Alternative pathways of NF-κB activation: A double-edged sword in health and disease

While the classical pathway of NF-κB activation plays critical roles in a wide range of biological processes, the more recently described “non-canonical” NF-κB pathway has important but more restricted roles in both normal and pathological processes. The non-canonical NF-κB pathway, based on processing of the nf-κb2 gene product p100 to generate p52, appears to be involved in B-cell maturation and lymphoid development. Deregulated activation of this pathway has been observed in a variety of malignant and autoimmune diseases, thus inhibitors that specifically target p100 processing might be predicted to have potential roles as immunomodulators and in the therapy of malignant diseases. We review current understandings of NF-κB activation, particularly the mechanisms of p100 processing under both physiological and pathological conditions.