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PATH 415 > Cytokines > Flashcards

Cytokines Flashcards

1
Q

What are cytokines?

A

Proteins/polypeptides secreted by cells of innate & adaptive immunity

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2
Q

When are cytokines produced?

A

In response to microbes/Ags in immune/inflammatory reactions

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3
Q

What is the nomenclature of cytokines based on?

A

Based on cellular sources previously
- “Monokines = produced by mononuclear phagocytes
- Lymphokines = by lymphocytes
- Interleukin = by leukocytes & act on other leukocytes

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4
Q

What are the general properties of cytokines?*

A
  1. Cytokine secretion is a BRIEF, SELF-LIMITED event
    - Synthesis is initiated by new gene transcription (not stored as preformed molecules)
    - Synthesis are transient & rapidly secreted when needed
  2. Cytokine actions are often “PLEIOTROPIC & REDUNDANT”
    - Pleiotropism: 1 cytokine can act on different cell types = diverse effects
    - Redundancy: multiple cytokines have same effects. Hence, antagonist against “a cytokine” = not effective because other cytokines could compensate
  3. Cytokine actions can be LOCAL and SYSTEMIC
    - Act on same cell (autocrine) or on nearby cell (paracrine)
    - Enter circulation & act at a distance from production site (endocrine) ➔ e.g. TNF-a
  4. SYNERGY & ANTAGONISM
    - Synergy - IFN-gamma & TNF = increased expression of class I MHC
    - Antagonism - eg. IFN-gamma activated MO while IL-10 inhibits MO activation
  5. Cytokines initiate their actions by binding to target cell receptors
  6. Expression of cytokine receptors:
    - Regulated by external signals (eg. Ag stimulates T/B cells ➔ increase cytokine receptors)
    - Also regulated by cytokines themselves (+ve amplification or -ve feedback)
  7. Cellular responses to cytokines:
    - Changes in gene expression in target cells
    - Leads to new functions & target cell proliferation (eg. Switching of Ab isotypes in B cells, Th cells differentiated Th1 or Th2 subsets)
    - TIGHTLY REGULATED to turn down these responses (eg. Cytokine induction of genes encoding inhibitors of the cytokine receptors)
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5
Q

There are two types of cytokine receptors. What are they and what are they for?

A

Cytokine receptors consist of 1 or more transmembrane proteins
- Extracellular portion: for cytokine binding
- Cytoplasmic portions: for initiating signalling pathways

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6
Q

What are the signalling pathways for cytokines activated by?

A

Receptor clustering
➔ bringing together the cytoplasmic portions of 2 or more receptors

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7
Q

What is the classification of cytokine receptors based on?

A

Based on structural homologies of the extracellular cytokine binding domains & shared intracellular signalling mechanisms

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8
Q

What are the different classifications of cytokine receptors?

A
  1. Type I cytokine
  2. Type II
  3. IL-1 family - IL-1
  4. TNF - TNF-alpha
  5. Seven-transmembrane a-helical -
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9
Q

What are the cytokine Type I receptors for?

A

IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-11, IL-12, IL-13, IL-15, GM-CSF, G-CSF

Except 1, 8, 10, 14

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10
Q

What are the cytokine type II receptors for?

A

IFN-a/b, IFN-g, IFN-λ, IL-10, IL-20, IL-24, IL-26

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11
Q

What are the cytokine IL-1 family receptors for?

A

IL-1, IL-18

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12
Q

What are the TNF receptors for?

A

TNF-a, TNF-b (lymphotoxin), CD40, Fas, nerve growth factor

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13
Q

What are seven transmembrane a-helical receptors for?

A

Chemokines

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14
Q

Receptors for different cytokines activate distinct signalling pathways. What are the different types of cytokine signalling based on their receptors?

A
  1. Type I & II receptor family (most ILs & IFNs)
    - Involve Janus Kinases (JAK - enzyme) & Signal Transducers & Activators of Transcription (STATs - transcription factors)
    - JAK-STAT: best defined signal transduction pathway
  2. TNF family - cytokine responses depends on particular receptor & cell type
    - pro-inflammatory responses = new gene response
    - TNF-R1 & Fas: cell death signals
  3. Seven transmembrane receptor (for chemokine): involves G protein & the signalling mechanism engages GTP activating various cellular enzymes
  4. Ig receptors: involves receptor-associated tyrosine kinase
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15
Q

What are the 3 main functional categories of cytokines?

A
  1. Mediators & regulators of innate immunity
  2. Mediators & regulators of adaptive immunity
  3. Stimulators of hematopoiesis
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16
Q

In innate immunity, what are cytokines produced by? How do cytokines mediate and regulate innate immunity?

A

Produced by mononuclear phagocytes (NK cells) in response to infectious agents

  1. LPS binds to TLRs on macrophage cell surface ➔ synthesis & secretion of impt cytokines of innate immunity (IL-1, IL-12, TNF-a, IFN-g)
  2. The same cytokine (IFN-g) may also be secreted by macrophage activated by Ag-stimulated T cells (part of adaptive response)
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17
Q

What is the source of tumor necrosis factor (TNFa)? What is the stimulus for the secretion of this cytokine?

A

Activated macrophages

LPS - most potent stimulus

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18
Q

What is the function of TNFa?

A

Recruits neutrophils & monocytes to infection sites ➔ activate these cells to eradicate microbes

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19
Q

What does TNFa act on?

A

Acts on EC & leukocytes: critical for local inflammatory responses to microbes

20
Q

What is bad about the secretion of TNFa?

A

It can injure the host, ex. autoimmune diseases like RA

21
Q

What is the source of IL-12?

A

Macrophages and activated dendritic cells

22
Q

When is interleukin-12 produced?

A

Is an important link between innate and adaptive immunity*
- Produced during early innate immune reactions against intracellular microbes & promoting adaptive immune response to these microbes

23
Q

Which receptor family does IL-12 interact with? Via what pathway?

A

Interacts with type I cytokine receptor family
via Jak-STAT pathway

24
Q

What is the function of IL-12?*

A

Enhances the cytotoxic functions of activated NK cells & CTLs
- Stimulate IFN-g production by T & NK cells*
- IL-12 + IFN-g promote Th1 differentiation*

25
Q

In adaptive immunity, what are cytokines produced by? How do cytokines mediate and regulate adaptive immunity?

A

Produced by T lymphocytes in response to specific recognition of foreign Ag

  1. Regulate growth & differentiation of various lymphocyte populations
  2. Recruit, activate, and regulate specialized effector cells to eliminate Ag
26
Q

What is interleukin-2 (IL-2) produced by?

A

CD4+ T cells

27
Q

What is the peak secretion of IL-2?

A

8-12 hours after activation

28
Q

What is the function of IL-2?*

A

IL-2 is a growth, survival and differentiation factor for T cells

29
Q

What is the source of IL-4?

A

CD4+ T cells & activated mast cells

30
Q

What are the functions of IL-4?

A
  1. Isotype switching to IgE and IgG1 (mouse), IgG4 (human)
  2. Differentiation and expansion of Th2 cells
  3. Inhibition of differentiation of Th1 cells
31
Q

What is the source of IFN-g?

A

NK. CD4+ Th1 & CD8+ T cells

32
Q

Which immune response (innate, adaptive) is IFN-g important to*

A

Both innate and adaptive

33
Q

Where is the site of production for the cytokines that stimulate hematopoiesis? What are their functions?

A

Produced by bone marrow stromal cells & leukocytes

Stimulate growth & differentiation of immature leukocytes

34
Q

What are the chemokines that stimulate hematopoiesis? What are they produced by?

A
  1. IL-7 - fibroblasts and BMSCs
  2. IL-3 - CD4+ T cells
  3. CSFs - activated T cells, MO, endothelial cells and BMSCs
35
Q

What is the function of IL-7?

A

Immature precursors ➔ B & T lymphocytes

36
Q

What is the function of IL-3?

A

Act on immature progenitors ➔ expansion & differentiation into all known mature hematopoietic cell types

37
Q

What is the function of CSFs?

A

Act on BM progenitors to increase production of inflammatory leukocytes

38
Q

What are chemokines produced by?

A

Leukocytes, endothelial/epithelial cells, fibroblasts

inflammation: leukocytes
cell traffic regulation: produced constitutively by cells in tissues

39
Q

What are the 3 key functions of chemokines?

A
  1. Recruit cells of host defence to sites of infection
  2. Regulate traffic of lymphocytes & other leukocytes through peripheral lymphoid tissue
  3. Promote angiogenesis & wound healing
40
Q

What are the examples of cytokines in the innate and adaptive immune system?

A

innate
- TNF-a, IL-1, IL-12

adaptive
- IL-2, IL-4, IL-5, IFN-g

41
Q

What are the sources of cytokines in the innate and adaptive immune system?

A

innate
- MO, NK cells

adaptive
- T lymphocytes

42
Q

What are the functions of cytokines in innate and adaptive immunity?

A

innate
- mediators of innate immunity and inflammation (local & systemic)

adaptive
- activation of lymphocytes growth & differentiation
- activation of effector cells

43
Q

What stimulates the innate immunity and adaptive immunity?

A

innate
- bacterial peptidoglycan
- LPS
- viral RNA
- IFN-g

adaptive
- protein Ag

44
Q

Does innate or adaptive produce more cytokines?

A

innate (high) > adaptive (low)

45
Q

Is innate and adaptive immunity local or systemic?

A

innate - both
adaptive - usually local

46
Q

What is the innate and adaptive immunity’s role in disease?

A

innate
- systemic disease (ex. septic shock)

adaptive
- local tissue injury (granulomatous inflammation)

47
Q

What are the inhibitors of innate and adaptive immunity?

A

innate - corticosteroids
adaptive - immunosuppressants

PATH 415 (10 decks)

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