Cell-Type Targeted NF-kappaB Inhibition for the Treatment of Inflammatory Diseases

Abstract

<jats:p>Deregulated NF-k activation is not only involved in cancer but also contributes to the pathogenesis of chronic inflammatory diseases like rheumatoid arthritis (RA) and multiple sclerosis (MS). Ideally, therapeutic NF-KappaB inhibition should only take place in those cell types that are involved in disease pathogenesis to maintain physiological cell functions in all other cells. In contrast, unselective NF-kappaB inhibition in all cells results in multiple adverse effects, a major hindrance in drug development. Hitherto, various substances exist to inhibit different steps of NF-kappaB signaling. However, powerful tools for cell-type specific NF-kappaB inhibition are not yet established. Here, we review the role of NF-kappaB in inflammatory diseases, current strategies for drug delivery and NF-kappaB inhibition and point out the “sneaking ligand” approach. Sneaking ligand fusion proteins (SLFPs) are recombinant proteins with modular architecture consisting of three domains. The prototype SLC1 binds specifically to the activated endothelium and blocks canonical NF-kappaB activation. In vivo, SLC1 attenuated clinical and histological signs of experimental arthritides. The SLFP architecture allows an easy exchange of binding and effector domains and represents an attractive approach to study disease-relevant biological targets in a broad range of diseases. In vivo, SLFP treatment might increase therapeutic efficacy while minimizing adverse effects.</jats:p>

Redox Homeostasis in Poultry: Regulatory Roles of NF-κB

“…It has been found that NF-κB is conserved across different phyla, and, in mammalian and avian species, it consists of a group of five related proteins (subunits) that are capable of binding to DNA: p50 (a 50 kDa protein also known as NF-κB1), p52 (known as NF-κB2), p65 (also known as RelA), c-Rel, and RelB. In fact, p65, RelB, and c-Rel are characterized by a C-terminal transcription activation domain (TAD) that participates in the positive regulation of gene expression [ 50 ]. Interestingly, the other NF-κB family members, NF-κB1 and NF-κB2, were shown to be synthetized as larger precursor proteins (p105 and p100) with subsequent proteolytic processing to p50 and p52 [ 47 ].…”

“…Therefore, it is believed that, in order to inhibit further transcription and restore the original latent state of NF-κB signaling, newly synthesized IκBα can enter the nucleus, remove NF-κB from DNA, and export the complex back to the cytoplasm [ 49 ]. Interestingly, the canonical NF-κB pathway is considered to be antiapoptotic, while the noncanonical pathway is proapoptotic [ 50 ].…”

“…It well known that NF-κB responds to a large variety of external and internal stress signals/stimuli including oxidative stress [ 62 ], playing essential roles in the development and maintenance of tissue homeostasis by regulating the transcription of an array of different genes, including proinflammatory cytokines, as well as adhesion molecules, antimicrobial peptides, and acute phase proteins [ 74 , 75 , 76 ]. In fact, NF-κB signaling can be considered as an emergency response system, since activation of NF-κB was shown to occur very quickly (within minutes) as a result of release from IκB or as a consequence of cleavage of the inhibitory ankyrin repeat domains of p100 and p105 [ 50 ]. Under physiological conditions, the majority of NF-κB-activated genes regulate biological processes associated with cell growth, protection, and repair.…”

“…), upstream kinases, sirtuins, Wingless-related MMTV integration site 4 (Wnt4), ROS, p53, and miRNAS, which determine the pattern of its effects on the expression of a battery of various genes [ 48 , 60 , 67 ]. Furthermore, there are regulatory mechanisms coordinating NF-κB association with various important pathways [ 50 ]. It has been suggested to consider NF-κB as a stress response factor, since NF-κB signaling is condition-dependent, and NF-κB-dependent cell death or survival would depend on the stimulus and the cell type involved.…”

The immunophilin protein FKBPL and its peptide derivatives are novel regulators of vascular integrity and inflammation via NF-κB signaling

“…This results in the expression of proinflammatory genes, the activation of the inflammasome and loss of vascular integrity in endothelial cells (8)(9)(10)(11). Unselective pharmacological inhibition of NF-κB, across cell types, results in multiple adverse effects; a major hindrance in drug development (12). The nuclear translocation of NF-κB dimers is dependent upon a dynein/dynactin motorimmunophilin complex, indicating that immunophilins can fine tune the signaling cascade (13,14).…”