Cytokines/Chemokines 1 & 2 Flashcards
(90 cards)
1
Q
3 chemical mediators of inflammation?
A
1) lipid mediators
2) plasma proteins
3) cytokines & chemokines
2
Q
cytokines
A
- cyto=cell; kine=movement
- secreted immunomodulatory proteins
- carry signals locally between cells, and thus have an immune system effect on other cells
3
Q
Chemokines
A
- chemoattractant cytokines
- are distinct from cytokines in structure & classes of receptors recognizing them
- play critical role in efficient & target recruitment of specific immune cell populations
4
Q
cytokines &Chemokines
A
- have diff structure & classes of receptors that recognize them
- some functions do overlap though
5
Q
Chemokines and cytokines functions?
A
- recruit cells to site of injury/infections
- activate specific pathway for differnetiation/activation in response to injury/infection
- help macrophages/dendrites find lymph node
6
Q
describe the kinetics (timing) of the inflamamtory response to microbial infection?
A
- inflammation, things happen in specific time zones
- controlled by specific chemokines & cytokines expressed
- see inflamm response is a regulated, choreographed dance
7
Q
What controls what Chemokines and cytokines are expressed?
A
- the signals sent by PAMPs/DAMPs/other inflamm receptors in respond to cell stress, injury, or pathogen
- the type of activating event will determine which chemokines & cytokines are released
8
Q
What are Chemokines?
1) size
2) function
A
- chemoattractants for specific leukocyte subsets
- very small 8-10KD
9
Q
Chemokines in healthy homeostasis?
A
- CCL21 chemokine is heavily expressed in lymph nodes; naive T cells are attracted them
- this signal retains naive T cells in the lymph node
10
Q
Chemokines in early innate immune response?
A
- CCL2 chemokine produced in damaged tissue (receptor= CCR2)
- recruits macrophages & neutrophils to tissue
- shows how diff chemokines recruits diff types of cells*
11
Q
vascular permeability & chemokines?
A
- chemokines regulate vascular permeability by only attracting specific leukocytes into the tissue
- if not being signaled, then the cell will not move into the tissue
- is how make vascular permeability more tightly regulated
12
Q
autoimmunity & chemokines?
A
- inappropriate induction of specific chemokines causes inappropriate recruitment of activated immune cells to the site of abnormal chemokines expression
13
Q
how else can chemokines stimulate specific immune cells?
A
- in a receptor specific manner
- can lead to proliferation & activation of specific immune cells
14
Q
How do chemokines act?
A
- through binding G-protein coupled receptors on leukocytes (very diff than how cytokines act)
- pathogens that interfere/impair GPCR can effect chemokine signaling
15
Q
2 ways chemokines bind GPCR
A
1) tethered presentation: bind extracellular matrix of cell that produced it; is anchored to parent cell & then bind GPCR of leukocyte to activate it
2) secreted: are soluble can be secreted by parent cell, diffuse away and bind GPCR of distant leukocyte
16
Q
tethered presentation of chemokines?
A
- chemokine receptor expressing cells can be recruited to specific sites by the tethered presentation of the recruiting chemokine to it’s parent cell
- is how can recruit leukocytes to specific tissue
17
Q
different classes of chemokines?
A
-target different classes of immune cells & promote different types of inflammatory response
18
Q
CXC chemokines? what do they target
A
- alpha chemokines
- have 1 AA residue separating first two conserved cysteine residues
- targeted to neutrophils than to other immune cells
19
Q
number of X’s tell you?
A
- number of X’s (0-3) tells you how many amino acids away the two conserved cysteines are from eachother
- have structure-function relationship, CXC’s bind similar receptors & have similar functions; CXXC’s bind similar receptors & have similar functions
20
Q
exception to CXC family?
A
- CXCL13
- this chemokine involved with lymphocyte homing, attracts B cells & makes B cell follicles
- doesn’t attract not neutrophils
21
Q
CC chemokines
A
- Beta chemokines
- have first two conserved cysteine residues directly adjacent (no amino acids in between)
- many produced by monocytes
- not chemoattractant for neutrophils
22
Q
CCL11 chemokines?
A
- is Eotaxin
- specifically recruits eosinophils
23
Q
C chemokines
A
- Gamma chemokines
- lack 1st & 3rd cysteines
- tend to be chemoattractant for specific lymphocyte subsets
24
Q
CXXXC chemokines?
A
-CX3CL1 is the only member & only example of a chemokine that’s cleaved from the cell surface
25
What recruits expression of specific chemokine? What happens after?
- PAMPs + DAMPs induce expression of specific chemokines
| - the specific chemokines recruit immune cells & cytokines to the vicinity of injury/infection
26
PAMPs
- anything bacteria has that humans do not
- have unique PAMP receptor for each one, depending on which is activated, leads to different activations of cytokines
ex: flagella, proteoglycan etc
27
DAMPs
- receptors for anything that is chemically abnormal in the host cells
- ex: high ATP (indicate cell lysis)
28
do chemokines make covalent bonds with ECM of leukocytes as they are secreted?
-no; are not covalent bonds, just stuck on the leukocyte
29
What is the receptor for CCL2? What does CCL2 and receptor do? Where are they expressed?
- CCL2 is chemokine produced in damaged tissues & expressed on damaged epithelia's extracellular matrix
- CCR2 is expressed on monocytes/ other leukocytes
- attracts them to site of injury/pathogen
30
Foam cell?
macrophage full of phagocytosed debris
31
Two ways CCL2 chemokine is secreted?
1) produced in damaged tissues & expressed on damaged epithelia's extracellular matrix
2) by activated Foam cells (macrophages that are full of phagocytosed debris)
32
How is adaptive immune response activated?
-coordinated by regulating both expression of chemokines & expression of the chemokine receptors
33
5 steps in chemokine activation of adaptive immune response
1) CCL21 high expressed in lymph node (LN)
2) Naïve T cells express receptor for CCL21 (CCR7); move to LN from thymus
3) Activated dendritic cells carrying antigen express CCR7; run to LN cuz drawn to it's CCL21 expression
4) Mature (activated) dendritic cells present antigen to naïve T-cells in LN
5) Activated effector T cells down-regulate CCR7 & leave LN cuz they are no longer retained in the lymph node by CCL21
34
-why can activated effector T cells leave lymph nodes once activated?
- their activation causes a down regulation of CCR7
| - without CCR7, they can no longer “see” CCL21 in lymph node so have no reason to stay
35
How do activated effector T cells get to other tissues after leaving LN?
-activation causes other chemokine receptor production which draw them to damaged tisses
36
What are Naïve T cells?
-antigen-inexperienced T cells, have never seen antigen before
37
CCL21?
-chemokine expressed highly in lymph nodes that attracts naive T-cells as well as activated (antigen carrying) dendrites/macrophages
38
CCL21 receptor?
- CCR7
| - naive T cells & ctivated (antigen carrying) dendrites/macrophages contain this receptor
39
When do dendrites/macrophages present CCR7 receptor?
- only after their PAMP/DAMP/ other receptors are activating signaling damage or pathogenicity
- when bind to antigen, is activated & CCR7 can be expressed on surface
40
Inappropriate expression of chemokines and/or receptors leads to?
- associated with specific inflammatory diseases
| ex: rheumatoid arthritis, MS
41
Chemokine Receptor Antagonists for therapeutics?
- in current trials as therapies for chronic inflammatory & autoimmune disorders as well as lymphomas
- no break out chemokine based therapies yet though
42
why no “break-out” chemokine based therapies?
- chemokines participate in a wide variety of functions (from development, normal function, tissue defense & repair)
- it's difficult to target a disease's specific process
43
How are GPCR receptors for chemokines organized?
- by they action/consequence
| - ex: inflammatory, homeostatic, atypical, viral
44
What are cytokines?
- cell derived factors
- small soluble molecules (~25KD); larger than chemokines
- can exist as monomer or multimer; can function alone or as trimer
45
how are cytokine actions mediated?
- via specific receptors.
- have both autocrine & paracrine actions
- have some systemic actions
46
Autocrine actions
- regulating self behavior
| - the action is on cell the producing the cytokine
47
Paracrine
- regulating adjacent cells
- the action is on cells in the vicinity of the cell that is producing the cytokine
- ex:
48
cytokine systemic actions?
- yes, some
| - effects of TNF, IL-6 & IL-1 on liver's production of chemical mediators of inflammation (CRP etc)
49
What determines which cytokine is made?
- the immune & tissue cells produce cytokines in response to cell damage or the presence of pathogens
- which cytokine made depends on which receptor was bound & activated, and how much of the signal was received (PAMP, DAMP etc)
50
3 steps of cytokine release & effects on. macrophage?
1) Bacteria bind macrophage & triggers to cleanse cytokines& chemokines
2) vasodilation & increased vascular permeability cause redness, heat & swelling
3) inflammatory cells migrate into tissue, releasing inflammatory mediators that cause pain
51
cytokine structure?
- cytokines are structurally diverse (diff than chemokines)
| - initially classified into interleukin families (ILs)
52
Cytokines receptors?
- cytokine actions mediated by Jak/Stat receptors
- NOT GPCR (chemokines use GPCR)
- cytokine receptors are activated by dimerization
53
Intracellular signaling pathways of cytokines & chemokines?
- they differ
- chemokines= GPCR
- cytokines= Jack/Stat
54
Jack/Stat overview?
1) cytokine receptor consists of 2 chains; the cytoplasmic domains bind JAK kinase
2) cytokine bind, dimerize receptor, cytoplasmic domains JAK activate eachother & phosphorylate receptor (cross-phosph)
3) Trxn factors (STAT) bind to phosphorylated receptor, are phosph. & activated by JAKs
4) phosph. STAts forom dimers, translocate unit nucleus & imitate new gene trxn
55
Which are easier to therapeutically target; JAK/STAT or GPCR?
- JAK/STAT
| - means cytokine pathway is easier to target
56
What are the 3 modes of cytokine action?
1) Global
2) Local
3) Final (net) effects)
57
Global cytokine action?
- behavioral responses and systemic immune responses
| - have literal effect on our personality/behavior
58
Local actions of cytokines?
-regulating differentiation of lymphocytes, antigen- presenting cells and innate immune cells
59
Final (net) effect actions of cytokines?
- Based on the ratio & concentrations of specific cytokines present
- tell concentration by seeing on how much signal transduction signals are coming from the receptors
- is how tailer & adapt our immune response
60
What are the 4 cytokines released from an activated macrophage?
1) IL-1B
2) TNF-a
4) IL-6
5) IL-12
61
IL-1B local effects? (x4)
1) activates vascular endothelium
2) activates lymphocytes
3) local tissue destruction
4) increases access of effector cells
62
IL-1B systemic effects? (x2)
1) fever
| 2) production of IL-6
63
TNF-a local effects? (x3)
1) activates vascular endothelium
2) increases vascular permeability, which allows increased IgG entry, increase cells into tissue, increased fluid drainage into lymph nodes
3) activates complement
64
TNF-a systemic effects? (x2)
1) fever
2) mobilization of metabolites
3) shock
65
IL-6 local effects? (x2)
1) lymphocyte activation
| 2) increased antibody production
66
IL-6-a systemic effects? (x2)
1) fever
| 2) induces acute-phase protein production
67
IL-12 local effects? (X2)
1) activates NK cells
| 2) induces differentiation of CD4 T cells into TH1 cells
68
cytokines & programmed sickness behavior?
-Cytokines shape a coordinated inflammatory response that includes programmed “sickness behavior”
69
what is sickness behavior? what causes it?
- anorexa, lethargy, slow-wave sleep, decreased social behavior, decreased reproductive behavior
- due to IL-1B, IL-6, TNF-a acting on brain as a result of a pathogen binding a macrophage
70
why is sickness behavior a good thing evolutionarily? From a biology standpoint?
1) are weak, don't want to be around others who can kill you
- isolate self until healed; protecting own gene pool
2) it promotes conservation of resources w/ generation of toxic env for the invading pathogen
71
Why sickness behavior include anorexia?
-if don't eat, blood isn't full of metabolites for the pathogen, make pathogen work harder for materials
72
Fever importance?
- fever means you're hot, means metabolism is faster
& require more energy to do the same work
-increased protein denaturation/lifespan
-hopefully both cause death of pathogen
73
side effects of certain cytokine inhibitors?
-certain inhibitors can cause depression and other symptoms cuz are blocking the healthy actions of cytokines on the brain
74
IL-1, IL-6, and TNF-a act on what tissues during sickness behavior?
1) liver
2) bone marrow epithelium
3) hypothalamus
4) fat/muscle
5) dendrtic cells
75
What determines the final effector function of antigen-activated T cells?
-Cytokines produced by antigen-presenting cells
(dendrites, macrophages, B cells)
-all are the same CD4 T cells; depending on PAMP/DAMp determines pathway/end result
76
TGF beta (alone) effect on CD4 T cell?
- made in high levels in brain, ovaries, testes
- makes Treg cells
- Treg cells cause increased production of TGF-B as well as IL-10 ( anti-inflamm cytokine)
77
IL-10
-anti-inflamm cytokine produced by T reg cell
78
TGF-Beta + IL-6?
- IL-6 made by innate cells, TGF-B in brain, ovaries, testes
- makes CD4 T cell--> TH-17
- TH-17 makes IL-6 & IL-17 which both activate more neutrophils
- indicates in early part of immunity
79
IL-12+ IFN-gamma effect on CD4 T-cell?
- turns it into TH 1 cell
- TH1 cell releases: IL-2 & IFN-gamma
- increases T cell proliferation, IFN-super killers, ROS species
80
IL-4 cytokine effect on CD4 T cell?
- makes CD4 into TH2 cells
- produce IL-4 & IL-5 cytokines
- both help make antibodies & fight parasites
81
IL-4 & IL-5
-help make antibodies & fight parasites
82
How does body determine stage & pathogen specific immune responses?
- cytokines produced vary by the severity and type of infection/tissue damage
- this help to determine severity- and pathogen- specific immune responses
83
cytokines & innate immune response? good or bad?
- Cytokine expression can amplify innate immune responses
| - if amplifies locally this is good; but if causes a systemic amplification is bad & can lead to septic shock
84
How does sepsis happen?
-when the inflamm response is worse than the pathogen
85
Explain how an over response of immune system could happen in response to a hand infection to gram - bacteria?
1) macrophages activated in liver & spleen to secret TNF-Alpha into bloodstream
2) systemic edema occurs
3) decreased blood volume causes collapse of blood vessels
4) disseminated intravascular coagulation leading to wasting & multiple organ failure
5) death
86
What does systemic edema cause?
1) decreased blood volume
2) hyperpoteinemia
3) neutropenia
4) neutrophilia
87
Explain how a correct response of immune system could happen in response to a hand infection to gram - bacteria?
1) macrophages activated to secrete TNF-alpha locally in tissue
2) increase: release of plasma protein into tissue. phagocyte & lymphocyte migration into tissue
3) phagocytosis of bacteria; local vessel occlusion, plasma + cells drain to lymph node
4) removal of infection w/ adaptive immunity
88
therapies to block cytokines?
- yes
- have anti-TNF therapies to treat Rheumatoid arthritis & Psoriasis
- but are not first line of defense
89
why are anti-TNF not our first line therapies for all chronic inflammatory diseases?
- TNF is required for normal pathogen defense
| - w/o TNF you are immunodeficient so on these anti-TNF meds your risk for infection is huge
90
issues with anti-TNF therapies and the brain?
- TNF promotes proliferation of myelinating cells & remyelination during demyelinating diseases (MS)
- Anti-TNF therapies associated w/ increased demyelination & nerve damage in individuals with diagnosed (and previously undiagnosed) CNS diseases
