Modulation of NF-κB Signaling as a Therapeutic Target in Autoimmunity

Abstract

Autoimmune diseases arise from the loss of tolerance to endogenous self-antigens, resulting in a heterogeneous range of chronic conditions that cause considerable morbidity and mortality worldwide. In Western countries, over 5% of the population is affected by some form of autoimmune disease, with enhanced or inappropriate activation of nuclear factor (NF)–κB implicated in a number of these conditions. Although treatment strategies for autoimmunity have improved significantly in recent years, current therapeutics are still not capable of achieving satisfactory disease management in all patients, and as such, the therapeutic modulation of NF-κB is an attractive target in autoimmunity. To date, no NF-κB inhibitors have progressed to the clinic for the treatment of autoimmunity, but a variety of promising approaches targeting multiple stages of the NF-κB pathway are currently being explored. This review focuses on the current strategies being investigated for the inhibition of the NF-κB pathway in autoimmune diseases and considers potential future strategies for the therapeutic targeting of this crucial transcription factor.

IκB kinase β Mediating the Downregulation of p53 and p21 by Lipopolysaccharide in Human Papillomavirus 16+ Cervical Cancer Cells

“…[345] Activated IκB kinase β (IKKβ) phosphorylates the inhibitor of NF-κB (IκB), which binds NF-κB to inhibit its function, leading to the degradation of IκB and free of NF-κB entering into the nucleus where it activates various target genes. [678] IKKβ can also phosphorylate p53, which is a critical tumor suppressor that activates lots of genes including p21, Bax, and Puma at the transcriptional level, promoting its degradation by β-TrCP. [9] Loss of IKKβ activity increases the stability of p53 and expression of p21 resulting in cell cycle arrest and apoptosis.…”

Association between rs2294020 in X-linked CCDC22 and susceptibility to autoimmune diseases with focus on systemic lupus erythematosus

“…Impairment in CCDC22 expression, due to rs2204020 SNP located in the 3’ UTR, may dysregulate NF-kB signalling [5], thus contributing to the inflammatory process in SLE. NF-kB is a master regulator of the immune response and its enhanced or inappropriate activation has been shown to be involved in several autoimmune diseases, including SLE [54,55]. In SLE, there is an increased production of autoantibodies by polyclonal activation of B cells, which may be maintained by the inducible transcription factor NF-kBp65 [56].…”

“…In SLE, there is an increased production of autoantibodies by polyclonal activation of B cells, which may be maintained by the inducible transcription factor NF-kBp65 [56]. NF-kB therapeutic modulation, through ubiquitination and degradation of individual subunits of this transcription factor, may represent an attractive approach in combatting autoimmune diseases [55]. …”

Small molecules to the rescue: Inhibition of cytokine signaling in immune-mediated diseases

“…NF-kB-mediated dysregulation has been shown to be crucial for the development of numerous pathological conditions beyond inflammation and/or autoimmunity: from AIDS and atherosclerosis to cancer and muscular dystrophy. Therefore, the signaling cascade involving NF-kB has been considered a primary target for pharmacological intervention [66–68] and a wide range of drugs targeting crucial steps of this pathway, such as kinases activation, phosphatase enzymatic activity, ubiquitination, nuclear translocation, DNA binding and post translational modifications, have been tested [67, 69]. …”

“…Bortezomib (trade name Velcade®) has been the first proteasome inhibitor approved for the clinical treatment of multiple myeloma [67, 69]. Moreover, preclinical studies in murine models of lupus nephritis, colitis, MS and myasthenia gravis have shown bortezomib efficacy [72–76].…”