NFKB PATHWAY
Presented by
Dr Benazir
I st year PG
Department of AEM
THE CANONICAL NF-kB PATHWAY
The canonical NF-kB pathway has been defined primarily in
response to TNFa and IL-1 signaling, prototypical
proinflammatory cytokines that have important roles in the
pathogenesis of chronic inflammatory diseases such as
1.Rheumatoid arthrtitis (RA),
2.Inflammatory bowel disease (IBD),
3.Asthma, and
4. Chronic obstructive pulmonary disease (COPD).
Proinflammatory cytokines are signaling molecules that trigger
inflammation. They are released by immune cells like
macrophages and helper T cells.
Cytokines play an important role in the functioning of the
immune system. After binding to specific receptors these
proteins are involved in all stages of the cell cycle, i.e. in the
processes of cell proliferation, growth, differentiation and
apoptosis.
They play a role in the course of inflammation, and they
regulate every part of the immune response. The cytokines
exhibit pleiotropic and redundancy action and can also interact
in a synergistic, additive, or antagonistic way.
The cytokines include: interleukins, interferons, chemokines,
grow factors, tumor necrosis factor family. Due to the nature of
the action, the following can be distinguished among them, e.g.
Network of cytokines formed during the inflammatory
response consists of a number of cytokines which are
mediators of the immune response.
They stimulate the processes necessary for tissue healing
(anti-inflammatory cytokines) and cause their degradation
(pro-inflammatory cytokines).
Chronic inflammation may play a significant role in the
formation and the further development of cancer, and some
cytokines, e.g. IL-6, IL-8, TNF, modify the immune response and
are associated with angiogenesis and metastasis
Increased secretion of particular pro-inflammatory cytokines
by the tumor:
IL-1 in gastric and ovarian cancer,
IL-6 in prostatic, kidney, cervix, ovary, colon carcinoma,
melanoma, lymphoma B-cell disease, multiple myeloma,
lymphoma, Hodgkin’s lymphoma,
TNF in ovarian cancer,
IL-8 in pancreatic cancer, prostate cancer, colon cancer,
stomach, liver, ovarian, squamous cell carcinomas of the head
and neck, melanoma.
Cytokines that are involved in the inflammatory response are,
Functional Significance of Apoptosis
The purpose of apoptosis is to remove unwanted cells without
causing any stress or damage to the neighboring cells. The
functional significance of apoptosis:
1. Plays a vital role in cellular homeostasis. About 10 million
cells are produced everyday in human body by mitosis. An equal
number of cells die by apoptosis. This helps in cellular
homeostasis
2. Useful for removal of a cell that is damaged beyond repair by
a virus or a toxin
3. An essential event during the development and in adult stage
A large number of neurons are produced during development of
central nervous system. But up to 50% of the neurons are
removed by apoptosis during the formation of synapses
between neurons
Apoptosis is responsible for the removal of tissues of webs between
fingers and toes during developmental stage in fetus.
It is necessary for regression and disappearance of duct systems
during sex differentiation in fetus
Activation of Apoptosis
Apoptosis is activated by either withdrawal of positive signals
(survival factors) or arrival of negative signals.
Withdrawal of positive signals
Positive signals are the signals which are necessary for the long-time
survival of most of the cells. The positive signals are continuously
produced by other cells or some chemical stimulants. Best examples of
chemical stimulants are:
i. Nerve growth factors (for neurons)
ii. Interleukin-2 (for cells like lymphocytes).
The absence or withdrawal of the positive signals activates apoptosis.
Arrival of negative signals
Negative signals are the external or internal stimuli which
initiate apoptosis. The negative signals are produced
during various events like:
1. Normal developmental procedures
2. Cellular stress
3. Increase in the concentration of intracellular oxidants
4. Viral infection
5. Damage of DNA
6. Exposure to agents like chemotherapeutic drugs, X-rays,
ultraviolet rays and the death-receptor ligands
Death-receptor ligands and death receptors
Deathreceptor ligands are the substances which bind with
specific cell membrane receptors and initiate the process of
apoptosis.
The common death-receptor ligands are tumor necrosis
factors (TNFα, TNFβ) and Fas ligand (which binds to the
receptor called Fas).
Deathreceptors are the cell membrane receptors which
receive the death-receptor ligands. Well-characterized death
receptors are TNF receptor-1 (TNFR1) and TNF-related
apoptosis inducing ligand (TRAIL) receptors called DR4 and
DR5
Role of mitochondria in apoptosis
External or internal stimuli initiate apoptosis by activating the
proteases called caspases (cysteinyl-dependent aspartate
specific proteases). Normally, caspases are suppressed by the
inhibitor protein called apoptosis inhibiting factor (AIF).
When the cells receive the apoptotic stimulus, mitochondria
releases two protein materials. First one is Cytochrome C and
the second protein is called second mitochondria-derived
activator of caspases (SMAC) .
Cytochrome C also facilitates caspase activation
Apoptotic Process
Cell shows sequence of characteristic morphological
changes during apoptosis, viz.:
1. Activated caspases digest the proteins of cytoskeleton and
the cell shrinks and becomes round
2. Because of shrinkage, the cell losses the contact with
neighboring cells or surrounding matrix
3. Chromatin in the nucleus undergoes degradation and
condensation
4. Nuclear membrane becomes discontinuous and the DNA
inside nucleus is cleaved into small fragments
5. Following the degradation of DNA, the nucleus breaks into
many discrete nucleosomal units, which are also called
chromatin bodies
7. Finally, the cell breaks into several fragments containing
intracellular materials including chromatin bodies and organelles of
the cell. Such cellular fragments are called vesicles or apoptotic
bodies
8. Apoptotic bodies are engulfed by phagocytes and dendritic cells.
Abnormal Apoptosis
Apoptosis within normal limits is beneficial for the body. However, too
much or too little apoptosis leads to abnormal conditions.
Common abnormalities due to too much apoptosis:
1. Ischemicrelated injuries
2. Autoimmune diseases like:
i. Hemolytic anemia , ii. Thrombocytopenia
3. Neurodegenerative diseases like Alzheimer’s disease.
Common abnormalities due to too little apoptosis:
1. Cancer
2. Autoimmune lymphoproliferative syndrome (ALPS
The NF-kB pathway does indeed regulate proinflammatory
cytokine production, leukocyte recruitment, or cell survival,
which are important contributors to the inflammatory
response.
But, the antiapoptotic functions of NF-kB can both
protect against inflammation, in the case of epithelial cell
survival and mucosal barrier integrity, and also maintain
the inflammatory response through persistent leukocyte
activation.
IL-1 and TNF receptor families and the Toll-like microbial
pattern recognition receptors (TLRs), which belong to the.
IL-1R family. IL-1 and TNFa represent the archetypal
NF-kB activity at sites of inflammation is associated with
activation of the canonical pathway and RelA- or cRel-
containing complexes. There have been several studies
to show proinflammatory cytokine and chemokine production
by disease tissue is NFkB-dependent.
Proinflammatory cytokine production in human atherosclerotic
plaques is also NF-kB-dependent.
But the association of NF-kB activity and inflammatory
disease is not easy to interpret because both pro and anti-
inflammatory mediators are produced during inflammation and
the balance between these factors is likely to dictate disease
progression.
Cre/lox gene targeting technology (Sauer 1998) has made it
possible to specifically target NF-kB activation in different cell
lineages, an approach that has shown that NF-kB plays a
tissue-specific role in the inflammatory response. The deletion
of IKKb or IKKg in intestine epithelial cells clearly revealed a
cytoprotective role for NF-kB.
The resulting breakdown in epithelial barrier integrity leads to
Increased inflammation because of commensal bacteria
activating tissue macrophages.
The specific targeting of NF-kB in lung epithelial cells did not
apparently affect the integrity of the epithelium but impaired
inflammation by inhibiting the expression of proinflammatory
cytokines and chemokines.
Expected role of NF-kB in proinflammatory gene induction
during the onset of inflammation but also showed a role for
NF-kB inexpression of anti-inflammatory genes and
induction of leukocyte apoptosis during the resolution of
inflammation.
Inhibition of NF-kB during the resolution of inflammation
prolonged inflammatory response and inhibited apoptosis, in
conflict with the generally accepted view that NFkB was
antiapoptotic in inflammatory cells.
NF-kB can have anti-inflammatory roles by directly inhibiting
expression of proinflammatory genes and by manipulating the
expression or activity of anti-inflammatory cytokines such as
IL-10. Apoptosis is an essential mechanism that prevents
prolonged inflammation.
Neutrophil apoptosis during acute inflammation and activation
induced cell death (AICD) of antigenspecific T cells are
important mechanisms that limit inflammatory and immune
responses.
NF-kB may have a proinflammatory role by enabling prolonged
macrophage activation. This would increase innate resistance
to infection and therefore block pathogen-induced
inflammation during infection.
The involvement of NF-kB in both pro- and antiapoptotic
function in T cells. Inhibiting NF-kB reduced FasL induction and
apoptosis in T cells but increased glucocorticoid-mediated
apoptosis.
THE ALTERNATIVE NF-kB PATHWAY
The alternative NF-kB pathway is characterized by the inducible
phosphorylation of p100 by LIKKa, leading to activation of
RelB/p52 heterodimers. The upstream kinase that activates
IKKa in this pathway has been identified as an NIK (NF-kB
inducing kinase)
Gene disruption studies have shown that IKKg and IKKb
subunits are required for IkBa phosphorylation and canonical
NF-kB activation, whereas the alternative pathway is
independent of both IKKg and IKKb.IKKa activation was shown
to limit the inflammatory response during bacterial infection
and inhibit canonical NF-kB activation.
Subsequent studies also showed that IKKa negatively regulates
IKKa-deficient macrophages showed increased expression of
proinflammatory cytokines and an enhanced ability to
stimulate T-cell proliferation
IKKa functions to promote the resolution of inflammation by
switching off the canonical NF-kB pathway, but regulates the
development of adaptive immunity through the alternative
pathway.
Although inflammation is classically considered to
prime the adaptive response, for example through promoting
DC maturation, the resolution of inflammation is required to
avoid tissue injury while supporting the development of
immunological memory..
Cross talk between the alternative and canonical NF-kB
pathways may regulate the transition from acute
inflammation to antigen-specific immune responses that
drive autoimmune diseases such as RA and multiple sclerosis
Ultimately, inhibition of IKKa may represent a therapeutic
target to prevent autoimmune inflammation while maintaining
innate immunity.
Thank you
