LECTURE 5 Flashcards

1
Q

describe cytokines in general

A

low MW –> 5-25 kDa

regulate nature, intensity, and duration of response

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2
Q

3 cytokines originally named based on their function

A
  1. Lymphocyte activating factor = IL1
  2. B cell growth factor = IL4
  3. B cell differentiation factor = IL5
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3
Q

6 main groups of cytokines

A
  1. lymphokines –> made by lymphocytes (IL2)
  2. monokines –> made by monocytes (TNF, IL1)
  3. interleukins –> made by leukocytes
  4. IFN –> pro-inflammatory, anti-viral
  5. CSF –> growth of immune cells at maturation stages (G-CSF)
  6. chemokines –> IL8/CXCL8
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4
Q

where are chemokines secreted?

A

at infection site or allergy

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5
Q

how do chemokines cause cell movement?

A

cause cells to follow concentration gradient
- promote cell shape change thru actin polymerization and breakdown
- leukocytes extend pseudopodia for cell movement

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6
Q

another function of chemokines besides cell movement?

A

promote recruitment and activation of cells

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7
Q

how do immune cells differ from other cells with regards to movement?

A

other cells have polarity inherently that allows movement

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8
Q

4 classes of chemokine receptors

A
  1. C –> 2 cysteines + 1 bond (lymphotactin/XCL1)
  2. CC –> 4 cysteines (1st 2 adjacent) + 2 bonds (rantes/CCL5)
  3. CXC –> 4 cysteines (1st 2 have aa btwn) + 2 bonds (IL8/CXCL8)
  4. CX3C –> 4 cysteines (1st 2 have 3 aa btwn) + 2 bonds (fractalkine/CXC3L1)
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9
Q

describe extravasation process

A
  1. pro-inflammatory cytokines
  2. selectin on endothelium, integrin on leukocytes
  3. leukocytes bind endothelium
  4. cell moves from blood to tissue
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10
Q

role of chemokines in LN/spleen
3 examples

A

allows immune cell segregation

  1. stromal cells –> CCL21 –> DCs move into LN
  2. DCs –> CCL19 –> recruit T cells to T cell zone
  3. fDCs –> CXCL13 –> recruit B cells to follicle
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11
Q

what is autocrine?

A

cytokine acts on the cell it came from –> ex. IL2 for T cell activation

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12
Q

what is paracrine?

A

cytokine acts on nearby cells –> IFN protects nearby cells from viral infection

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13
Q

5 major cytokine receptor families

A
  1. Type 1 (hematopoietic)
  2. Type 2 (IFN)
  3. TNFR
  4. IL1R
  5. chemokine receptor
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14
Q

examples of cytokines signaling thru type 1 receptors
- and signaling pathway

A

IL2-9, IL11, IL12, G-CSF

signals thru diff combos of JAK and STAT

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15
Q

how does IL6 signaling work?

A
  1. IL6 binds common alpha chain and gp130 chain
  2. JAK binds and is phosphorylated
  3. STAT3 is phosphorylated and dimerizes
  4. STAT3 goes to nucleus
  5. activates TFs for apoptosis, proliferation, and survival genes
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16
Q

examples of cytokines signaling thru type 2 receptors
- and signaling pathway

A

IFNalpha, IFNbeta, IFNy, IL10, IL20, IL24, IL26

signals thru diff combos of JAK and STAT

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17
Q

role of Type I IFN and signaling path

A

Type I IFN = a and B –> anti-viral

phosphorylates STAT1/STAT2 complex –> binds IRF9

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18
Q

role of Type II IFN

A

Type II IFN = y –> activate macrophage, anti-viral

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19
Q

examples of cytokines signaling thru TNF receptors
- and signaling pathways (3)

A

TNFa, TNFB, LTb, FasL, CD40L, and NGF

  1. NF-kB –> pro-inflammatory
  2. AP1 –> proliferation + differentiation
  3. Caspase 8 –> apoptosis
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20
Q

General effects of TNF

A
  1. vasodilation/vascular leak
  2. recruit leukocytes
  3. coagulation, NETs
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21
Q

when are there positive effects of TNF?
what are they?

A

positive when LOCAL infection
- increased blood flow
- increased vessel permeability
- increased cell migration to tissue
- increased endothelial adhesiveness for cells
- increased clotting (prevent spreading infection)

22
Q

when are there negative effects of TNF?
what are they?

A

negative when SYSTEMIC infection
- vasodilation = decreased BP
- permeability = decreased plasma vol
- septic shock
- clots in small vessels, using up clotting proteins
- bleeding, organ failure

23
Q

what happens if there’s mutant TNFR

A

no septic shock but increased local infection

24
Q

what happens with anti-TNF Ab?

A

infection spreads via blood

25
Q

examples of cytokines signaling thru IL1R receptors
- and signaling pathway

A

IL1a, IL1b, IL18, IL33

NFkB + MAPK/AP1 –> pro-inflammatory genes

26
Q

2 examples of chemokine receptors, signaling pathway?

A

IL8, CCL5

signals thru MAPK

27
Q

structure of type 1 cytokine receptor

A

4 alpha helix strands

28
Q

3 subclasses of type 1 cytokine receptor

A

common gamma
common alpha
common beta

29
Q

IL2 receptor subfamily of type 1 receptors

A

IL2, IL15, IL7, IL9, IL4
uses common gamma

30
Q

IL6 receptor subfamily of type 1 receptors

A

IL6, IL11, CNTF, LIF/OSM
uses common alpha with common gp130

31
Q

GM-CSF receptor subfamily of type 1 receptors

A

GM-CSF, IL3, IL5
uses common beta

32
Q

what does pleiotropic mean?

A

1 cytokine = different response

33
Q

what could cause pleiotropy?

A

diff ORF, alternative splicing, and epigenetics

34
Q

what is redundancy?

A

many cytokines = same response

35
Q

describe how redundancy helps/doesn’t help if person has a mutation

A

without IL2, person is fine bc IL15,7,9 take over

without specific receptor subunit, no effect

without common receptor subunit = XSCID

36
Q

what is synergy?

A

multiple cytokines work together to give a respone

37
Q

what is antagonism?

A

cytokines with opposite response

38
Q

what is purpose of antagonism?
example?

A

limit a response and achieve balance

IFNy activates macrophage and IL10 inhibits macrophage

39
Q

describe cytokine potency

A

act at very low concentrations: nanomolar (10^-9) to fentomolar (10^-15)

too potent = cytokine storm

40
Q

what is cytokine cascade effect?

A

cytokines stimulate production of other cytokines

41
Q

4 ways cytokines are regulated

A
  1. cytokine expression
  2. receptor expression
  3. signaling
  4. inhibitory cytokines
42
Q

describe regulation of cytokine expression (4)

A

A. pre-forms that are activated (IL18)
B. rapid induction (IL6, TNF, IL12)
C. brief release and self-limiting
D. sequestered by binding proteins

43
Q

describe how cytokine receptors help with regulation (5)

A

A. receptors only on certain cells
B. IL1R antagonist blocks IL1
C. expression affected by environment
D. endocytosis after binding
E. receptor shedding –> cleaved by enzymes and acts as soluble decoy receptor

44
Q

describe how signaling helps with regulation (2)

A

A. SOCS
B. IkB binds NFkB and blocks its nuclear transport in unstimulated cells

45
Q

describe SOCS

A

induced by JAK/STAT and work via negative feedback loop

46
Q

describe how inhibitory cytokines help with regulation

A

A. IL10 inhibits T cell differentiation
B. TGFB

47
Q

what would happen without cytokine regulation? (3)

A
  1. chronic infection/inflammation
  2. autoimmunity
  3. allergy
47
Q

anti-cytokine Ab (3)

A
  1. anti-TNF, anti-IL1, anti-IL6 for RA
  2. anti-TNF for septic shock
  3. anti-IL2 for graft rejection
47
Q

4 examples of cytokine therapy

A
  1. IL2 (melanoma and kidney cancer)
  2. G-CSF, GM-CSF (neutropenia during cancer therapy)
  3. IFNa –> virus, cancer
  4. erythropoietin –> increased RBC in anemia
47
Q
A
48
Q
A