Biomedical Engineering Reference
In-Depth Information
coordinate specialized functions carried out by specific cell types. The NF-
κ
B family
of transcription factors is pivotal for the modulation of the innate and adaptive
immune responses (
Chapters 6
and
7
). Additionally, they control cell numbers by
regulating the apoptotic machinery of the cell. More importantly, as discussed in
Chapter 8
, there is ample data available showing that NF-
κ
B hyperactivation con-
tributes to inflammation-associated cancer and many severe chronic (inflammatory)
diseases, such as rheumatoid arthritis, SLE, multiple sclerosis, insulin resistance,
and Alzheimer's disease [1-3]. This realization has led to an explosion of interest
in NF-
κ
B signaling from basic researchers and pharmaceutical companies, with a
significant part of their concerted effort aimed at the development of drugs that
specifically inhibit NF-
B signaling. Considering the rapidly expanding array of
strategies used to inhibit NF-
κ
B signaling, here we can only give a bird's eye view
of what we consider significant, rather than an exhaustive list of all the proposed
strategies of inhibiting NF-
κ
B activity. For a more complete list, we will direct the
reader to excellent reviews where appropriate.
Out of necessity, nature has provided several ways to attenuate NF-
κ
κ
B activity,
since continuous NF-
B signaling can be severely detrimental, leading to chronic
inflammatory diseases, the development of autoimmunity, and even hyperplasia. To
prevent sustained NF-
κ
B activation, the cell has several endogenous molecules
available that will downregulate the NF-
κ
B pathway. In addition, investigators have
found that viruses and bacteria encode proteins that inhibit NF-
κ
B signaling as a
means of preventing an immune response that would otherwise eradicate the viral
or bacterial threat.
Many drugs (natural and synthetic) in use for decades to inhibit inflammation
or malignancy have been shown recently to modulate NF-
κ
B activity. Based on these
findings, some of these drugs are being modified on the molecular level to yield
more potent inhibitors. We will give examples of drugs (or drug classes) that are
most interesting from a clinical point of view.
Instead of direct intervention in the NF-
κ
B pathway, researchers are trying to
modulate other pathways that mediate the adverse effects of constitutive NF-
κ
κ
B
activation. Additionally, the application of antibodies against NF-
κ
B-activating
cytokines and soluble receptors for NF-
B-activating cytokines are now being
applied clinically to decrease the induction of NF-
κ
B signaling.
The lessons learned from nature and from clinical experience with drugs that
are known to modulate NF-
κ
B activity have been very helpful in rationally designing
synthetic compounds, peptides, DNA oligonucleotides, and RNA molecules that can
interact with and downregulate the NF-
κ
κ
B pathway.
10.2
NATURE'S WAY OF INHIBITING NF-
κ
B
NF-
B plays a pivotal role in eliciting a strong proinflammatory, proliferative, and
antiapoptotic response. After execution of the essential task, this powerful response
has to be downregulated by endogenous proteins in order to prevent chronic inflam-
mation, autoimmunity, and hyperproliferation. The best known endogenous NF-
κ
κ
B
inhibitors are members of the I
κ
B-family (I
κ
Bs) that can lead to cytosolic seques-
tering of NF-
κ
B, thereby attenuating NF-
κ
B signaling [4]. Here we will discuss
