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Biochemistry > Exam 2 Lecture 13 > Flashcards

Exam 2 Lecture 13 Flashcards

1
Q

In the inflammatory response, what key actions do cytokines control?

A

Proliferation, differentiation, migration, and apoptosis

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2
Q

What happens if there is dysregulation of the inflammatory response?

A

Excessive inflammation in chronic inflammatory disease or abnormal proliferation in cancer can occur

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3
Q

How does the network of cytokine targeted immune cells demonstrate the pleotropic nature and cascade effect of cytokine signaling?

A
  • Certain cytokines (like IL-1) can stimulate many cell types
  • Some cytokines can trigger the expression of other cytokines (cascade effect)
  • Some can stimulate a broad inflammatory response in response to injury or infection (like IL-1, INFs, and TNF𝛼)
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4
Q

How does the cytokine network typically start?

A

Macrophages are the ones that normally starts a lot of the pathways.

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5
Q

What role does cytokine signaling pathways and regulation play in immunology?

A
  1. Macrophage release of chemokines induces the migration of lymphocytes
  2. B cell development and gene recombination to produce antibodies
  3. Cell differentiation of blood cells (like T cells)
  4. T cell activation
  5. Cell proliferation
  6. Wound healing
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6
Q

For both pro-inflammatory and anti-inflammatory responses, is the expression of cytokines and cytokine receptors regulated?

A

Yes, the expression of both cytokines and cytokine receptors is highly regulated

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7
Q

Infection/injury activates macrophages to do what?

A

Macrophages are able to detect when there’s a problem so then when an infection or injury occurs, resident macrophages of a tissue are activated to release cytokines which will then recruit other cells to the area.

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8
Q

What are the prominent cytokines that are released when pro-inflammation is needed?

A

IL-1𝛽, IL-6, IL-12, TNF-𝛼, CXCL8 (a chemokine)

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9
Q

What are the biological effects of IL-1𝛽 and TNF-𝛼?

A

They induce blood vessels to become more permeable which enables effector cells and fluid containing soluble effector molecules to enter the infected tissue.

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10
Q

What are the biological effects of IL-6?

A

It induces fat and muscle cells to metabolize, make heat and raise the temperature in the infected tissue.

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11
Q

What are the biological effects of CXCL8?

A

It recruits neutrophils from the blood and guides them to the infected tissue.

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12
Q

What are the biological effects of IL-12?

A

It recruits and activates natural killer (NK) cells that then secrete cytokines that strengthen the macrophages’ response to infection.

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13
Q

What is the process of the recruitment of neutrophils?

A

Overall process: neutrophils go from rapidly traveling in blood capillaries (minimal attachment via selectin protein) to tight binding and migration into the infected tissue

  1. Tight binding due to interaction with ICAM-1 whose expression is induced by cytokines
  2. CXCL8 is secreted by macrophages which adds to the interaction and leads to the penetration of the endothelium
  3. Neutrophils migrate along the concentration gradient of CXCL8 to the infected tissue
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14
Q

What allows neutrophils to roll along the endothelium?

A

Weak selectin mediated adhesion

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15
Q

What are the 4 steps to the recruitment of neutrophils to the infected tissue?

A
  1. rolling adhesion
  2. tight binding
  3. diapedesis
  4. migration
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16
Q

What are the 3 interactions that pull neutrophils into the area?

A
  1. Weak selectin mediated adhesion
  2. Interaction with ICAM-1
  3. Interaction with CXCL8
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17
Q

Many cytokines involved in cell growth and immunity use which types of cytokine receptors?

A

Type I and type II cytokine receptors that have multiple chains

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18
Q

Cytokines that recognize the common gamma chain activate what 3 major signaling pathways that promote cellular survival and proliferation?

A
  1. PI3 kinase/Akt pathway
  2. RAS-MAPK pathway
  3. JAK-STAT (signal transducer and activator of transcription) pathway
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19
Q

The 3 major signaling pathways have what type of inflammatory response?

A

Pro-inflammatory response

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20
Q

The common gamma chain family cytokines serve as critical regulators of what?

A

The development, survival, proliferation, differentiation, and/or function of multiple immune cell types

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21
Q

What is JAK and STAT?

A

JAK are tyrosine kinases and STAT is more intracellular and not associated with the receptor. STAT is able to dimerize and can then interact with DNA.

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22
Q

What do the RAS-MAPK pathway and the JAK-STAT pathway have in common?

A

Both pathways involve a nuclear component and activate gene expression.

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23
Q

IL-6 is secreted by what?

A

Macrophages and other cells

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24
Q

What is the structure of IL-6?

A
  • Helical structured cytokine with 4 helical bindles
  • Has multiple subunits: common gamma chain, gp130, and IL-6R alpha chain (multiple chain receptor)
  • The association of IL-6 with IL-6 R alpha promotes the association with gp130 and the formation of a heterohexameric complex
  • Activation upon IL-6 binding turns on 3 signaling pathways
25
Q

What does IL-6 do?

A

It stimulates acute phase protein synthesis, production of neutrophils, and regulates inflammation

26
Q

What is the disease role of IL-6?

A
  • Contributes to inflammatory and auto-immune processes in RA, multiple sclerosis, systemic lupus, prostate cancer, and multiple myeloma
  • Cancer: role in chronic inflammation and regulating tumor microenvironments and metastasis
  • Enterovirus 71: contagious, causes mild illness hand/foot/mouth disease but also encephalitis (in children)
27
Q

What are some examples of anti-IL-6 agents?

A
  1. Tacilizumab and Sarilumab: antibodies against IL-6 R alpha to treat RA (FDA approved)
  2. Siltuximab: antibody against IL-6 for Castleman disease (lymphoproliferative disorder)
    - Antibodies are so large that they only work on the extracellular side!
28
Q

What is unique about IL-6?

A

It is a heterohexameric complex that can activate the same 3 pathways (PI3K/Akt pathway, JAK-STAT pathway, and MAPK pathway)

29
Q

What are the important takeaways of IL-6?

A
  1. IL-6 binds to IL-6R alpha chain which then triggers an association with gp130
  2. IL-6 is pro-inflammatory so it turns on inflammation and if it’s activated too much, it can cause autoimmune diseases
30
Q

What is IL-13 thought of to be?

A

The central mediator of physiologic changes induced by allergic inflammation

31
Q

What is the biological effect of IL-13?

A

Anti-inflammatory by inducing expression of matrix metalloproteinases to protect against excessive allergic inflammation

32
Q

What is the receptor for IL-13?

A

Heterodimer complex of IL-4R𝛼 and IL-13R1

-the heterodimerization of receptors upon binding of IL-13 and the assembly recruits and activates STAT6

33
Q

What are the target cells of IL-13?

A

Airway fibroblast cells and gut cells

34
Q

What is the mechanism of signaling for IL-13?

A

IL-13 signals through STAT6 to regulate gene expression of cells critical to the balance between immune defense and allergic inflammation and differentiation into TH2 cells (T helper cells) → pathological TH2 cell activity is hallmark allergic inflammation

35
Q

What is the drug target for IL-13?

A

Dupilumab is an antibody against the heterodimeric receptor to treat asthma (aka receptor blockade)

36
Q

Why does the name of the receptor not dictate what cytokine binds to it?

A

For example, IL-13 is first recruited by IL-13R𝛼1 and then IL-4R𝛼 binds

37
Q

What is the essence of cytokine receptor interactions?

A

Receptor cytokine interactions involve multiple chains of the receptor and multiple steps of receptor binding to form these hetero-oligomeric complexes that is the active form

38
Q

How many Ig domains does IL-4R𝛼 have?

A

2 Ig domains

39
Q

How many Ig domains does IL-13R𝛼1 have?

A

3 Ig domains

40
Q

When was IL-17A discovered?

A

1993 from rodent T-cell hybridoma

41
Q

What is IL-17 secreted as?

A

Secreted as a homodimer and heterodimer IL-17A/F from several immune cells including activated T cells

42
Q

What are the receptors of IL-17A?

A

Heterotrimer IL-17RA/IL-17RC

43
Q

What are the target cells of IL-17A?

A

Macrophages, T cells, endothelial cells, and fibroblasts

44
Q

What is the signaling pathway of IL-17A?

A

Signaling pathway involves ACT1 (an adaptor protein) association with intracellular receptor regions (activates them and trimerizes them) and series of kinases (activated by adaptor proteins) which promotes the expression of pro-inflammatory cytokines, chemokines, and anti-microbial peptides

45
Q

What are the biological effects of IL-17A?

A

Primarily pro-inflammatory immune responses and is beneficial against infection from bacteria and fungi

46
Q

How is IL-17A detrimental?

A

It is highly expressed in chronic inflammatory diseases like asthma and COPD and dampens anti-tumor immunity

47
Q

What is the drug target for IL-17A?

A

Secukinumab: antibody against IL-17A that has FDA approval to treat psoriasis

48
Q

TNF𝛼 exists as what?

A

Exists as a membrane anchored form and as a soluble form (that gets cleaved off) and both forms bind to the same receptor

49
Q

What are the receptors of TNF𝛼?

A

cys rich domains, TNFR1, and TNFR2 (TNFR = tumor necrosis factor receptor)

50
Q

How do TNFR1 and TNFR2 have a yin-yang effect?

A

TNFR1 is constitutively (always) expressed on most cell types and is pro-inflammatory and apoptotic. TNFR2 is restricted to endothelial, epithelial, and some immune cells and is anti-inflammatory and promotes cell proliferation. TNFR2 activity is regulated.

51
Q

When infection is detected, what cells release TNF𝛼?

A

Lymphocytes and monocytes release TNF𝛼 along with IL-1, IL-6, and interferon 𝛾

52
Q

What is the role of TNF𝛼?

A

TNF𝛼 regulates immune cells and can induce fever, apoptosis, and inflammation.

53
Q

What is the signaling pathway of TNF𝛼?

A

The signaling pathway is complex and involves a number of components → leads to receptor oligomerization and changes in intracellular protein-protein interactions to generate the active complex of multiple proteins

54
Q

What pathways does TNF𝛼 activate?

A

Activates NK-kB or MAPK pathways and specific gene expression → signaling effects are complicated and conflicting (but caspase 3 and Bid pathway leads to apoptosis)

55
Q

What is the disease role of TNF𝛼?

A

Cancer and autoimmunity but dysregulation is implicated in Alzheimer’s, depression, and IBD

56
Q

What is a drug target of TNF𝛼?

A

Tasonermin: TNF𝛼 (itself) is used as an immunostimulant drug to treat certain cancers → basically stimulates its own system to fight cancer

57
Q

How does the TNF𝛼 complex form?

A

The complex forms intracellularly, and the activating receptor results in differences in the complex formed which can lead to activation of various pathways

58
Q

How do we interfere with protein-protein interactions?

A

Using biologics which have a large surface area that may/may not have an easy way to bind a small molecule (usually binds/sits inside a small pocket that looks like substrate) → high affinity that can involve a large surface area so a small molecule is not the same thing

59
Q

Do antibodies have high specificity?

A

Yes they have high specificity and since we want to bind multiple things, we have to compete with a lot of things

Biochemistry (18 decks)

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