What are small soluble proteins and glycoproteins that regulate and mediate host immune responses via direct action on cells?
How many cytokines are there? How much variety?
Have significant _____ role in host defense
Do they locally or at a distance?
Rapidly _____ or ____ immune activites
- large number, lots of variety
- activate, suppress
Cytokines vs. Hormones/Neurotransmitters
numerous -- usually single source
many -- single cell or tissue
pleiotropic and overlapping -- single, defined activity
autocrine (acts on self), paracrine (acts on another cell of same type), endocrine (acts on different type of cell) -- endocrine
picomolar -- nanomaolar
Can cytokines cross the blood brain barrier?
What are the two ways they get into things (and explain)?
What makes cytokines in the brain?
- Diffusion (circumventricular organs - lack a blood brain barrier), transportation (transported by transporters)
- microglial cells (like the brains macrophages)
(Cytokines - general properties)
Are they antigen specific in action?
Are they pleiotropic? What does this mean?
Can an individual cytokine be made by more than one cell type?
Can they act on many cell types?
- What type of expression do they show?
- Have ____, ____ actions
- Influence the ____ and _____ (____ and _____) of other cytokines
- Signal through what?
- Do they serve strictly immune functions?
- no (they act on other host cells)
- yes, may have different activities in different situations
- brief, highly regulated
- redundant, overlapping
- synthesis, action (synergy, antagonism)
- specific receptors
- no - they have non-immune functions
(Cytokines - Families/Nomenclature)
_____ - stimulators of hematopoiesis that regulate immature _____ growth and differentiation. These factors drive the ______ of hematopoietic _____. Examples?
______ - Mediators and regulators of lymphocytes and leukocytes. These factors are regulators of both ____ and ____ functions of other immune cells. This group is very ____ in structure and function. WIDE RANGE OF FUNCTIONS Examples?
______ - Mediators and regulators of antiviral and innate immunity. These factors can activate intracellular processes that inhibit _____ replication. In addition, several members are key regulators of ____ activity and tolerance of the developing _____. Examples?
_____ - Chemoattractants. These factors regulate the directed movement of immune cells from the blood into tissues. Examples?
- growth factors, leukocyte, terminal differentiation, progenitors
- granulocyte-colony stimulating factor (G-CSF); marcophage-CSF; oncostatin M; Interleukin-3 (IL-3)
- Interleukins (IL), innate, adaptive, diverse.
IL-2, IL-6, IL-8, IL-10, IL-12, Tumor necrosis factor -a (TNF-a)
- Interferons (IFN), viral, macrophage, fetus.
- IFN-gamma, IFN-alpha, IFN-beta
- MIP-1a, IL-8, RANTES, MCP-2
- expressed on ____ cell types and show ________.
- How specific for their ligands?
In regards to structure?
- Do receptors share some subunits?
- How are they grouped into families?
- How many types of cytokine receptors can a cell express?
- many, considerable regulation of expression
- very specific
- can be single subunit, or multimeric (homomultimeric and heteromultimeric)
- based on signal transduction mechanisms or molecular structure
- many kinds
- ______ interferons with related ____ (and _____)?
- Expressed in response to _______
Why are they called interferons?
How many types?
Type IFNs are any ____ or _____
- 3-5, structure, function
- immune response
- interfere with viral replication
- IFN-alpha or IFN-beta
(IFN-a/b type 1)
- Actually consists of a family of _____; involved in _____. Released from ______ cells of all types - but ____, _____, and _____ are primary sources. These cells can accelerate the differentiation of _____, thereby influencing the ____ response to specific antigens.
What are the three things this type does to fight viruses?
HE JUST SAID - JUST REMEMBER - IFN-a/b are antiviral
- glycoproteins, anti-viral activity, virus-infected, T cells, macrophages, fibroblasts, B cells, antibody
1. activate host genes to inhibit viral RNAs and replication
2. induce MHC class I expression on the host cells (presenting more antigens - increase chances of encountering cytotoxic C-cells)
3. activate NK cells to kill virally-infected cells
Produced mainly by?
Most Potent what?
(Are viruses always endogenous?)
(HE DIDN:T TALK ABOUT THE REMAINDER OF THIS SO DON't STUDY - just read - he just wants us to remember macrophage activation)
(It stops macrophage migration, activates pro-inflammatory cytokine gene expression, augments phagocytosis, increases anti-tumor and antibacterial processes, and upregulates MHC expression. It also influences the production of immunoglobulin isotypes and stimulates the nerutophil respiratory burst. Finally, IFN-gamma activates vascular endothelial cell adhesion molecules expression)
- T helper cells and NK cells
- activator of macrophage immune function
What animal is interferon gamma deficient at birth? What does this mean they will have trouble with?
- foals, bacteria?
- Promote the terminal differentation of ______ or _____ progenitor cells.
- Many are constitutively expressed in certain tissues, but all show altered _____ during _____
What are the four he wants us to know and what do they do?
- omnipotent, polypotent
- expression, inflammation
1. Granulocyte colony-stimulating factor (G-CSF): neutrophils, eosinophils
2. Macrophage CSF (M-CSF or CSF-1): monocyte/macrophages
3. GM-CSF: macrophages or granulocyes
4. IL-7: produced by stromal cells in the bone marrow or spleen; proliferation of lymphoid progenitors
- Many cytokines affect differentiation of _____, and how many cells of a given cell type are produced in the bone marrow can change during ____ events because the cytoknes produced change over time. THAT IS _ HEMATOPOEISIS IN NOT STATIC!
- leukocytes, inflammatory
- A principal regulator of ______
- produced by wide variety of cell types, esp. activated _____ and _____
What two forms does it exist in?
What are the three funtions he wants us to remember that IL-1 (+ where they occur)?
- host inflammatory response
- macrophages, epithelial cells
- IL-1alpha and IL-1beta (have overlapping activities)
1. Hepatocytes - acute phase protein expression
2. CNS - fever induction, sleepiness
3. vascular endothelia - adhesion molecule expression (important for getting cells out of blood and into the site of inflammation) and IFN-gamma synthesis
What is it produced by?
What does it do (main thing)?
- regulates proliferation of _____ (in cooperation with IL-1) as well as augments ___ synthesis
- Stimulates _____ and ____ activity against tumors
- Enhances ____ function
- IL-2 is the primary growth factor for ______ proliferation. A ____ T cell recognizes an antigen on the surface of an APC respsonds to IL-2 by undergoing a burtst of _____ primor to terminal differentiation to effector cells.
- T cell use IL-2 to make copies of itself
- activated TH1
- autocrine proliferation of T-cells
- B cells, Ig
- T cytotoxic cell, NK cell
- naive, replication
- produced by activated ______, and _____
- What are the functions?
- macrophages, T cells
- acts on the liver hepatocytes to induce synthesis of acute-phase proteins (important for clearing bacteria) - these stick to bacteria and give macrophages and nuetro;hils a better chance of phagocytosing bacteria
- Also an endogenous pyrogen which acts on the hypthalamus to cuase fever
- a critical cytokine that influences _______
- produced primarily by ____ and _____
Because IL-12 impacts the ___ vs. ___ balance, it is extremely important for determining the type of immune response that predominates
- Important for making T cells into ____
- differentiation of naive T cells toward Th1 pathway
- dendritic cells, macrophages (major antigen presenting cells)
- Th1 (make cytokines for innate immunity), Th2 (helpful for B cells)
(Tumor Necrosis Factor)
- What is the most important and powerful and active cytokine?
- principal mediator of ______
- Produced by activated ___ and ____
- elicits _____
DOES THE FOLLOWING
3. Tumor Cells
4. Endothelial Cells
- endotoxic shock (gram negative sepsis)
- macrophages, NK cells
1. increased catabolism, acute phase protein expression, proliferation
2. decreased proliferation, terminal differentiation, increased phagocytosis, reactive oxygen products, adhesion molecule expression, IL-1 production, IL-6 production, IL-12 production, GM-CSF secretion
4. IL-1 expression, adhesion molecule expression
- TNF-alpha affects the biology of many cell types, and greatly impacts the strength of the ______ response
these are the ones to know
What is the biggest stimulus for macrophages?
1. TNF, IL-1, IL-6
2. activates monocytes and macrophages to make more cytokines, adhesion molecules, coagulation factors, iNOS
4. acute phase proteins
- endotoxin-LPS (give it gamma interferons and THF-alpha?)
- Macrophages make TNF and IL-1 that act on the ________ and express adhesion molecules (cause things like _____ to go into site of inflammation through _____)
- so really important for getting ___ out of the blood to where you need them
- vascular endothelium, neutrophils, tight junctions
(Local and System Effects of TNF)
Release of TNF induces local _____, but can cause _____ when released in ____ or _____. This _____ cytokine has numerous and powerful effects on other cells and systems.
What can too much cause?
- protective effects, damage, excess, systematically, pleiotropic
- leaky vasculatare throughout whole body, deprivation of nutrients, death
What happens at
low quantities? (< 10^-9)
High quantities (> 10^-7)
- local inflammation
- systemic effects (brain - fever, liver - acute phase proteins, bone marrow - make luekocytes)
- septic shock (thrombus (clot up), leakiness in blood vessels), liver-hypoglycemia, heart -low output)
Cytokines _____ to impact peripheral immune events, and ______ can lead to tissue injury, shock, and death
Remember that there is much overlap in cytokine activity - for example (____/____/____-alpha) (Liver - ____) - (Hypothalamus - increased ____)
Remember that cytokines are very important for ____
- synergize, cytokine storms
- IL-1, IL-6, TNF-alpha
- acute phase proteins, body temp
(Endotoxic of Septic Shock)
What causes this?
induced by products derived from ______ (___ or ___)
- shock characterized by.... (don't memorize these)
What is the major cytokine responsible for pathogenesis of septic shock?
Cytokines mediate intravascular coagulation during shock - what does this lead to.... (don't memorize these very well)
- Do mammalian species have different sensitivies to LPS?
- overexpression of cytokines
- gram-negattive cell walls (LPS or endotoxin)
- rapid rise in temp, vascular leakage, intravascular coagulation, acute phase production, eventually multiorgan failureWhat is the major cytokine responsible for pat
- cold extremities, low blood pressure, organ injury, rapid heartbeat, rapid shallow breathing (basically lead to clotting and occlusion of blood vessels - good if local - if systemic not so much)
- yes (cat, horse, pig, sheep, human > dogs > mice >> birds)
(IL-4 and IL-10)
- Principal regulators of the _______
- produced mainly by ___ cells, but activated ____ release ___ from stored vesicles
- Are considered _____
What do they do?
1. Macrophages (IL-4 and 10)
2. T Cells (I-10 only)
3. T cells (IL-4 only)
- humoral immune response
- Th2, mast cells, IL-4
1. inhibit activation
2. inhibition of Th1 differentiation
3. promote growth of Th2 cells, Enhanced proliferation, production of Th2 cytokines, inhibition of Th1 differentiation
- Families of small cytokines which regulate _______ into inflammtory loci
- Produced by ____, ____, ____, ____ (dm)
- induced by a variety of stimuli during ___
- Divided into __ classes based on ____
- How many chemokines? one for each cell type?
- Chemokines are important contributors to coordination of the ____ and ____
- migration of immune cells
- phagocytic cells, T cells, endothelial cells, fibroblasts
- 4, AA sequence
- 50, no!
- immune response, inflammation
What Chemokines (3) does he want us to know and what do they do?
Any white blood cell can be moved to where you want it to go by using chemokines!
- Chemokines are important contributors to coordiation of the _____ and _____
1. CXCL8 (IL-8) - moves neutrophils and naive t-cells to correct spot
2. CCL3 (MIP-1alpha) - drives movement of monocytes and NK and T cells
3. CCL5 (Rantes) - drives movement of monocytes, and NK and T cells
- immune response, inflammation
(Misc. Cytokine Info)
involved in all aspects of immune response
- B and T cells communicate using cytokines for (three things)
- just look at (don't memorize picture)
- for example, cytokines assist in antibody _____ switching. This impacts the effectiveness of the _______.
1. initial activation of B cells
2. B cell differentiation into plasma cells
3. Ig class switching
- isotype switching, adaptive immune response
- The Th cells which are generated can influence disease outcome based on the ____ they produce. This is often determined by _____ of the host animal
What form has more TH1 cytokines present?
What form has TH2 cytokines present?
- cytokines, unknown genetic factors
- dry form
- wet form
(Manipulation of the Immune Response)
- how is this done?
- for example, you give _____ to mute ____ - they do this by blocking gene expression of _____
- transplant recognition can be inhibited via _____ treatment, which targets ____ activation
- by using cytokines
- corticosteroids, inflammation, proinflammatory cytokines
- cyclosporin A
(Steroids inhibit inflammation)
- Many cytokine genes are regulated by the transcription factor ____. ____ inhibit NK-kB activation of cytokings, thus limiting ____.
- Anti TNF-alpha therapy is used for ________
- NF-kB, steroids, inflammation
- rheumatoid arthritis