Lectures 16 & 17: Cytokines & Chemokines Flashcards
What is the typical molecular weight of cytokines?
low (usually <30 kDa)
cytokines mediate effects via specific ___ on target cells
receptors
most cytokines are secreted, but some do exist in ____ forms and are active
membrane-bound
what is the structure of most cytokines? Are there any exceptions? well as some others
most are single polypeptide chains. Exception: aggregated forms like tumor necrosis factor (TNF) which is a heterodimer as well as some others
what makes the following cytokines different from the typical structure: IL-12, IL-23, IL-27, IL-35 and IL-39
they are heterodimers when most cytokines are monomeric
cytokines can have potent effects at ____ concentrations
picomolar
In general, what is the overarching function/role of cytokines?
to regulate the intensity and duration of immune response by stimulating or inhibiting activation, proliferation and or differentiation and migration of multiple cell types and by regulating the synthesis and secretion of Ig and other cytokines, or in some cases cell death in target cells
autocrine signalling
cytokine binds to receptors on the same cell that secreted it
paracrine signalling
cytokine binds to receptors on a nearby cell
juxtacrine signalling
cytokine binds to a neighbouring cells
endocrine cytokine signalling
cytokine binds to receptors on distant target cells
what is pleiotropy?
a cytokine has different effects on different target cells
what is redundancy?
different cytokines have the same effect on a target cells
what is a synergistic effect?
an effect greater than the additive effect of each cytokine alone
what is antagonistic effects of cytokines?
when two cytokines have opposing effects
what is a cascade effect with cytokines?
cytokine signalling that stimulates other cytokines, forming cytokine networks
Give 7 subclasses of cytokines
- lymphokines
- monokines
- chemokines
- interferons
- tumor necrosis factor
- colony stimulating factors
- interleukins
what are lymphokines?
cytokines secreted by lymphocytes
what are monokines?
cytokines secreted by monocytes and macrophages
what are chemokines?
cytokines with chemoattractant properties
what are interferons?
cytokines initially described as having anti-viral activity
give an example of a colony stimulating factor
GM-CSF
what are interleukins?
cytokines with a role in communication between leukocytes
how many interleukins have been described?
41
how many chemokines have been described?
over 50
what are the 6 classes of cytokines & receptors?
- IL-family
- hematopoeitin (aka class 1) family
- interferon (class 2) family
- tumor necrosis factor family
- IL-17 family
- chemokines
give 2 examples of cytokines from the hematopoeitin family
IL-2, IL-4
give 2 examples of cytokines from the IFN (aka class 1) family
IFNs and IL-10
give 2 examples of cytokines from the TNF family
TNF and IL-10
give 2 examples of cytokines from the IL-17 family
IL-17A and IL-17C
give 2 examples of chemokines
CXCL8 and CCL2
the IL-1 family of cytokines are made how soon after antigenic challenge? What cells release these cytokines?
early; innate cells
are the IL-1 family of cytokines pro or anti inflammatory?
generally pro-inflammatory
some IL-1 cytokines are transcribed as the ___ form (longer proteins than the active form) and will need to be cleaved before secretion
pro
in the case of IL-1 beta, what enzyme is used to cleave the pro-form of the cytokine into the active form?
caspase 1
caspase 1 is an important component of the ____
inflammasome
when pro-forms of IL-1 cytokines are cleaved into the active forms, what is removed? What is the significance of this?
the leader sequence, so they are not secreted by the typical process
the hematopoeitin family has many members which are classified by a common ____ structure
tertiary
what are some of the functions of the hematopoeitin family?
broad functions including proliferation, AB seretion and isotype switching
what are the 2 type 1 IFNs?
alpha and beta
what is type 2 IFN?
IFN-gamma
what is the main function of type 1 IFN (IFN alpha and beta)?
response to viral infection
what are 3 cell sources of type 2 IFN?
T cells, NK cells and innate lymphoid cells
what is the function of IFN gamma?
activates macrophages to heighten cytokine secretion and destroy intracellular microbes and promotes the differentiation of Th1 lymphocytes
what is type 3 IFN?
IFN lambda
where is IFN-lambda made? what is its function ?
made by plasmacytoid DC and promotes antiviral reponse
t/f TNF has many activities that include and extend beyond the immune system
t
TNF is highly inflammatory and can cause ____
cachexia
TNF is produced at what stage of the immune challenge?
early and directly by the challenge
when the TNF is produced as a result of an immune challenge, it assembles into what structure?
trimers (some homo, some hetero)
t/f some TNF family members are membrane-bound and are not secretedm but are able to bind to a receptor
t
what are the functions of IL-17?
mainly pro-inflammatory, especially mobilizing neutrophils
what is the structure of chemokines?
small polypeptides
chemokines selectively control the ____, ____ and ___ of leukocytes
adhesion, chemotoxis, and activation
some chemokines are constitutively expressed and are likely involved in ____ or ____ roles
hemostatic or developmental
what happens when there is gene knockout of some chemokines?
can be fatal, embryos may fail to develop
CXC chemokines are also called ____ chemokines and the “X” is a _____
alpha; variable amino acid
CXC WITH ELR motif are _____ chemotractants
neutrophil
CXC chemokines WITHOUT ELR motif are _____ chemotractants
mononuclear
CC chemokines are also called ____ chemokines
beta
CC (beta) chemokines are ____ cell chemoattractants
mononuclear
C or XC chemokines are also called ____ chemokines
gamma
gamma chemokines have ___ members (#)
2
CX3C chemokines are also called ____ chemokines
delta
delta chemokines have a singular member (_____)
fractalkine
what is fractalkline?
a gamma chemokine that is a neutrophil chemoattractant that can be membrane bound
t/f chemokines show considerable promiscuity
t
what are 7 ways non-specific cytokines maintain the specificity of the immune response?
- regulated production of the cytokine
- if only 1 chain of a heterodimer is made
- limited radius of effectiveness
- short half-life
- regulation of cytokine receptor expression
- activation of multiple receptors
- antagonism
explain “regulated production of cytokines”
often, cytokines are only made after a stimulus: macrophage phagocytosing bacteria, engaging the T cell antigen receptor; processing (ex: IL-1 & IL-18 are cleaved before they are released)
explain the significance of cytokines having a limited radius of effectiveness
only those cells in physical contact with or in the immediate vicinity of the cytokine-secreting cell will be exposed to an effective concentration of cytokine
what is the signficance of cytokines having a short half-life?
means that they can only act for a limited period of time (helps maintain specificity of immune responses)
explain “regulation of cytokine receptor expression” in maintaining cytokine specificity
example: only lymphocytes which have interacted with antigen can express certain cytokine receptors
explain the role of “activation of multiple receptors” in cytokine specificity
tune up or tune down expression of particular transcription factors or activites of enzymes
what does antagonism mean in the context of cytokine specificity?
there are multiple ways of intercepting a cytokine
what are 4 examples of antagonsim of cytokines?
- shedding receptors
- decoy receptors
- specific cytokine antagonists
- binding proteins
explain the “shedding receptors” method of cytokine antagonism
shedding receptors that may occupy a cytokine in solution to prevent it from binding to another receptor
give 4 examples of cytokine receptors that are shed
- TNFR
- IL-1R
- IL-4R
- IL-6R
explain the “decoy receptor” method of cytokine antagonism
decoy receptors that in the transmembrane or secreted form are not capable of transmitting signal
give an example of a decoy cytokine receptr
IL-1RII
give an example of specific cytokine antagonism
the IL-1 receptor antagonist (IL-1RA) binds to the IL-1RI and the receptor fails to transmit a signal (IL-36)
give an example of how binding proteins can cause cytokine antagonism
ex: IL-18 has a specific IL-18 binding protein that bind the cytokine preventing it from binding the receptor
a naive CD4+ T cell exposed to IL-4 will become a ____ cell
TH2
a naive CD4+ T cell exposed to IL-6, IL-23 or TGF-B may be encouraged to become what type of T cell?
TH17
a naive CD4+ T cell exposed to IL-2 and or TGF-B may be encouraged to become what type of T cell?
a peripheral T reg cell
a naive CD4+ T cell exposed to IL-12, IFN-y and/or IL-18 may be encouraged to become what type of T cell?
Th1 cells
what is the master transcriptional regulator of peripheral T reg cells?
FoxP3
what is the master transcriptional regulator of TH17 cells?
RORyt
what is the master transcriotional regulator for TH2 cells?
GATA3
what is the master transcription factor for TH1 cells?
T-Bet
what cytokines are secreted by peripheral T reg cells? What is the function of these?
IL-10 and TGF-B; suppress the immune response
what cytokines are secreted by TH17 cells? What is the function of these cytokines?
IL-17A, IL-17F, IL-22 (combat extracellular pathogens in barrier tissues)
what cytokines are secreted by TH2 cells? What is the function of these cytokines?
IL-4, IL-5 and IL-13 (combat helminth infection and activates eosinophils)
what role to peripheral T reg cells have in disease?
suppress imune response, inhibit antitumor resposne
what role do TH17 cells have in Dx?
autoimmunity and tissue inflammation
what is the role of TH2 cells in Dx?
allergy
what is the role of TH1 cells in Dx?
tissue inflammation
what are 3 functions of TH1 cells?
- promote opsonization of immunoglobulin
- cell-mediated immunity (extracellular parasite)
- differentiation of CD8+ cells to become cytotoxic
TH2 cells promote which immunoglobulin isotyoes?
IgM, IgE and noncomplement-activating IgG
TH17 cells are involved in resistance to what types of infections?
fungal and extracellular bacterial infections
peripheral T reg cells contrast ____cells which mature in the thymus
thymic regulatory T cells
t/f the cytokines that promote the differentiatio of one helper subset may also suppress the development of an alternate subset
t
the cross regulation of TH1 and TH2 explains the inverse relationship between classical cell-mediated and antibody responses leading to ____
allergy
in Th1 Th2 cross-regulation, what cytokine prevents antigen presenting cells from secreting IL-12?
IL-4
in TH1:Th2 cross regulation, what cytokine directly inhibits the proliferation of TH2?
INF-gamma
in TH17: Treg cross-regulation, ____ contributes to polarizing both, but if ___is added, TH17 will overpower
TGF-beta; IL-6
along with IL-6, what two cytokines promote TH17 over Treg in their cross-regulation?
IL-21 and IL-23
what things favour Treg cells in the TH17:Treg cross regulation?
retinoic acid and TGF-beta
t/f subfamilies of hematopoietin class receptors may share the signalling polypeptide
t
IL-2R is a well characterized cytokine receptor among the ____ receptor family
hematopoietin
the IL-2 receptor consists of what polypeptide chains?
alpha, beta and gamma
what is the low affinity structure of IL-2R?
monomeric form (alpha chain only)
what is the intermediate affinity IL-2R structure?
dimeric form (beta and gamma chains)
what is the high affinity structure of the IL-2R?
trimeric form (alpha, beta and gamma)
signal transduction from the IL-2R requires the presence of what 2 polypeptide chains?
gamma and beta
what is the role of the alpha chain in the IL-2R?
unique and associates with the cytokine then non-covalently with the signal transducing chain
the common gamma chain of the IL-2R faimily implies what?
that the transmembrane signal is similar for different receptors in the class
receptors may occur in soluble forms which typically retain ___ (low or high) affinity for the cytokine and thus are capable of bindin g the cytokine in solution
high
what are the 2 mechanisms by which cytokine receptors become solubilized?
- porteolytic cleavage of the extracellular domain
2. splicing out of the transmembrane encoding exon of the primary RNA transcript resulting in a protein that is secreted
proteolytic cleavage of the extracellular domain causes release of the cytokine receptor from the _____
cell membrane
proteolytic cleavage of the extracellular domain often follows a specific ____ event acting on the cell
activation
give an example of a cytokine receptor that is activated by proteolytic cleavage of the extracellular domain. How does this process occur for this receptor?
TNF receptors (p55 and p75); solubilization of p75 can occur following the binding of TNF to p55
give 3 examples of cytokine receptors that undergo splicing out of their encoding exon to be solubilized
- IL-1RII
- IL-4R
- IL-7R
what are 4 roles of soluble receptors?
- receptor down regulation
- become binding protein that protects ligand from degradation
- binds cytokine to prevent it from binding further membrane-bound receptors (acts as direct antagonist)
- binding of soluble a chain to ligand can confer sensitivity to another cell that may only have the signalling chain
explain the role of receptor down-regulation by soluble cytokine receptors
the receptor can no longer serve as the signalling molecule to the cell, limiting the response of the cell
when a soluble cytokine receptor acts as a binding protein to protect ligand from degradation, the receptor now has no role in ____ but to facilitate the delivery of ligand to ____
signalling; additional membrane-bound receptors
give 3 examples of cytokine receptors that can bind to cytokine to prevent it from binding to membrane-bound receptors
IL-1, IL-4, and TNF receptors
what is the significance of soluble cytokine receptor alpha chain binding to the ligand to confer sensitivity?
This greatly expands the number and types of cells sensitive to the soluble receptor / ligand complex
t/f the more steps in the process of activating a cytokine, the more fine-tuned its regulation
t
cells can make cytokines and keep them in ____ cells until an infection arises
mast cells
which form, IL-1a or IL-1B has greater affinity for the receptir?
the alpha form
once naive T cells have been stimulated and have gotten their T helper identities, they are now called ____ cells
effector T
describe the structure of the IL-1 family of receptors
immunoglobulin-like loops with 5-6 AA with inter-chain disulphide bonds
t/f class 1 and 2 cytokine receptors can have multiple polypeptides
t
describe the structure of TNF receptors
usually a single polypeptide, but have repeating cysteine motifs which give them their identity
describe the structure of IL-17 recptors
multimeric
describe the structure of chemokine receptors
7 membrane spanning G coupled protein receptors
