Cytokines Flashcards
cytokine characteristics
usually act locally, however, on occasion, they may exhibit endocrine action
they act by binding to specific cytokine receptors on the cells that they effect
cytokines
soluble proteins secreted by the cells of innate and adaptive immunity that stimulate ( occasionally suppress ) the growth, maturation, and functioning of the cells of the immune system
lymphokines
cytokines primarily produced by lymphocytes
monokines
cytokines primarily produced by monocytes and macrophages
interleukins
cytokines produced by leukocytes that act on other leukocytes
cytokines are produced during the ___ and ___ ___ of innate and adaptive immune responses.
activation
effector phase
cytokines are active in very ___ concentrations
low
properties of cytokines
cytokine secretion is a brief, self limited event( not stored as preformed molecules) and often influence the synthesis of other cytokines
cytokine receptors
cytokines bind to specific high affinity receptors, which then triggers a series of biochemical events that influence the activities of immune cells and organs.
the expression of many cytokine receptors is regulate by ___ ____. the signal may be ___ ____ or ____ ____ to the cell
specific signal
another cytokine
antigen binding
the cytokine receptor can have ___ ___ that block the cytokine before it reaches its cellular target.
circulating forms
regulates the activity of the cytokines
individual cytokines may be produced by multiple cell types, which include:
pleitropism
redundancy
synergism
antagonism
pleiotropism
a single cytokine may have multiple activities
redundancy
a single activity can be caused by multiple cytokines
synergism
a cytokine may work best in association with another cytokine
antagonism
a cytokine may antagonize the effects of another cytokine
proinflammatory cytokines
contribute to the initiation of a wide spectrum of activities during the inflammatory responses, such as fever, acute phase response
what does proinflammatory cytokines include:
IL-1
IL-6
tumor necrosis factor- alpha
proinflammatroy cytokines act in concert with____ and ___ ___ to ensure the development of physiological responses to a wide variety of stimuli, such as microbial infections and tissue injury.
chemokines
hematopoietic cytokines
Interleukin-1 (IL-1) source
Macrophages (activated)
what are the two types of interleukin -1
IL-1 alpha (local)
IL-1 beta(endocrine)
IL-1 alpha
binds to macrophage membranes, enabling macrophages to activate lymphocytes that come in contact with them.
IL-1beta
secreted by cells,thus, most of the IL-1 found in circulation is this one.
T or F:
Both forms of Interleukin -1 bind to the same IL-1 receptor and mediate the same biological activities
T
IL-1 receptor antagonist
Third form that binds to IL-1 but is biologically inactive so that it functions as a competitive inhibitor of IL-1.
Also an endogenous regulator that serves to prevent excessive IL-1 driven inflammatory response.
Principal activities of IL-1
- lymphocyte activation
- acts on endothelial cells to increase expression of adhesion molecules that mediate leukocyte extravasation and secret chemokines that activate leukocytes
- stimulates the production of neutrophils and platelets by the bone marrow
- acute phase reaction
- nervous system- causes fever, lethargy malaise and lack of appetite
- initiates metabolic wasting( mobilization of aa from muscle)
acute phase reaction
stimulates hepatocytes to synthesize increased levels of acute phase proteins in response to inflamation
fever
IL-1 acts on the thermoregulatory center in the anterior hypothalamus, resulting in prostaglandin- induced fever
Interleukin-6 (IL-6) sources
Macrophages (activated)
Interleukin-6 principal activities
- stimulates synthesis of acute phase proteins; endogenous pyrogen (fever)
- bone marrow( stimulation of hematopiesis, in concert with colony-stimulating factors, it promotes the production of neutrophils and platelets)
- T cells
- Bcells
tumor necrosis factor -alpha (TNF-alpha) sources:
most dangerous of all
Macrophages
T cells
Principal activities for TNF-alpha
- Vascular endothelium( expression of adhesion molecules and synthesis of chemokines)
- activates neutrophils and macrophages, enhancing their microbial activities
- stimulate synthesis of acute- phase proteins; potent endogenous pyrogen
- pathologic abnormalities(prolonged production or high concentrations)
pathological abnormalities include
intravascualr thrombosis
cachexia
septic shock
intravascular thrombosis
TNF stimulates endothelial cell expression of tissue factor, a potent activator of coagulation. thrombosis of tumor blood vessels accounts for tumor killing activity
Cachexia
characterized by wasting of muscles and fat cells ( due to TNF induced appetite suppression)
Cachectin
TNF is referred to this
general wasting of animal
septic shock
TNF is the principal mediator for this in gram negative septicemia
very large amounts of TNF result in inhibition of muscle tome and cardiac contractility, resulting in decreased blood pressure and shock
Chemokines ( chemotactic cytokines)
comprise a large family of small proteins that are involved in the migration of leukocytes (especially phagocytes and lymphocytes) from the blood to tissues and activation of leukocytes
play a central role in inflammatory reactions
Chemokines are produced by_____ and various tissue cells such as ____, _____, _____.
leukocytes
fibroblast
endothelial
epithelial
secretion of chemokines are produced by ____ and by ____ ____, principally TNF-alpha and IL-1. However some are produced constitutively in ____ _____, where they aid in the traffic of lymphocytes through the organs in the _______ of _______.
pathogens proinflamatory cytokines lymphatic organs absence inflammation
chemokine receptors
consist of seven-transmembrane polypeptide chains( the chains traverse the plasma membrane seven times) and belong to the large family of G-protein-coupled receptors
chemokines are classified according to the type of chemokines they bind, what are some examples:
CXCRs
CCR
chemokines are classified into cubfamilies based on the position of two of the four higly conserved NH-2 terminal _____ _______ they possess
cysteine residues
CXC chemokines
alpha chemokines
first two cysteines separated by one amino acid
mostly attract active neutrophils
most importnat is CXCL8 (IL-8)
CXCL8
- is a chemotactic for neutrophils and effector T cells
- activates neutrophils, increasing their expression and rearrangement of integrins
- also enhances degranulation, the respiratory burst
CC chemokines
- beta chemokines
- have two adjacent cysteine residues
- mostly recruit and activate monocytes, lymphocytes, basophils, NK cells, and eosinophils
CC chemokines include:
- CCL3/CCL4(macrophage inflammatory proteins)
- CCL2(monocyte chemoattractant protein-1)
- CCL11( eotaxin)
- CCL5( RANTES, regulated upon activation, normal T cell expressed and secreted)
Hematopoietic cytokines
stimulate the growth and differentiation of bone marrow precursor cells
Hematopoietic cytokines include:
interleukin-3
interleukin-7
stem cell factor
GM-CSF; M-CSF
Interleukin 3 sources
T-cells, macrophages, mast cells
Interleukin -3 job
promotes the growth and differentiation of stem cells into all known mature cell types (multi lineagecolony- stimulating factor multi-CSF)
Interleukin- 7sources:
bone marrow, and thymic stromal cells
Interleukin-7 job
growth of T and B cell progenitaors ( called lymphopoietic cytokine)
stem cell factor source:
constitutively produced by bone marrow stromal cells
active as membrane form or secreted form
stem cell factor job:
- required for the earliest stages of leukocyte development in the bone marrow
- may also play a role is sustaining the viability and proliferation of immature T cells in the thymus and of mast cells in mucosal tissues
GM-CSF; M-CSF source:
T cells, macrophages, endothelial cells, mast cells, and bone marrow stromal cells
GM-CSF; M-CSF
these cytokines are assayed in vitro by their ability to stimulate the formation of cell colonies in bone marrow cultures
G-CSF; M-CSF job:
promote the expansion and differentiation of bone marrow progenitor cells
Cytokines of adaptive immunity
interleukin-2
interleukin- 4
interleukin -5
Interleukin-2 source
- main source is naive CD4+ cells and Th1
- CD8 T cells secrete low levels
Interleukin-2 principal activities
stimulates growth and differentiation o T cells, B cells, and NK cells(proliferation and enhanced cytolytic activity
Interleukin-4 source:
Th2cells
Interleukin-4 principal activities
-stimulates the development and clonal expansion of Th2 cells from naive CD4+T cells
- Bcells
stimulates bcell differentiation and antibody synthesis
principal cytokine that stimulates B cell immunoglobulin class
switching IgE isotype
-Th1
down regulates IFN-zeta synthesis by Th1 cells, thereby inhibiting
macrophage activation and suppressing cell mediated immune
response
-stimulates growth of mast cells
Interleukin-5 sources
Th2 cells and mast cells
Interleukin- 5 principal activities
-eosinophils
stimulates growth and differentiation of eosinophils; activation
of mature eosinophils
-Bcells
growth and differentiationCytokine antagonists
proteins that inhibit the biological activity of cytokines
cytokine antagonist function in two ways
1) they can bind directly to a cytokine receptor without activating it (IL-ra)
2) they can bind directly to a cytokine, inhibiting its activity
vireceptorc
secreted viral proteins that inhibit cytokine signaling by mimicking host cytokine receptors
several poxviruses encode homologs of IFN- zetaR, soluble TNF-binding protein, and soluble IL-1 binding protein
virokines
secreted viral proteins that mimic host cytokines
Epstein-barr virus encodes a homolog of IL-10
soluble cytokine receptors
generated by enzymatic cleavage of the extracellular domains of cytokine receptors
have been identified in the blood stream and extracellular fluid
include IL-2 receptors and sIFN-zeta R
soluble cytokine receptor job:
bind with their respective cytokine preventing the cytokine form interacting with the membrane bound receptor
sIL-2R
used as a clinical marker of chronic T cell activation and has been observed in various pathologies, including autoimmune disorders, allograft rejection, and AIDS
high concentrations of cytokines or chronic exposure to a cytokine can result in:
- High levels of IL-2 results in fever chills, and vascular leak syndrome
- toxic shock syndrome
toxic shock syndrome
enterotoxins produced by some strains of S. aureus can act as a superantigens and trigger polyclonal T cell response
TNF-alpha-causes fever, hypotension and damage to the liver and kidney
cytokine based therapy includes
the use of monoclonal Abs produced against specific cytokines, recombinant cytokines and soluble cytokine receptors
IL-ra
under investigation as a possible treatment for chronic inflammatory disease
erthropoietin (EPO)
used in cats and dogs with nonregenerative anemia due to endogenous EPO deficiencies in chronic renal failure
Colony stimulating cytokines
such as GM-SCF( sargramostim) and G-CSF (filgrastim)
given after chemothearpy or radiation thearpy improves bone marrow recovery( stimulate production of myeloid progenitor cells)
interferon
induces an antiviral state in host cells;
has anti tumor activity;
promotes processing and presentation of cytosolic proteins
Horses: treatment of inflammatory airway disease
cats: treatment of feline leukemia; together with corticosteroids
used in the treatment of effusive feline infectious peritonitis
