Cytokines and Receptor properties Flashcards
Cytokines, despite being antigen nonspecific, regulate the ___ and ___ of the immune response
Intensity and Duration
Most cytokines are what structure?
Single polypeptide chains
What is an example of a cytokine that circulates as a homodimer? as a homotrimer?
some interferons cirulate as homodimers and TNF as a homotrimer
What are 4 cytokines that are exceptions and are composed of two different polypeptide chains (heterodimers)
IL-12, IL-23, IL-27, IL-35
Which two ILs contrain the polypeptide p40?
IL-12 and IL-23
Autocrine
bind receptors on same cell that secretes the cytokine
Paracrine
bind receptors on cells nearby to cell that secretes cytokine
Juxtacrine
Bind receptors on cells directly beside secreting cell
Endocrine
Bind to receptors on distant target cells
Pleiotropy
a cytokine that has different biological effects on different target cells
Redundancy
two or more cytokines having the same effect on a target cell
Synnergy
the effect of two cytokines acting on a target cell is greater that the additive effect of each cytokine used alone
Cascade action
A cytokine stimulates other cytokines, forming cytokine networks
Chemokines def.
cytokines that have chemoattractant properties
What are the 6 groups of cytokines and their receptors?
- Hematapoietin family (Class I)
- Interferon family (Class II)
- IL-1 family
- TNF family
- IL-17 family
- Cytokines
What are the 7 ways in which the specificity of the immune response is maintained with non-specific chemokines
- Regulate production of the chemokine
- Make only one chain of a heterodimer
- Limited radius of effectiveness
- Short half life
- Regulation of receptor expression
- Activation of multiple receptors
- Antagonism
Explain how regulation production of chemokines helps maintain the specificity of the immune response
often cytokines are only made following some stimulus
Processing and secretion are also regulation steps
-ex: cleavage required prior to secretion
Explain how releasing only one chain of the heterodimer helps maintain the specificity of the immune response
if only one chain of a heterodimer is made the cytokine may not be effective
Explain how a limited radius of effectiveness helps maintain the specificity of the immune response
nly those cells in physical contact with or in the
immediate vicinity of the cytokine-secreting cell will be exposed to an effective
concentration of the cytokine
Explain how short half lives help maintain the specificity of the immune response
cytokines can only act for a limited period of time before they are
either removed or are catabolized
Explain how regulating the cytokine receptor expression helps maintain the specificity of the immune response/can be achieved
For example, only lymphocytes which have
interacted with antigen may express particular cytokine receptors
Explain how activation of multiple receptors helps maintain the specificity of the immune response
By up or down regulating the expression of certain transcription factors and activities of enzymes
What are the 4 ways in which antagonism can be acheived?
- Shedding receptors
- Decoy receptor
- Specific cytokine antagonists
- Binding proteins
How does shedding receptors work to antagonize chemokines?
Can occupy a cytokine in solution and prevent it from binding to a membrane bound receptor
How do decoy receptors function in antagonism?
Bind up antigen in solution but do not initiate cellular signalling responses (even in the transmembrane form)
How do specific cytokine antagonists work? What are is an example
IL-1 receptor agonist IL-1Ra binds to the IL-1 receptor but fails to transmit a signal
How do binding proteins act as agonists? Give an example
Ex: IL-18 has a specific IL-18 binding protein that binds the cytokines, preventing them from interacting with the receptor
What do chemokines control?
Adhesion, chemotaxis, and activation of leukocytes
What are the four classes of chemokines?
- CXC (alpha)
- CC (beta)
- C or XC (gamma)
- CX3C (delta)
What differentiations can be made within the CXC subgroup?
with or without the ELR motif
CXC with ELR =
neutrophil chemoattractants
CXC without ELR =
mononuclear cell chemoattractants
what are the CC subgroup?
mononuclear cell chemoattractants, also called the beta chemokines
how many members in the C or XC subgroup
2
how many members in the CX3C group? name it
a single member, fractalkine, is a neutrophil chemoattractant and is membrane-bound,
also called the delta chemokines
What cytokines do Th1 cells make and secrete
IL-2 and IFN-gamma (and TNF?)
What kind of immune response are Th1 cells involved in ?
cell mediated immunity
- intracellular parasites
- inflammation
- macrophage activation
- differentiation of cytotoxic T cells
What 3 cytokines signal to a naive CD4+ T cell to become a Th1 cell?
IL-12, IL-18, IFN-gamma
What cytokines do Th2 cells make and secrete?
IL-4, IL-5, IL-13
What kind of immune response are Th2 cells involved in?
Allergy and extracellular parasitic responses
-promote IgM and especially IgE as well as non-complement activating IgG
What cytokine(s) signal a naive CD4+ T cell to become a Th2 cell?
IL-4
What cytokines do Th17 cells make?
Il-17A and F, IL-22
What kind of immune response are Th17 cells involved in ?
Inflammation, resistance to fungal infections, and autoimmunity
What cytokine(s) signal a naive CD4+ T cell to become a Th17 cell?
TGF-ß, IL-1, IL-6, IL-23
What phenomena does cross-regulation explain?
The inverse relationship between classical cell-mediated antibody responses and antibody responses leading to allergy
IL-12 binding to the cell will activate the STAT __ path and then TF ___
STAT 4, T-Bet
IL-4 binding to the cell will activate STAT __ and the TF__
STAT 6 and GATA-3
T-Bet promotes transcription of genes for which cytokine
IFN-gamma
GATA-3 promotes transcription for which cytokines?
IL-4 and IL-5
IFN-gamma downregulates which immune response
Th2 by inhibiting proliferation
What 2 cytokines indirectly downregulate Th1 by acting on APCs?
IL-4 and IL-10
What 3 subunits compose the IL-2 receptor?
alpha, beta, and gamma
What is the low affinity form of the IL-2R?
alpha chain only
What is the intermediate affinity form of the IL-2R?
beta and gamma chains
What is the high affinity form of the IL-2R?
alpha beta and gamma chains
Which of the IL-2R receptor chains is responsible for cell signalling
Transduction of signal requires both the beta and gamma chains
Which chain is expressed constitutively by T cells?/
Gamma chain
What 2 cells express the intermediate affinity gamma beta chain receptor?
NK cells and resting (To) T cells
Expression of alpha and beta chains by T cells is enhanced following….
Antigenic stimulation
-makes sure they can only bind IL-2 with high affinity if they are activated
Explain the redundancy of the gamma chain in the IL-2R
The gamma chain of this receptor is also used in the IL-4, -7, -9, and IL-15 receptors.
Each of these receptors has a unique low affinity alpha chain which is responsible for the specificity of the receptor to the particular cytokine; however, the common gamma chain implies that the transmembrane signal is similar for the different receptors.
What are 2 ways in which receptors can occur in soluble high affinity forms?
- Proteolytic cleavage of extracellular domain
2. Splicing out of the transmembrane encoding exon of the primary RNA transcript
How does proteolytic cleavage result in a soluble receptor? What causes it?
releases the receptor from the cell
membrane.
This is often a result of some specific activation event acting on the cell
How does splicing out the transmembrane encoding region work?
splicing out of the transmembrane encoding exon of the primary RNA transcript resulting in a protein that is secreted, and not anchored in the plasma membrane.
What are examples of cytokine receptors solubilized by splicing?
IL-1, IL-4, IL-7
What are the 4 roles/mechanisms of soluble receptors?
- Down regulation of receptors
- Binds the ligand and protects it from degradation
- Binds the cytokine and prevents it from binding a signalling receptor
- Binding the alpha chain to a ligand can make it more sensitive to another cell
- Down regulation of receptors
The receptor can no longer serve as the signaling molecule to the
cell, limiting the response of the cell to the cytokine ligand
- Binds the ligand and protects it from degradation
soluble receptor may become a binding protein that protects the ligand from degradation
or clearance in the extracellular space. The receptor now has no role in signalling but
facilitate the delivery of the ligand to additional membrane-bound receptors.
- Binds the cytokine and prevents it from binding a signalling receptor
soluble receptor binds to the cytokine preventing it from binding further membrane-
bound receptors- becoming a direct antagonist
- Binding the alpha chain to a ligand can make it more sensitive to another cell
For receptor families consisting of multichain receptors, such as the IL-6R family, binding of
the soluble alpha receptor chain to the ligand can confer sensitivity to another cell which may have only the beta chain (gp130). This greatly expands the number and types of cells sensitive to the soluble receptor/ligand complex.
Explain the process of the JAK/STAT pathway ( 5 steps)
- cytokine binding induces the association of the two separate cytokine receptor subunits and activation of the associated JAKs
- activated JAKs create docking sites for the signal transducers and activators of transcription or “STAT” transcription factors by phosphorylation of specific tyrosine residues on the receptors.
- Docking occurs between the “SH2” domain of the STAT and the phophorylated tyrosine on the receptor.
- The JAK then phosphorylates the docked STAT.
- after phosphorylation the STATs translocate from the receptor as dimers, to the nucleus to initiate the transcription of specific genes.
What controls which genes are transcribed by the STATS?
Which genes are transcribed is determined by specific DNA sequences to which monomeric or dimeric STATs bind in the promotor region of the gene
The specificity of a cytokine effect is due to what 3 factors?
- Particular JAK/STAT pathway
- STAT specific sequences in the promoter regions of the genes
- Only certain target genes can be activated in a particular cell type
give an example of stat heterodimerization
IL-6 results in STAT3 and interferon-gamma results in STAT1 phosphorylation and when both cytokines bind receptors on the same cell, then STAT1/STAT3 heterodimers can result.
How do chemokines signal ?
Through 7 membrane g protein coupled receptors
What kind of signalling does chemokine binding initiate?
generation of second messengers
What are 4 second messengers that can be initiated by chemokine binding and what do they do?
Ras (MAP kinases)
PKC (survival)
Rho (cell movement)
PLCß (mediates gene expression)
What is necessary for chemokine receptors to signal through the JAK/STAT pathway?
dimerization of chemokine receptors
-can include homodimers or heterodimers
What STATS does JAK activation of chemokines initiate?
1, 3, and 5
IL-1, TNF, and IL-17 receptor activation pathways converge at which points
Activation of NFkappaB and MAPK
-to get to this point all the pathway use serial phosphorylations of different proteins
NFkappaB is a ___dimer
Heterodimer
Explain the steps in the NFkappaB pathway
- NFkappaB sequestered in the cytoplasm by IkappaB (also a heterodimer)
- IkappaB becomes phosphorylated by IKK (kinase)
- IkappaB becomes ubiquinated and targeted for destruction in the proteosome
- NFkappaB can now translocate to the nucleus where it is free to direct gene transcription
What genes are activated by NFkappaB?
cytokines, other mediators and adhesion molecules
Also transcribes the genes for its own regulator IkappaB alpha
The MAPKs are ____ kinases
Serine/threonine
What are the three final pathway effectors of the MAPKs?
ERK, p38, and JNK
What do the three final effectors activate
TFs that regulate inflammatory and immune molecules
