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The
cytokine network
Cytokines have over time been given many different names most
of which are still in use. You may come across the words lymphokines
(cytokines produced by lymphocytes), leucokines (cytokines produced
by all white blood cells), chemokines, monokines, interferons,
interleukins and lymphotoxins. Cytokine is the popular umbrella
term for any kind of communication molecule regardless of what
cell produces it or what it does.
There are a plethora of cytokines and we keep finding new ones
all the time. They are small polypeptide molecules less than 80kilodaltons
in weight that may or may not be glycosylated. They have very
important roles in a whole range of body functions from general
maintenance through regulating inflammatory responses to directly
interfering with invading pathogens.
Cytokines are produced in large amounts by many cells but are
very potent even at minute concentrations. Their action is usually
limited to affecting other cells in the local area of their production
but they can also have an overall systemic effect acting much
like hormones. Cytokines act on other cells by bonding to cytokine
receptors on the surface of cells. We assume that each cytokine
has its own particular cytokine receptor, but only some of the
cytokine receptors have been identified so far. The difficulty
in finding cytokine receptors is that there are so few of them
on each cell, between 10 and 10,000. With so few it is difficult
to purify them and identify their structure. Cytokine binding
to cell receptors can induce a significant change in cell activity
and production of proteins.
Different cytokines have different actions on the same cell.
However, there is a large degree of overlap between the action
of one cytokine and another. Cytokines interact first to stimulate
and regulate production of more cytokines and then by altering
cell activity. Attempting to work out how all the different cytokines
work together is practically impossible. The functions of each
cytokine is generally worked out by isolating each one in a cell
culture and monitoring the effects on cells. We supplement this
information with observations on cytokine concentrations in people
with different disease states, using antibodies to neutralize
different cytokines in animals and monitoring the results, administering
injections of individual cytokines and observing their effects,
and using drugs that knock out production of cytokines. Obviously,
none of these methods are a good model of what happens with multiple
cytokines in the human body but so far its the best method available
of working out cytokine activity.
IL-1, (IL=interleukin) IL-2, IFNs (interferons), and TNF (tumor
necrosis factor) are the key groups of cytokines that carry out
the most important functions. There are actually two subtypes
of IL-1, IL-1alpha and IL-1beta but they have pretty much the
same functions. IL-1 is a key mediator in amplifying many immunological
actions. There is always a slow release of IL-1 into the body
and the key producers are macrophages. IL-1 concentration increases
rapidly when tissue is damaged or threatened by pathogens. IL-1
acts directly on target cells and also promotes the production
of other cytokines that further stimulate the immune system. IL-1
can protect cells against the effects of radiation, encourage
proliferation of immune cells, and stimulates T cells into a responsive
state. Radiation protection comes from IL-1s ability to stimulate
cells into making superoxide dismutases which are neutralizing
molecules against highly destructive superoxide radicals that
radiation creates in body tissues.
IL-1 is very similar in its actions to TNF and TNF acts in synergy
with IL-1. TNF alpha is produced mostly by macrophages in response
to infection by bacteria and other pathogens. TNF promotes the
production of more cytokines including IL-1. TNF will enhance
the stimulation of T and B cells and other immune system cells
to make a response to antigenic challenge more potent. It also
increases expression of MHC class I and II molecules and so improves
antigen presentation. TNF is an anti-viral cytokine. It inhibits
of RNA viruses and DNA viruses such as herpes simplex. Herpes
simplex infection will trigger release of TNF from macrophages.
TNF acts on viral infected cells and helps in their destruction
and break down.
As the name suggests TNF has anti tumor properties. Its ability
to increase the activity of Tc cells is important in tumor destruction
but it also has a selective affect on the blood system in tumors
reducing the vasculature and effectively helping to slow down
or even reverse tumor growth by starving the cancer cells of the
large amounts of nutrients they require for the continuous cell
division.
However, the properties of TNF can also be a disadvantage too.
TNF can adversely affect endothelial cells that make up our blood
vessel walls. This may be good in combating tumors but bad for
healthy tissue. Endothelial cells normally have anticoagulant
properties. You don't want blood clots forming in healthy blood
vessels. However, TNF does promote blood clotting and constriction
subsequent restriction of the blood flow. TNF may also promote
adherence of some immune system cells to the surface of blood
vessels and cause production of oxygen radicals which destroy
the blood vessel and surrounding tissue. This may happen if there
is prolonged release of TNF at high concentrations. For example,
TNF is a key mediator of tissue destruction in bacterial septicaemia.
The term interferon covers a multitude of sins. There are three
main types of IFN, IFNalpha, IFNbeta and IFNgamma. Each type of
interferon can be structurally quite distinct from the other two.
Within each of these types are several subtypes, IFNalpha has
at least 15 subtypes and we still keep finding more variants.
IFNs are produced by a wide range of cells when under attack
from viruses and other non-self pathogenic antigens. IFNgamma
is mostly released by activated T cells and so takes longer to
enter the system and exert its effects compared to IFNalpha or
beta. IFNgamma is by far the most potent class of IFN. All IFNs
act largely in synergy with IL-1 and TNF to promote resistance
to pathogenic attack. IFNs promote expression of MHC class I and
II molecules improving antigen presentation. IFNs will activate
T cells and macrophages into their destructive and phagocytic
abilities against infection. IFNs can also directly limit viruses
by blocking their multiplication. IFNs stimulate cells to produce
two enzymes called kinase and adenyl synthetase. Kinase blocks
production of proteins from reading gene codes and synthetase
acts to cut up RNA, which is the gene coding material used by
many viruses. While this activity is largely antiviral the enzymes
do not discriminate between blocking viral replication or our
own cell replication.
When you have a fever and feel tired during an infection, it
is the result of IFNs and IL-1 acting together on the brain. Fever,
is of course an increase in body temperature. Many pathogens are
temperature sensitive and fever helps make the body an unfavorable
environment for some infectious agents to survive. Sleep helps
in conserving energy, increasing immune activity and encourages
repair of damaged tissues.
The
Th1 - Th2 type cell response and cytokines
Previously we have discussed different types of T cells those
that are cytotoxic (Tc, CD8) and those that are helper (Th, CD4)
cells. We also briefly mentioned T suppressor (Ts) cells. Ts cells
act as a brake on the immune system, they help restrain the activities
of Tc and Th cells. Ts cells are important, without them any immune
response the system made to a pathogen would spiral out of control.
Once a pathogen or other threat is removed from the body by the
immune system the inflammation must be switched off. If it is not
the inflammation could continue indefinitely feeding on itself even
though the pathogen may no longer be present to act as a trigger.
This could result in development of an autoimmune response. Suppressor
cells operate to help switch off an inflammatory response once a
pathogen is removed from the system.
Suppressor cells are not a unique line of T cells. They were originally
identified as CD8 cells and so part of the Tc cell line. However,
recently it has been suggested that Th cells can also be suppressor
cells. Two types of Th cell response has been identified designated
Th1 type and Th2 type response. The different responses are identified
by measuring the type of cytokines that Th cells produce. When Th
cells are involved in inflammation and helping Tc cells destroy
a pathogen they are making a Th1 type response. This involves producing
one or more cytokines such as; IL-1, IL-2, IL-6, IL-12, TNFalpha,
TNFbeta, and IFNgamma. These cytokines are very stimulating for
Tc and more Th cells. These cytokines promote even more inflammation
and encourage an ever increasing potent reaction against a pathogen.
Once a threat diminishes and a pathogen has been destroyed the Th
cells gradually switch to a Th2 type response that involves production
of cytokines like; IL-4, IL-10 and TGFbeta. These cytokines deactivate
Tc and Th cells and so down regulate an inflammatory response and
return the T cells to a resting state.
Cysteine rich TGFbeta is arguably the most important suppressor
cytokine identified so far. It promotes suppressor cells and it
inhibits production of inflammatory cytokines like IFNgamma and
IL-2. It's mainly produced by the T cells themselves but can be
found in a range of cell types. It is found in the thymus but circulating
T cells in the blood are the main source. TGFbeta is unique among
cytokines as being secreted from cells that are in an inactive state.
It is released in an inactive form that has to be cleaved by an
enzyme (perhaps a protease) before it becomes active.
It has been suggested that alopecia areata is a Th1 type response
to the hair follicle and some investigators believe they can push
the Th cells into a Th2 type response using contact sensitizing
treatments like DPCP (diphenylcyclopropenone). Sensitizers like
DPCP do not reduce inflammation, quite the reverse, they increase
numbers of T cells in an inflamed area. The increase in T cell numbers
seems to be due to an increase of largely CD8 Ts cells and CD4 Th2
type responding cells. This influx of suppressor and down regulator
cells may be strong enough to block other cells responding to the
hair follicles. One day it may be possible to skip the use of sensitizing
treatments and apply the appropriate down regulating cytokines directly
to the inflamed areas.
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