CYTOKINES IN THE INNATE IMMUNE RESPONSE

Interleukin-1 (IL-1) Tumor Necrosis Factor-a(TNF-a) IL-6

The IL-1 family consists of:
o IL-1a,
o IL-1b and
o IL-1RA (IL-1 receptor antagonist).
IL-1a and IL-1b
o are proinflammatory cytokines produced by monocytes and macrophages.
o . IL-1a and IL-1b exhibit the same activities in many test systems and share
about 25 percent sequence
o homology.
IL-1 production may be induced by the presence of:
o Microbial pathogens,
o bacterial lipopolysaccharides,
o or other cytokines
IL-1a
o remains intracellular within monocytes and macrophages and is rarely
found outside these cells.
o can be released after cell death and can help attract inflammatory cells to
areas where cells and tissues are being killed or damaged.
IL-1b
o is responsible for most of the systemic activity attributed to IL-1,
including:
fever,
activation of phagocytes,
and production of acute phase proteins.
o It is cleaved intracellularlyto an active form that is then secreted by
monocytes.
IL-1 acts as an endogenous pyrogen
o and induces fever in the acute phase response through its actions on the
hypothalamus.
The hypothalamus acts as the thermostat for the human body, and IL-
1 sets the thermostat at a higher level.
Elevated body temperatures may serve to:
o inhibit the growth of pathogenic bacteria and viruses and
o also increases lymphocyte activity.
Additionally, IL-1 induces the production of:
o vascular cell-adhesion molecules as well as
o chemokines and
o IL-6.
These chemokines and cell-adhesion molecules attract and assist leukocytes
to enter the inflamed area by a process known as diapedesis (see Chapter 1).
IL-1
o also induces the production of colony stimulating factors in the bone
marrow,
thereby increasing the available number of phagocytic cells that can
respond to the damaged tissues.
IL-1RA
o is also produced by monocytes and macrophages.
o It acts as an antagonist to IL-1 by blocking the IL-1 receptor and limiting
the availability of the receptor for IL-1.
o This helps to regulate the physiological response to IL-1 and turn off the
response when no longer needed.
TNF -> were first isolated from tumor cells and were so named because they induced lysis in these
cells.
TNF-a
is the most prominent member of the TNF superfamily,
which consists of at least 19 different peptides that have diverse biological functions.
exists in both membrane-bound and soluble forms and
causes:
o vasodilation and
o increased vasopermeability.
The soluble form
o is derived from the membrane-bound form by proteolytic cleavage with TNF-a-converting
enzyme.
o is unstable and
o has a short halflife.
Membrane-bound TNF-a
o can mediate all the cytotoxic and inflammatory effects of TNF through cell-to-cell contact.
The main trigger for TNF-a production is:
o the presence of lipopolysaccharide, found in gram-negative bacteria.
TNF-a secreted by activated monocytes and macrophages can activate T cells through its ability to
induce expression of :
o MHC class II molecules,
o vascular adhesion molecules, and
o chemokines, in a similar manner to IL-1.
These actions enhance antigen presentation and activate T cells to respond to the pathogen that
triggered the initial inflammatory response.
However, when secreted at higher levels, TNF can Have:
o deleterious systemic effects
o , leading to septic shock.
This condition results from large amounts of TNF secreted in response to gram-negative bacterial
infections, causing a
o decrease in blood pressure,
o reduced tissue perfusion
o , and disseminated intravascular coagulation. The latter may lead to uncontrolled bleedin
TNF-a and IL-1 are both present in :
o rheumatoid synovial fluids and
o synovial membranes of patients with rheumatoid arthritis(RA).
Studies with anti-TNF-a and anti-IL-1 demonstrate that:
o TNF-a is the central mediator of pathological processes in RA and other inflammatory illnesses
such as Crohns disease.
TNFR1 (TNF receptor 1)
o is constitutively expressed on most tissues,
o binds soluble TNF-a, and
o is the primary mediator of TNF-a signal transduction in most cell types.
TNFR2
o is usually expressed in epithelial cells and cells of the immune system and
o is activated by the membrane-bound form of TNF-a.
Overall, TNF-a activity is at least partially regulated by soluble forms of both TNF receptors.
o These act to bind excess TNF-a and, combined with the short half-life of the soluble form, serve to
limit the cytokines signaling activity.
is a single protein produced by both lymphoid and
nonlymphoid cell types.
It is part of the cytokine cascade released in response
to lipopolysaccharide and
plays an important role in acute phase reactions and
the adaptive immune response.
IL-6 is expressed by a variety of normal and
transformed cells, including:
o T cells
o , B cells,
o Monocytes
o and macrophages,
o fibroblasts,
o hepatocytes,
o Keratinocytes
o astrocytes,
o vascular endothelial cells, and
o various tumor cells.
IL-1 primarily triggers its secretion.
This pleiotropic cytokine affects:
o inflammation,
o Acute phase reaction,
o immunoglobulin syntshesis,
o and the activation states of B cells and T cells.
IL-6 stimulates B cells to proliferate and differentiate
into plasma cells and induces CD4+T cells to produce
greater quantities of both pro- and anti-inflammatory
cytokines.
Only one IL-6 receptor has been identified, and it
consists of:
o IL-6Ra (the IL-6-specific receptor) and
o gp130 (the common signal-transducing receptor
subunit utilized by several cytokines).
Binding of IL-6 to the IL-6Ra induces:
o dimerization of gp130 with the a-subunit (Fig. 5
2).
Homodimerization following IL-6 binding causes:
o conformationalvchanges in gp130 that expose
tyrosine residues in the intracellular portion of
the molecule.
Through a seriesvof phosphorylation reactions, genes
for acute phase proteins such as CRP, C3, and
fibrinogen are activated, as is interferon regulatory
factor-1 (IRF-1). B- and T-cell genes are turned on in
the same manner.
Chemokines TGF-B IFN-a and IFN-B
are a family of cytokines that:
o enhance motility and
o promote migration of many types of white blood cells toward the source of the chemokine (chemotaxis).
Most of the chemotactic activity of leukocytes is regulated by the:
o activities of chemokines,
o including the response to infectious diseases, autoimmune inflammation, cancer,
o and the homing of lymphocytes to all the lymphoid tissues.
classified into four families based on the position of N-terminal cysteine residues.
The first group
o the alpha, or CXC, chemokines
o contains a single amino acid between the first and second cysteines.
The second group
o the beta, or CC, chemokines
o has adjacent cysteine residues.
The third group
o the C chemokines
o lacks one of the cysteines. CX3C,
the last (4
th
) major group,
o has three amino acids between the cysteines.
Chemokines play key roles in:
o the initiation and
o development of inflammatory responses in numerous disease processes.
Currently:
o over 40 chemokines and
o 20 chemokine receptors have been identified (Table 51).
Both TNF-a and IL-6 are among the many cytokines that induce chemokine production in the inflammatory response.
Combined with cell adhesion molecules, the chemokines facilitate the :
o extravasation of leukocytes into the tissues.
Leukocytes rolling on capillary endothelial cells activate their chemokine receptors in the presence of chemokines.
This, in turn, activates integrins, or cell adhesion molecules, on leukocytes and leads to firm adhesion to the endothelial
cells.
Shared expression of chemokine receptors among different types of leukocytes allows:
o for the co-localization of multiple cell types to the damaged tissue and
o helps to broaden the response to tissue damage.
The gradient of chemokine concentration enables the leukocytes to:
o migrate between the endothelial cells into the tissue in the direction of increasing chemokine concentration.
The spectrum of chemokines and cytokines expressed in the inflammatory response determines the types of cells that
respond and the genes that are turned on in response to the stimuli.
The types of cell surface receptors expressed by leukocytes are often developmentally regulatedfor example:
o immature T cells possess only the chemokine receptors related to lymphoid tissue homing.
o Only mature T cells express the receptors that allow them to participate in an ongoing immune reaction.
The chemokine receptors CXCR4 and CCR5
o Are utilized by HIV as co-receptors for infection of CD4+ T lymphocytes and macrophages.
Individuals with certain polymorphisms in these chemokine receptors are:
o long-term nonprogressors.
o They remain asymptomatic,
o have normal CD4+ T-cell counts and
o normal immune function, and
o Have low or undetectable viral loads.
The altered protein sequences of the receptors block or diminish the viruss ability to enter the cells and thereby increase
the infected individuals chances of survival.
The CCR5-32 polymorphism
o is a 32 bp deletion in the CCR5 gene and
o is the most important of the host resistance factors.
Homozygous individuals are protected from HIV infection while heterozygous persons exhibit longer periods from
infection to AIDS development.
In addition, certain polymorphisms in:
o SDF1 (the ligand for CXCR4) and
o RANTES (the ligand for CCR5)
can block the viruss ability to bind to and enter T cells and can delay the progression to full-blown AIDS.
The transforming growth factor beta (TGF-B) superfamily
is composed of three isoforms: TGF-B1,B2, and B3.
was originally characterized as a factor that induced growth
arrest in tumor cells.
Later, it was identified as a factor that induces antiproliferative
activity in a wide variety of cell types.
Active TGF-B is primarily a regulator of:
o cell growth,
o differentiation,
o apoptosis,
o migration, and the
o inflammatory response.
Thus, it acts as a control to help down-regulate the
inflammatory response when no longer needed.
In the immune response:
o TGF-B functions as both an activator and an inhibitor of
proliferation,
o depending on the developmental stage of the affected cells.1
TGF-B:
o regulates the expression of CD8 in CD4CD8 thymocytes
and
o acts as an autocrine inhibitory factor for immature
thymocytes.
It inhibits the activation of macrophages and the growth of many
different somatic cell types and functions as an anti-inflammatory
factor for mature T cells.
blocks the production of IL-12 and strongly inhibits the induction
of IFN-Y.
In addition, the production of TGF-B by T helper 2 cells is now
recognized as an important factor in the establishment of oral
tolerance to bacteria normally found in the mouth.
In activated B cells, TGF-B
o typically inhibits proliferation and may function as an
autocrine regulator to limit the expansion of activated cells.

Interferons
were originally so named because they interfere with
viral replication.
However, it is the type I interferons consisting of IFN-
a and IFN-B that function primarily in this manner.
o These interferons are produced by dendritic cells
and
o induce production of proteins and pathways that
directly interfere with viral replication and cell
division.
o this helps limit the infection to one relatively small
area of the body.
Type I IFN activates
o natural killer cells and
o enhances the expression of MHC class I proteins,
thus increasing the recognition and killing of virus-
infected cells.
o also active against certain malignancies and other
inflammatory processes.
For instance, IFN-B is efficacious in treating
multiple sclerosis, although the exact
mechanism of action remains unclear.
IFN-a has been used to treat hepatitis C and
Kaposis sarcoma, as well as certain leukemias
and lymphomas.