Computational Molecular Biology 2016, Vol.6, No.1, 1-20
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that the actin filament of the cytoskeleton sequesters excess inhibitors to the NFkB pathway regulating the steady
state kinetics (Pogson et al., 2008). Most recently Fagerlund et al. used computational modeling to explain that
NFkB negative feedback is not only dependent on the induction of NFkB pathway but rather it also depends on
the nuclear import and export of IkBα and IkBα-NFkB complex and also on the half life of IkBα (Fagerlund et al.,
2015).
Initiated by Hoffman, computational modeling has come a long way in solving various complex networks in the
NFkB s ignaling pathway using programs such as MATLAB. Hence, computational modeling studies are a very
helpful tool in solving the complex signaling pathways and may provide a better perspective in understanding
cancers and other inflammatory diseases.
3 Inflammation, NFkB and disease
Regulation of the NFkB pathway is essential for cells to changing environmental conditions. Inflammation is
body’s protective response to fight against any injury or infection. Most of our knowledge on inflammation is
derived from studying the signaling pathway mediated by IL-1, TNF (TNFR1 and TNFR2) and Toll Like receptor
families. The inflammatory response is mediated by ac tivated macrophages and other immune cells which
ultimately results in the transcriptional up regulation of TNF-α, IL-1 and proinflammatory cytokines (Landskron
et al., 2014; Popa et al., 2007). Introduced in 2002, a new term “inflammasome” came in the limelight (Martinon
et al., 2002). Inflammasomes are multimeric protein complexes which comprise of danger sensing proteins which
are activated during microbial attack or free radicals. They assemble in the cytosol after sensing pathogen
associated molecular patterns (PAMPs) or damage associated molecular patterns (DAMPs). There are NLRP1,
NLRP3, IPAF and AIM2 type of inflammasome known so far which regulates IL-1β maturation. Inflammasome
mediated pathway is one in many of the pathways used by activated NFkB to signal the cell to produce proteins
related to inflammation. Inflammasome activation is a three step process. Firstly NFkB pathway is initiated in
response to incoming signal. Then, NFkB directs the cells to form protein complexes which would function as
inflammasomes. Lastly, these activated inflammasomes mediate the response by signaling the production of
inflammatory proteins (Guo et al., 2015; Martinon et al., 2002; Rahman et al., 2009). Insufficient inflammation
can result into persistant microbial infection whereas excess of inflammation result in chronic inflammatory
diseases. Chronic inflammation refers to the prolonged low-level state of inflammation which can last from days
to month. Chronic inflammation is associated with almost every chronic disease including cancer and
neurodegenerative diseases (Maqbool et al., 2013; Multhoff et al., 2011; Popa et al., 2007; Rakoff-Nahoum,
2006) . It contributes to cancer pathogenesis by promoting angiogenesis, invasion and metastasis. It also known to
result in resistant to chemotherapy (Koti et al., 2015). During chronic inflammation cells produce a large amount
of deleterious free radicals which interact with DNAand cause DNAdamage by introducing mutations. As long as
the cell is able to escape this condition by either undergoing DNA damage repair or apoptosis cancerous cells do
not develop (Mittal et al., 2014). However, during the state of chronic inflammation there is constant NFkB
signaling which shuts down the DNA repair mechanism and apoptosis. As a result, a large number of mutated
cells aggregate which ultimately transforms into cancer cells. The inflammatory signals block the immune cells to
reach the newly formed cancer cells. These signals promote the invasion and proliferation of malignant cells into
their surroundings. One of the most lethal actions of these cancer cells is that they turn on their own NFkB
pathway therefore taking over the whole tissue repair system of the body. They turn on the similar inflammatory
response in the surrounding tissues (Lawrence, 2009; Tak and Firestein, 2001). Chronic inflammation is also
known to reduce insulin sensitivity of the cells resulting in high sugar levels which leads to metabolic disorders,
diabetes type II and obesity (Luft et al., 2013). Under normal conditions, NFkB is constitutively expressed in a
few cell types such as neurons and inactive in other cells, but in cancer cells it remains constitutively active
(Mauro et al., 2009; Nakshatri et al., 1997). A defective TNFR2 system gives rise to many autoimmune diseases.
High levels of TNFR2 are associated with rheumatoid arthritis, Crohn’s disease (Sandborn, 2001) and systemic
lupus erythematosus (Aringer and Smolen, 2008) . Receptor shedding may be a way to decrease the concentration
of TNFR2 in the cell which will ultimately lower down the inflammatory response (Deng et al., 2015; Xanthoulea
