Lecture 5 - Cytokines Flashcards
What are cytokines?
small soluble proteins and glycoproteins that regulate and mediate host immune response via direct action on cells
What are some features of cytokines?
- large number of them and variety
- have significant homeostatic roles in host defense
- acts locally or at a distance
- rapidly activate or suppress immune activities
cell source? target cell? activities? effect? concentration?
numerous, many, pleiotropic and overlapping, autocrine, paracrine and endocrine, picomolar
General properties of cytokines
- not antigen-specific (act on other host cells)
- individual cytokines are pleiotropic and may have different activities in different situations/conditions
- may be made by more than one cell type
- may act on many cell types
- usually show brief, highly regulated expression
- have overlapping, redundant actions
- influence the synthesis of other cytokines
- influence the action of other cytokines
- signal through specific receptors
- have many non-immune functions
What are the 4 families of cytokines?
Growth Factors, Interleukins, Interferons, Chemokines
How are families grouped?
based on functional activity
What is the fn of GFs?
stimulators of hematopoiesis that regulated immature leukocyte growth and differentiation –> drive terminal differentiation of hematopoietic progenitors
Give an example of some GFs
Granulocyte-colony stimulating factor (G-CSF)
What is the fn of ILs?
mediators and regulators of lymphocytes and leukocytes –> regulators of both innate and adaptive fns of other immune cells.
-gp is very diverse in structure and fn
Give an example of ILs?
IL-2, tumor necrosis factor - alpha
What is the fn of IFNs?
mediators and regulators of antiviral and innate immunity –> can activate intracellular processes that inhibit viral replication
-several are key regulators of macrophage activity and tolerance of developing fetus
Give an example of IFN?
IFN-2
What is the fn of Chemokines?
chemoattractants - regulate the directed movement of immune cells (WBCs) from blood into tissues
Give some features of cytokine receptors
- expressed on many cell types and show considerable regulation of expression
- highly specific for their ligand
- can be single subunit or multimeric
- some share common subunits
- can be grouped into families based on signal transduction mechanisms or molecular structure
- a cell can express receptors for many cytokines
How many types of IFNs?
3-5 IFN with related structure expression in response to immune stimulation
-IFN alpha/beta, IFN-2
What’s the fn of IFN-alpha/beta?
- consists of a family of glycoproteins
- involved in anti-viral activity
- released from virus-infected cells of all types (T cells, macrophages and fibroblasts are primary sources)
- can also accelerate the differentiation of B cells –> influencing Ab response to specific Ag
- **inc MHC class I expression –> greater chance of encountering cytotoxic T cell
Describe the antiviral activity of IFN-a/b
1) antiviral proteins that activate host genes to inhibit viral RNAs and replication
2) induce MHC class I expression on the host cells
3) activate NK cells to kill virally-infected cell
What produces IFN-gamma?
mainly T helper cells and NK cells
What’s IFN-gamma fn?
- most potent activator of macrophage immune fn
- stops macrophage migration
- activates proinflammatory cytokine gene expression
- augments phagocytosis
- increases anti-tumor and antibacterial processes
- upregulates MHC expression
- influences production of immunoglobulin isotypes
- stimulates neutrophil respiratory burst
- activates vascular endothelial cell adhesion molecule expression
Describe the 4 main functions of IFN-gamma
1) macrophage activation
2) isotype switching
3) development of TH1 effector cells
4) increased MHC expression, Ag presentation
What are foals born with?
IFN-gamma deficiency –> susceptible to bacterial infections
What’s the fn of Colony-stimulating factors?
- promote terminal differentiation of polypotent progenitor cells
- many expressed in certain tissues, all show altered expression during inflammation
Give some examples of CSF?
G-CSF (granulocyte colony-stimulating factor): neutrophils, eosinophils
Macrophage CSF: monocyte/macrophages
GM-CSF: macrophages or granuloctyes
IL-3: macrophages or granulocytes
IL-7: produced by stromal cells in bone marrow or spleen; proliferation of lymphoid progenitors
IL-11: megakaryocytes
True or False: hematopoiesis is not static
True; many cytokines affect differentiation of leukocytes, and how many cells of a given cell type are produced in the bone marrow can change during inflammatory events because the cytokines produced change over time
What produces IL-1?
wide variety of cell types especially activated macrophages and epithelial cells
-exists in 2 forms: IL-1a and IL-1b (overlapping activities)
What’s the fn of IL-1?
- principal regulator of the host inflammatory response
- Fever induction
- adhesion molecule expression (vascular endothelial)
- acute phase protein expression (hepatocytes)
- activate T cell proliferation during Ag presentation
- synergizes with IL-2 to regulate B cell proliferation
- induces epxression of IL-6 by hepatocytes and macrophages
What produces IL-2?
activated T helper 1 cells
What’s the fn of IL-2?
- cause autocrine proliferation of T cells
- primary growth factor for T cell proliferation
- regulates proliferation of B cells, augments Ig synthesis
- stimulates T cytotoxic cell and NK cell activity against tumors
- enhances macrophage fn
How does IL-2 affect T cell proliferation?
naive T cell recognizes an Ag on surface of an APC responds to IL-2 by undergoing a burst of replication prior to terminal differentiation to effector cells
What produces IL-6?
activated macrophages, T cells, fibroblasts and stromal cells of the bone marrow
What’s the fn of IL-6?
- wide variety of effects on different target cells
- acute phase reactant production (liver)
- endogenous pyrogen which acts on hypothalamus to cause fever
- induces IL-2 expression
- promotes CD8+ T cell differentiation and activation
- acts as cofactor for IgM and IgA synthesis
What produces IL-12?
primarily by dendritic cells and macrophages
-has several subunits synthesized at diff rates
What’s the fn of IL-12?
critical cyotkines that influences differentiation of naive T cells toward T helper 1 pathway (imp for determining type of immune response that perdominates)
-activates NK cells to secrete IFN-gamma
What produces Tumor Necrosis Factor (TNF-alpha)
- principal mediator of endotoxic shock (Gram- sepsis)
- hepatocyte: proliferation (liver regeneration), acute phase protein expression
- macrophage: decreased proliferation, terminal differentiation, increased phagocytosis, adhesion molecule secretion
- endothelial cells: IL-1 expression, adhesion molecule expression
- tumor cells: cytolysis
- elicits fever
What are the local and systemic effects of TNF?
release of TNF induces local protective effect, but can cause damage when released in excess or systemically.
- pleiotropic cytokine has numerous and powerful effects on other cells and systems
- causes leaky channels
- **low quantities: local inflammation
moderate: systemic effects
high: septic shock
Cytokines synergize to do what? What can cytokine storms cause?
impact peripheral immune events and “cytokine storms” can lead to tissue injury, shock and death
What causes endotoxic or septic shock?
overexpression of cytokines (can be induced by products derived from gram- cell walls - LPS or endotoxin) –> induce shock characterized by rapid rise in temperature, vascular leakage, intravascular coagulation, acute phase production and eventually multiorgan failure
What is the major cytokine responsible for pathogenesis of septic shock?
TNF-alpha; produced so quickly that damage is done by time of tx
Do mammalian species vary in their sensitivity to LPS-induced shock?
yes; cat/horse/pig/sheep>dogs>mice»birds
During shock, what do cytokines mediate?
intravascular coagulation –> cold extremities, low BP, organ injury, rapid HR, rapid shallow breathinng
What produces IL-4 and IL-10?
Th2 cells, but activated mast cells release IL-4 from stored vesicles
What’s the fn of IL-4 and IL-10?
considered anti-inflammatory
- T cells: promotes growth of TH2 cells, enhanced proliferation, production of TH2 cytokines, inhibition of TH1 differentiation
- macrophages: inhibits activation
What produces chemokines?
phagocytic cells, T cells, endothelial cells and fibroblasts –> induced by a variety of stimuli during inflammation
-divided into 4 classes based on AA seq (species variation in some genes)
What’s the fn of chemokines?
families of small cytokines which regulate the migration of immune cells into inflammatory loci (contribute to coordination of immune response and inflammation)
***IL-8, MIP-1a, RANTES (coordinates migration of neutrophils, naive T cells, monocytes, NK cells)
How do B and T cells communicate?
using cytokines for both initial activation of B cells, for B cell differentiation into plasma cells, and for Ig class switching (isotype switching)
Give an example of B and T cells communicating with cytokines
ex: cytokines produced by B cells when present Ag –> influence TH0 cells to differentiate into TH2 cells –> augmenting humoral immune responses
ex: assist in Ab isotype switching –> impacts effectiveness of adaptive immune response
T cells generated can influence what?
disease outcome based on cytokines they produce –> often determined by unknown genetic factors of host animal
How does disease relate to cytokines?
numerous diseases known to have a dysregulated cytokines associated with severity or onset
-particularly transplant rejection –> inhibited via cyclosporin A tx and inflammationwhich can damage host cells –> regulated via corticosteroids which inhibit proinflammatory cyotkine production
What are many cytokine genes regulated by?
txn factor NF-kB
What inhibits NF-kB?
steroids inhibit NF-kB activation of cytokines –> limiting inflammation
What is used for rheumatoid arthritis?
anti-TNF-alpha therapy
