Cytokines Flashcards
What is a cytokine?
Proteins secreted by cells that mediate the functions of the immune system.
soluble proteins/glycoproteins
regulate the intensity and duration of the immune response
necessary for leukocyte activation
Cellular sources of cytokines
Lymphocytes (originally called lymphokines)
Monocytes/macrophages (originally called monokines)
All cells of innate immunity
All cells of adaptive immunity
Other cells, e.g., endothelial and epithelial cells
Term interleukin refers to fact that many
proteins are produced by one immune cell to act on neighboring cells (i.e., they work between cells)
Term cytokine is the preferred name because it is the most i
nclusive term.
Cytokines that attract cells are called
chemokines.
Cytokine secretion is
brief and self-limited
Cytokine action is
pleitropic and redundant
Cytokines influence
each other
Cytokines can act
locally and systemically
Cytokines initiate their actions by
binding to specific membrane-bound receptors.
Cytokine receptor ligation leads to
gene expression which alters cellular function.
Cytokines increased hours after
challenge.
mRNA is unstable, so expression is transient
Cytokines can act in
synergy
Cytokines can be
antagonistic to each other
Cytokines Primarily Involved in Innate Immunity
Typically these cytokines impact inflammation
Proinflammatory
TNF-α, IL-1α/β, IL-6, IL-12, IFN (as well as many others)
Anti-inflammatory
IL-10, TGF-β
Innate immunity Importance for immunity:
Activate immune cells
Recruit immune cells to site of infection
Help to activate adaptive immune response
TNF-α
The principal mediator of the acute inflammatory response to Gram-negative bacteria (as well as other infectious microbes), endotoxic shock, and chronic inflammatory conditions.
Many cells can make TNF-α, but
monocytes, macrophages, NK cells, some DC cells, and T cells are the primary sources.
Stimulates the recruitment of
neutrophils, monocytes, and activated T cells to site of infection.
Activated leukocytes have increased expression of
selectin ligands first and can have increased expression of integrins later—TNF-α can facilitate this
TNF-α increases the expression of
E-selectin and then P-selectin
Low concentrations of TNF-α in blood plasma (i.e., approximately 1 nM) can be
beneficial
Participates in cellular recruitment
Participates in activation of macrophages and T cells
Moderate concentrations of TNF-α in blood plasma (i.e., ~10-50 nM) can have
systemic effects, but they are often beneficial systemic effects
Acute phase proteins are increased (see slides for IL-6)
Migration of cells out of the bone marrow is increased
Fever (and sickness) develops
High concentrations of TNF-α (>100 nM) in blood is
BAD.
Reductions in muscle contractions (leads to hypotension)
Immune cells are sticky leading to blood clots in circulation
Glucose release from liver becomes depleted
IL-1
Two forms, IL-1α and IL-1β (only share 30% homology)
Bind to the same receptor (i.e., the IL-1 receptor)
Have same biological function
Many cells produce IL-1, but primary producers are
mononuclear phagoyctes (i.e., monocytes/macrophages, dendritic cells) and neutrophils Shares many of the same effects with TNF-α
IL-6
Primarily produced by macrophages and T cells (but many other cells can make it).
Involved with induction of inflammatory response (can have similar effects as TNF-α and IL-1).
But, primarily involved with induction of the acute phase response.
The Immune System Communicates with the Brain Through the Production of
Cytokines
IL-12
Primary mediator of innate immune response to intracellular pathogens
Important for the generation of adaptive immune response that would be appropriate for intracellular pathogens (i.e., T helper cell type 1 (Th1) immunity
IL-12 Importance for Innate Immunity is in
Activation of Macrophages
IL-12 Induces the Production of
IFN-γ.
IFN-γ can be produced by:
NK cells, T helper cells, and Cytotoxic T cells.
Macrophages that phagocytose a pathogen can kill the pathogen when they are also exposed to IFN-γ.
Cytokines involved with Th1 type immunity
IFNγ (and IL-2)
Cytokines involved with Th2 type immunity
IL-4, IL-5, IL-13 (and IL-2)
IL-2
IL-2 is needed for growth, survival, and differentiation of T cells (needed for BOTH T helper cells and cytotoxic T cells).
Clonal expansion is IL-2 dependent
IL-2 is produced by T helper cells (a.k.a. CD4+ T cells)
Adaptive immunity most effective against intracellular pathogen:
T heper type 1 (Th1).
Involves macrophages and cytotoxic T cells
Involves IFN-γ (and IL-2)
Adaptive immunity most effective against extracellular pathogen:
T helper type 2 (Th2).
Involves antibodies produced by B cells, mast cells, and eosinophils
Involves IL-4, IL-5, IL-13 (and IL-2)
One function of IFN-γ is to facilitate the ability of macrophages to
kill intracellular microbes
Enhance microbicidal activity
Increase production of opsonizing antibodies
In addition, IFN-γ will:
Increase
antigen presentation (so that cytotoxic T cells can kill intracellular pathogens)—we’ll learn about this next week.
Th2 cytokines/immunity
Immune response primarily involved with protection against extracellular pathogens (e.g., parasites).
IL-4
It is a key Th2 cytokine. It can induce naïve Th cells to differentiate into Th2 cells (i.e., Th cells that will produce more IL-4 or IL-13 or IL-5) The primary stimulus for Ig class switching to IgE.
IL-13
Very similar to IL-4 (both functionally and structurally).
Primary job is to help induce Ig isotype switching to IgE.
Also stimulates mucous production in gut and lung.
IL-5
Primary job is in eosinophil differentiation, proliferation, and activation.
Eosinophils are necessary for protection against parasites
IL-10 is an
inhibitory cytokine
IL-10 Produced by
macrophages, dendritic cells, T helper cells.
Its primary function is to inhibit production of IL-12 by activated macrophages (and dendritic cells).
Essentially chemokines are
chemotactic cytokines.
They are small, soluble proteins
They work primarily in paracrine or endocrine manner
There are a lot of them (over 50 identified)
Chemokines make up the largest category of cytokines
Chemokines Primary role is to
regulate migration of cells to peripheral tissues or to lymph nodes.
Receptors
All have at least 1 extracellular binding domain and at least 1 intracellular signaling domain.
5 receptor families for cytokines and chemokines
Type I cytokine receptor
Type II cytokine receptor
TNF receptor family
IL-1 receptor family
7 transmembrane G-protein-coupled receptors
Families are distinguished by extracellular cytokine-binding domains and intracellular signaling domains
Type I cytokine receptor
Receptors for IL-2, IL-4, IL-5, IL-6, IL-12, and IL-13 are in this family
Signal via Jak-STAT cascades
Type II Cytokine Receptors
Receptors for IFN-γ and IL-10
Signals via Jak-STAT
Similar to Type I except that extracellular cytokine binding domain differ
TNF Receptor Superfamily
Receptor for TNF-α belongs to this family (as well as many other receptors for things like growth factors and other proteins)
Multiple signaling cascades can be induced, can lead to transcription factor expression OR apoptosis
IL-1 Receptor Family
Receptor for IL-1 belongs to this family
Signaling has many similarities to the Toll-like receptors
Conserved cytosolic sequence, called the Toll-like/IL-1 recptor (Tir) domain that activates IRAK. IRAK initiates the signaling cascade.
7 transmembrane G-protein-coupled receptors
All the chemokine receptors.
7 transmembrane receptor
Signaling via G-proteins
Rapid and transient signaling cascade
