Exam 2 Lecture 12 Flashcards by Alexandria Munnicha

What are cytokines?

Cytokines are small proteins (50-180 residues) that are crucial for controlling growth and activity of immune system cells and blood cells to execute inflammation responses. They can vary a bit in their structure and are encoded by many human genes.

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What biological roles do cytokines have in immunity, inflammation, and hematopoiesis?

immune cell proliferation and differentiation
cell migration
chemoattractant/chemotaxis
cell-cell communication during an immune response
cytotoxicity

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How are cytokines like kinases in tis role for biological processes?

Cytokines can affect nearly every biological process such as embryonic development, disease pathogenesis, immunity, cognitive function, and degeneration in aging.

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What are some examples of sender cells that produce and release cytokines?

macrophages
B cells
effector T cells
mast cells
endothelial cells
fibroblast cells

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What are some target cells of cytokines?

macrophages
B cells
effector t cells
tumor cells
plasma cells

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What are the different types of cell-cell communication methods cytokines utilize?

autocrine (self)
paracrine (nearby)
endocrine (distant)

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What was the original nomenclature used to group cytokines?

They were grouped based on function, cell secretion or target of action (aka which cells secrete them and which cells are targeted).

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What are the groups of cytokines based on the original nomenclature?

interleukins
chemokines
tumor necrosis factor
interferons

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What are the cytokine receptor types based on common structural features?

Ig superfamily
interferon receptors
TNF receptors
chemokine receptors
TGF receptor
hematopoietin receptors

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What is the basic definition of a chemokine?

It is a chemotaxis cytokine

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What are the 3 cellular effects of cytokines?

Pleiotropic: same cytokine can have different target cells and receptors with different outcomes (can bind to multiple receptors simultaneously)
Redundant: different cytokines can produce similar effects
Cascade effect: cytokines can stimulate the production of other cytokines (also called cytokine storm)

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What is an example of cytokines being pleiotropic?

IL-4 can bind to B cells and mast cells

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What is an example of cytokines being redundant?

IL-2, IL-4, and IL-5 are released by activated effector T cells and all stimulate B cells to proliferate.

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What are interleukins?

They are secreted by one leukocyte and act on other leukocytes in an inflammatory response. They regulate growth and differentiation of hematopoietic cells.

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What are chemokines?

They are a subtype of a cytokine involved in cell migration (chemotaxis). They are involved in cell migration during development, immune response, inflammation, and cancer. They have less than 100 residues and can be monomeric or homodimeric.

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Some interleukins are also what?

Chemokines! For example, CXCL8 is produced by macrophages and is also called IL-8.

Chemokine receptors are what?

GPCRs (G protein coupled receptors)!

What is tumor necrosis factor (TNF)?

They are released upon infection by macrophages (an example is TNF-𝛼) and can exist in 2 forms: a transmembrane form that is anchored to the membrane (mTNF-𝛼) and a soluble form (sTNF-𝛼) that results from enzymatic cleavage. The ribbon structure on TNF is a 17 kDa monomer that forms a beta-pleated sandwich and associate to form a bell-shaped TRIMER.

What is the difference between the transmembrane form that is anchored to the membrane (mTNF-𝛼) and the soluble form (sTNF-𝛼)?

mTNF-𝛼 is on monocytes and macrophages. It binds to two TNF receptors on tissue cells (juxtacrine).
sTNF-𝛼 binds selectively to only one TNF receptor.

What are interferons?

They regulate signaling among cells infected with viruses or bacterial pathogens so they basically interfere with viral replication. They also regulate the immune response by activating immune cells such as macrophages and NK cells, upregulate antigen presentation, and underlie feelings like fever, muscle pain, and flu-like symptoms. An example of an interferon is IFN-𝛼.

What is the structure of interferons?

They have an overall helical structure that is different than the helical structure of interleukins.

What are the 3 types of interferons?

The 3 types include I, II, and III which are based on the receptors they bind to. For example, type I interferons bind to IFN-𝛼 receptor (IFNAR).

Does each cytokine have a matching receptor?

Yes and the activation of the receptor involves a number of membrane proteins as well as cytokine binding. They are associated with immune disease and overly expressed on tumor cells.

What are the 6 types of cytokine receptors?

Ig family
hemopoietic growth factor (type 1) family
interferon (type 2) family
tumor necrosis factor (TNF) (type 3) family
G protein coupled receptors (GPCRs)
interleukin-17 receptor (IL-17R) family

What are the Ig family receptors?

They are expressed on many different cells and tissues of the vertebrate body. They have the Ig domain of immunoglobulins. Examples include IL-1 and IL-18 receptors

What are the hemopoietic growth factor (type 1) family of receptors?

They have certain conserved motifs in their extracellular domain. Examples include the IL-2 receptor in which deficiency is directly responsible for the disease X-SCID and the IL-6 receptor.

What are the interferon (type 2) family of receptors?

The members are receptors for IFN-𝛽 and 𝛾.

What are the tumor necrosis factor (TNF) (type 3) family of receptors?

The members share a cysteine (C) rich extracellular binding domain. In addition to trimeric TNF cytokines, these receptors bind to several non-cytokine ligands such as CD40, CD27, and CD30.

What are the GPCR family of receptors?

They bind chemokines. An example of this would be CD4 and CCR5 that are able to bind to HIV to enable HIV to enter the immunological cells, so they are involved in viral entry.

What are the interleukin-17 receptor (IL-17R) family of receptors?

These are very specific and have little structural homology with any other cytokine receptor family. Members include IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE. IL-17 cytokines induce proinflammatory responses and allergic responses. They are currently being investigated for treating RA, psoriasis, and IBD. The signaling pathways for this type of receptor is not well defined.

What is vMIP-II/CXCR4 complex?

It is a chemokine receptor complex, more specifically a GPCR with 7 transmembrane domains, that consist of the chemokine at the top and the receptor at the bottom. It also has a large hole in the middle of the complex that acts as a cavity. vMIP is a viral chemokine antagonist from herpesvirus which is thought to bind like the endogenous chemokine CXCL12. This complex has an extensive binding surface that is comprised of GPCR external loops and extends into the transmembrane helical region.

Certain cytokine receptors can show what with multiple different cytokine receptors?

Cross-reactivity! For example, 3 receptors from the class I cytokine receptor family (𝛾 chain, gp130, and 𝛽 chain) each have multiple cytokine ligands and have multiple chains. The 𝛾 chain interacts with 6 cytokines. gp130 interacts with 10 cytokines. The 𝛽 chain interacts with 3 cytokines.

What may be the cause for cross-reactivity?

Multiple interactions of different protein chains. For example, type 1 cytokine receptors have an extracellular domain in which the receptor has 2 chains (IFNAR1 and IFNAR2) and is in complex with the cytokine IFN𝛼.

Why are intracellular domains (ICD) of type I cytokine receptors atypical?

They have a long disordered region that is composed of a large number of residues (up to 600) without apparent structural order and no kinase activity so it could be variable in length. The disordered region has no tertiary structure, is flexible, and random.

Even though the intracellular domains (ICD) are atypical, what do they do?

Complex intracellular signals are transduced via the ICDs, presumably by binding effector proteins. Essentially, they serve as docking sites for the effector proteins so that the signal can be transduced downstream.

What does the extracellular domain of the cytokine receptor do?

The extracellular domain interacts with the cytokine.

What is the importance of chemokines?

They are a subset of cytokines that direct migration of leukocytes to regions of infected tissue. The human chemokine family consists of 46 proteins and there are 23 chemokine receptors (GPCRs).

What is the mechanism of cytokine receptors?

Once it binds to the cytokine, the cytokine ligands trigger an immune response, growth, and differentiation. An example of this is IL-1 and its receptor in which their interaction is targeted in different ways by different drugs.

What are the characteristics of cytokine activity that demonstrate that the selectivity between cytokines and cytokine receptors is unusual?

1. Redundancy of cytokines 2. Pleiotropic nature of cytokines 3. The interplay of cellular effects of cytokines 4. Recognition of multiple cytokines by single receptors (aka cross-reactivity)