of NF-κB activation involves TNF-α binds to TNFR1 and recruits the adaptors like TRAF2, TRADD and RIP to the membrane. These changes mediates the activation of IKK complex and subsequent phosphorylation of IκBα leading to its degradation. P65/p50 heterodimer is released and migrates to nucleus and activates target genes. The alternative pathway is triggered by DNA damage and is dependent on p38 and CK2 activation. Another alternate pathway of NF-κB activation is triggered by binding of CD40 ligand to its receptor. Recruitment of TRAF proteins leads to the activation of NIK and IKKα which causes processing of inhibitory protein p100 resulting in release of p52 which forms homodimers with RelB. Activation of NF-κB through TLR4 mediated pathway stimulated by LPS. Cigarette smoke activates NF-κB by inducing ROS production

Fig. 2

Respiratory pathogens activate complex signaling pathways via Toll-like receptors (TLR) and Nod-like receptors leading to the activation of NF-κB