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84 Cards in this Set

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What are cytokines?
Small secreted proteins or glycoproteins. Their are about 200 known cytokines.
How do cytokines act on target cells?
They act on target cells by binding specific membrane receptors and altering gene expression via 2nd messengers. Usually involves tyrosine kinase cascades.
Name 3 activities that cytokines play a role in.
They mediate immunity, inflammation, and hematopoiesis.
When are cytokines produced?
They are produced de novo (only if required) in response to an immune stimulus.
Do cytokines have a short or long half-life? What does this mean?
They have a short half-life. They are potent. They are active in picomL.
Do cytokines function in innate or adaptive immunity?
Cytokines function in innate and adaptive immunity.
'Cytokine' is a general name. List 4, more specific, names that they may be referred to as.
1. Lymphokine (made by lymphocytes)

2. Monokine (" " monocytes)

3. Chemokine (have chemotactic activities)

4. Interleukin (made by one leukocyte and act on other leukocytes)
List 5 characteristics of cytokines.
1. Pleiotropy

2. Redundancy

3. Synergy

4. Antagonism

5. Cascade induction
What does the characteristic of pleiotropy refer to?
Cytokines are able to act on different cell types. Receptors just need to be available.
Cytokines display the characteristic of redundancy. Explain.
Similar functions can be stimulated by different cytokines. So if you are lacking one another could do it.
Cytokines display the characteristic of synergy. Explain.
Two or more cytokines can act together.
Cytokines display the characteristic of antagonism. Explain.
Cytokines can cause opposing activities.
Cytokines may be involved in cascade inductions. Explain.
One cytokine can stimulate its target cells to make other cytokine by signaling cascades.
Describe the autocrine action of cytokines?
When a cell makes both cytokines and receptors for those cytokines.
Describe the paracrine action of cytokines?
When cells produce cytokines that target nearby cells.
Describe the endocrine action of cytokines?
When Th produce cytokines that are transported into the blood stream and targets distance cells (like hormones).
List the principal producers of cytokines.
Th cells, macrophages, and dendritic cells.
How many proteins have cytokine activity?
More than 200 proteins have cytokine activity.
What do most cytokines stimulate?
Most stimulate immune cell proliferation and differentiation. (This is not the only effects that they may have, such as their role in cell death)
Do cytokines typically act alone?
No, they tend to act together. They rarely act alone. Target cells are exposed to a milieu containing a mix of cytokines.
Cytokine roles are ? and ?. They are required for the ? response.
Cytokine roles are varied and wide. They are required for the immune response.
Cytokines promote activation, differentiation, and proliferation. They also play a role in the cell death of what cells?
Of T cells, B cells, macrophages, dendritic cells, NK cells, and other leukocytes.
List the 4 cytokine families.
1. Hematopoietin

2. Interferon

3. Chemokine

4. Tumor necrosis factor
List the five cytokine RECEPTOR families. What varies between them?
1. Ig superfamily

2. Class I (hematopoietin)

3. Class II (Interferon)

4. TNF

5. Chemokine (very different from rest)
List 3 Ig superfamily receptors.
1. IL-1R (Type 1)

2. IL-1R (Type 2)

3. IL-18
IL-1R (type 1) of the Ig superfamily receptors are expressed on what cells?
They are expressed on many cell types.
IL-1R (type 2) of the Ig superfamily receptors are expressed on what cells?
They are expressed on B-cells.
IL-18 or the Ig Superfamily Receptors is related to what? Explain. What is this an example of?
IL-18 is related to IL-1 structurally. It has similar function and uses the same receptor family. This is an example of redundancy.
Describe the overall general characteristics of the Ig superfamily group of receptors.
It is a large extracellular motif held together by disulfide bonds (one of these are transmembrane).
List 4 ligands associated with the Ig superfamily receptors?
1. IL-1

2. M-CSF

3. C-Kit

4. IL-18
The Class I (Hematopoietin) cytokine receptor family is comprised of dimers or trimers?
They are composed of either one.
Which of the cytokine receptor families is the best characterized?
Class I (hematopoietin) receptors.
How many subunits do the Class I (hematopoietin) receptors have? List them.
2 subunits

1. Cytokine specific subunits

2. Signaling transducing subunits
Class I (hematopoietin) receptors have conserved ? sequences. They also have conserved ? and an ? domain.
They have conserved Trp-Ser-X-Trp-Ser sequences. They also have conserved cysteines and an extracellular domain.
If a Class I (hematopoietin) Receptor is a dimer one of the subunits is specific for ? and the other is for ?.
One is specific for transmembrane moiety and the other one is signal transducing.
List the ligands associated with Class I (hematopoietin) receptors.
IL-2 thru IL-7

IL-9

IL-11 thru IL-13

IL-15

GM-CSF

G-CSF

LIF

Growth Hormone Prolactin
The Class II (INF receptor family) has a conserved ? motif.
The class II (interferon receptor family) has a conserved CCCC family.
List the key ligands of the Class II (INF receptor family).
1. IFN-alpha

2. IFN-beta

3. IFN-gamma

4. IL-10
The TNF receptor family has how many extracellular domains?
It has 4 extracellular domains. This is a large extracellular motif.
List the ligands associated with the TNF receptor family?
1. TNF-alpha

2. TNF-beta

3. CD27L

4. CD30L

5. CD40L

6. Nerve growth factor (NGF)

7. FAS
The chemokine receptor family is structurally ? from the other families.
The chemokine receptor family is structurally different from the other families.
The chemokine receptor family has 7 ? ?.
The chemokine receptor family has 7 transmembrane helices.
The chemokine receptor family interacts with what protein that the other receptor families don't interact with?
The chemokine receptor family interacts with G-protein.
What is a general rule of thumb about 7 transmembrane helices?
7 transmembrane helices usually indicate an association with G-proteins.
The chemokine receptor family looks more like a ? receptor.
The chemokine receptor family looks more like an acetylcholine receptor.
Some of the ligands of the chemokine receptor family are under intense investigation for the tx of what? List them.
Intense investigation for Asthma drugs.

IL-8

RANTES

MIP-1
The best known cytokine receptor is ?.
The best known cytokine receptor is IL-2R. (the 'R' stands for 'receptor')
IL-2R plays a central role in what?
IL-2R plays a central role in the proliferation of T-cells.
IL-2R occurs in how many different forms? These different forms exhibit different what?
IL-2R occurs in 3 forms exhibiting different affinities for IL-2.
The IL-2R-alpha form of IL-2R is only expressed by what cells.
The IL-2R-alpha form of IL-2R is only expressed by activated T-cells (TAC; CD25)
List the steps of signal transduction by most class I and class II cytokine receptors.
1. The receptor subunits dimerize upon the binding of a cytokine

2. Activation of JAK tyrosine kinases by phosphorylation

3. Activated JAKs phosphorylate tyrosine residues forming docking sites for STATs

4. STATs dimerize

5. Dimer acts on DNA and enhances gene transcripion.
Which ligand is the exception, and does not signal via the JAK-STAT pathway? What does it utilize?
IL-1. It utilizes IRAK in place of STAT. IL-1 receptor associated kinase.
Cytokine antagonists are ?.
Cytokine antagonists are proteins.
List the two ways in which cytokine antagonist act.
1. Direct binding to a cytokine receptor but fail to activate the cell

2. Direct binding to a cytokine receptor, inhibiting its activity.
Cytokine inhibitors are found where?
They are found in the bloodstream and extracellular fluid.
Where do cytokine inhibitors originate from?
They originate from the enzymatic cleavage of the extracellular domain of cytokine receptors.
Which is the best characterized of the cytokine inhibitors? When is it released?
sIL-2R is the best characterized ('s' stands for soluble). It is released during chronic T-cell activation.
When is sIL-2R observed?
It is observed in some autoimmune diseases, transplant rejections, and AIDs.
Some ? can thwart cytokines.
Some viruses can thwart cytokines.
List 6 strategies that viruses may use to thwart cytokines.
1. Cytokine homologs (mimicry of cytokines)

2. Soluble cytokine binding proteins (like competitive inh.s)

3. Homologs of cytokine receptors (mimicry)

4. Interference with intracellular signaling

5. Interference with cytokine secretion

6. Induction of cytokine inhibitors in the host cell
Cytokine secretion is predominantly from these sources.
Cytokines secretion is predominanlty from Th1 and Th2 cells.
Describe the cytokines secreted by Th1 cells. What is the bottom line?
1. Delayed type hypersensitivity

2. Activation of Tc cells

3. Production of opsonization promoting IgG Abs

BOTTOM LINE : Promotion of excessive inflammation and tissue injury
Describe the cytokines secreted by Th2 cells. What is the bottom line?
1. Stimulates eosinophil activation

2. Helps B-cells

3. Promotes production of IgM, IgE, noncomplement IgG

BOTTOM LINE: Supports allergic reactions
List 5 cytokines secreted by Th1.
1. IL-2

2. IFN-gamma

3. TNF-beta

4. GM-CSF

5. IL-3
List 5 cytokines secreted by Th2.
1. IL-4

2. IL-5

3. IL-10

4. IL-13

5. IL-3
List 3 functions of cytokines?
1. Macrophage activation

2. Delayed type hypersensitivity

3. Tc cell activation
The cytokine ? influences the development of T-cell subtypes.
The cytokine environment influences the development of T-cell subtypes.
A Th2 response requires what cytokine?
IL-4
Th1 development requires which cytokines? Explain.
IFN-gamma, IL-12, IL-18 are all required.

1. IFN-gamma up-regulates (helps produce) IL-12 production by macrophages and dendritic cells

2. IL-18 promotes proliferation and IFN-gamma production by TH1 cells and NK cells
Exposure of IL-4 to ? ? ? causes them to become Th2 subtypes.
Exposure of IL-4 to naive helper cells causes them to become Th2 subtype.
T-cell subtype balance influences ? outcomes.
T-cell subtype balance influences disease outcomes.
What is leprosy caused by?
Mycobacterium leprae. It can survive within phagosomes of macrophages.
List two types of leprosy.
1. Tuberculoid leprosy

2. Lepromatous leprosy
Describe tuberculoid leprosy.
1. Cytotoxic cell mediated immune response forms granulomas ("hard-balled pkgs", "knobby")

2. Some damage to skin and traps peripheral nerves (ie, in the face)
Describe Lepromatous leprosy.
1. Cell-mediated response is depressed and high levels of Ig result

2. Progresses into disseminated infection of bone and cartilage with extreme nerve and tissue damage (this is serious because there is no vascular flow in the bone and cartilage)
Tuberculoid leprosy has a ? response with ? and high levels of ?,?,?.
Tuberculoid leprosy has a Th1 response with delayed-type hypersensitivity and high levels of IL-2, INF-gamma, and TNF-beta.
Lepromatous leprosy has a ? response with high levels of ?,?,?.
Lepromatous leprosy has a Th2 response with high levels of IL-4, IL-5, and IL-10.
IL-1 is pyrogenic, what does this mean?
IL-1 is responsible for fevers. It effects temperature regulation of hypothalamus.
What is septic shock?
It is a cytokine related disease. Caused by certain gram (-) bacteria. Endotoxins bind TLRs on dendritic cells and macrophages and IL-1 and TNF-alpha are overproduced leading to septic shock. (Bacterial Superantigens)
What is Kawasaki disease?
It is a cytokine related disease. It affects children under the age of 5 (19:100,000); mostly of Japanese or Korean descent. It affects the skin, mouth, and lymph nodes. It is treatable if caught early. If it is not caught the disease attacks the cardiovascular system. Can lead to vasculitis and cardiac arrhytmias.
What does the treatment for Kawasaki disease?
It includes high dose aspirin and gamma globulin.
List some signs and symptoms of Kawasaki disease.
Redness in both eyes, swollen lips, swollen feet, rash, and peeling skin.
What is the most successful of the cytokine based therapies?
The most successful is TNF-alpha inhibitor. An example is Humira made by Abbott. It also just received FDA approval for Chron's disease.
Are there a lot of cytokine based therapies?
There are very few really effective ones.