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4th Year > Lecture 6 and 7: Cytokine Processing and Activation > Flashcards

Lecture 6 and 7: Cytokine Processing and Activation Flashcards

1
Q

What do cytokines act as?

A

Intracellular messengers

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2
Q

What are cytokines

A

Structurally diverese polypeptides that function as messenger molecules

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3
Q

How do cytokines act as messenger molecules

A
  • They communicate signals from one cell type to another
  • Instruct the cell receiving the signal to proliferate, differentiate, secrete additional cytokines, migrate or die
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4
Q

How do cytokines signal

A

Via plasma membrane borne receptors

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5
Q

How do cytokines interact with their receptors

A

They bind with tight affinity and show high specificity

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6
Q

why are cytokines present at low concentrations

A

They have high affinity for their cognate rerceptors

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7
Q

What do cytokines switch on and off

A

Specific cellular effector funtions

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8
Q

what do cytokines initate

A

Differentiation from one cell state to another

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9
Q

How is cytokines switching on or off effector functions or initiating differentiation achieved

A

Initiating the transcription of a new cohort of genes within the cells, the products of which endow the cell with new or enhanced capabilities

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10
Q

What does IL-2 trigger

A

A transcriptional programme within T cells that enables cells to proliferate upon receipt of a signal

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11
Q

What does TNF induce

A

the trancriptional upregulation of over 50 different cytokines, chemokines, anti-bacterial proteins as well as other immune responses within responsive target cells

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12
Q

What does TNF trigger

A

Activation of neutrophils and local endothelium to upregulate integrins that facilitate extravasation of immune cells and plasma proteins (complement and acute phase) into tissues

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13
Q

What is one of the most important cytokine groupings

A

Interleukins

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14
Q

What does the interleukins contain

A

cytokines that act as communicators between leukocytes

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15
Q

Why are members of the interleukin family diverse

A

The membership is based on biology (evidence of activity on leukocytes) rather than sequence or structural homology

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16
Q

How many interleukins have been described to date

A

38

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17
Q

What other cytokines familes (other than interleukins) have been established based on

A
  • support the proliferation of hematopoietic precursors (colony stimulating factors)
  • cytotoxic activity towards transformed cell types (TNF)
  • ability to interfere with viral replication (interferons)
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18
Q

What do cytokines frequently have

A

pleiotropic effects

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19
Q

What does the response of many cytokines depend on

A

the context in which the cytokine is delivered as well as the cell type receiving the signal

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20
Q

How would you describe the weight of cytokines

A

low weight (15-25kDa)

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21
Q

How are cytokines produced

A

In a transient manner tightly coupled to the presence of foreign material or tissue injury

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22
Q

What primes the mRNA of cytokines for rapid degradation

A

the AU rich sequences in the 3’ untranslated regions

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23
Q

Unlike endocrine hormones, the majority of cytokines normally act in what type of fashion

A

They act locally in a paracrine or even autocrine fashion

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24
Q

What do cytokines derived from lymphocytes rarely do

A

Persist in the circulation

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25
Q

What do the cytokines produced by non lymphoid cells such as endothelial cells and fibroblasts do once the cells are triggered by bacteria

A

they can release cytokines that may be detected in the bloodstream

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26
Q

what is septic shock

A

a life threatening condition that largely results from the massive overproduction of cytokines like TNF and IL-1 in response to bacteria infection

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27
Q

what does septic shock illustrate

A

the necessity to keep a tight rein on cytokine production

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28
Q

What can certain cytokines like TNF and Fas exist as and do

A

membrane anchored forms and can exert their stimulatory effects without becoming soluble

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29
Q

What levels are cytokine production and downstream effector function kept under control at

A
  1. transcriptional
  2. translational
  3. decoy receptors
  4. cytokine receptor antagonists
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30
Q

what do decoy receptors do

A

bind cytokines but do not signal

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31
Q

what do cytokine receptor antagoinsts do

A

compete with cytokines for binding to their cognate receptors

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32
Q

How do cytokines acti

A

in hierarchal cascades

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33
Q

what do cytokines that exert systemic powerful effects lead to

A

the production of numerous additional cytokines, chemokines, complement, anti-microbial peptides and other pro-inflammatory proteins

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34
Q

what do cytokines that have more restricted effects do

A

they have their activities confined to specific cell types and their effects on the production of additional cytokines and chemokines being more limited

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35
Q

how would you sum up cytokines acting in hierarchial cascades

A

some cascades act as apical or upstream regulators of many additional inflammatory factors, while others act in a more distal or downstream role

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36
Q

What are most cytokines regulated by

A

Synthesis and golgi-ER/golgi mediated secretion

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37
Q

Where are most proteins (including cytokines) synthesised and secreted from

A

-Synthesied in the endoplasmic reticulum
-Secreted from the golgi apparatus into the extracellular space

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38
Q

What happens to the certain cytokines that do not undergo Er to golgi secretion

A

They are translated into the cytoplasm and then stored either there or become imported into the nucleus

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39
Q

what are the certain cytokines that do not undergo ER to golgi secretion known as

A

DAMPs

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40
Q

why are DAMPs stored in the cytoplasm or important into the nucleus

A

because their function is to become released upon tissue damage

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41
Q

Why are the selection of the certain cytokines called DAMPs

A

as they are constituitively expressed in tissues and their release is regulated through cell death

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42
Q

What did Polly Matzinger advance

A

the danger hypothesis

43
Q

what does polly matzingers danger hypothesis explain

A

Why cell death in a sterile setting can be a strong initiator of inflammation

44
Q

what does Polly Matzingers danger hypothesis propose in response to cell death in sterile settings initiating inflammation

A

Tissue damage released some sort of cytokine like molecule that could initiate inflammation called danger signals

45
Q

when was the danger hypothesis conceived

A

1994

46
Q

What did Matzinger proprose that the danger would be

A

evolutionary conserved molecules that may have dual functions, one function inside the cell, but a cytokine like function upon release into the extracellular space due to necrosis

47
Q

What do DAMPs now represent

A

hidden self that is revealed during necrosis

48
Q

What probably represents the best candidate for DAMPs

A

Members of the extended IL-1 cytokine family

49
Q

What does the detection of a PAMP signify

A

Danger and warants the initiation of an inflammatory response to coordinate the innate and adaptive immune system

50
Q

What may be insufficient to warrant a full blown inflammatory response

A

The detection of a PAMP in isolation unless this is accompanied by evidence of tissue damage

51
Q

How would the immune response to a PAMP be increased

A

Use of an adjuvant

52
Q

What do adjuvants do

A

They trigger cell death at the site of injection increasing immunogenicity

53
Q

What does the danger hypothesis argue as a result of the adjuvant idea

A

The concurrrent detection of cell death that qualifies whether a non self antigen is dangerous or not and therefore dictates whether an immune response should be elicited

54
Q

Why does using tissue damage to temper the severity of an immune response make good biological sense

A

As ignoring non-self antigens where there is no evidence of tissue disturbance avoids mounting unecessary responses to foreign antigens that are harmless, thus saving tissues from the collateral damage caused by an unwarranted inflammatory response

55
Q

How are IL-1 family members released

A

Via necrosis

56
Q

What is one of the major features required of a DAMP

A
  1. The ability to act as cytokine like molecules upon release into the extracellular space
  2. The molecules should ideally be retained by viable cells and only released in circumstances where necrosis has occured
57
Q

What are the IL-1 family members retained by

A

Viable cells that released in response to a variety of cues that share in common the ability to provoke cell death

58
Q

What do signal 1 (LPS) and signal 2 (toxins, drugs etc) which activate IL-1 have in common

A

the ability to promote plasma membrane permeabilisation leading to necrosis

59
Q

What does the introduction of LPS into the cytosol initiate

A

Pyroptosis

60
Q

How does pyroptosis occur as a result of LPS stimulation

A

The non-canonical inflammasome activation leading to caspase 11 dependent processing of gasdermin D, which permeabilises plasma membranes leading to necrosis

61
Q

what do mice deficient in gasdermin D do/not do

A

they do not undergo pyroptosis and consequently fail to release IL-1B

62
Q

What does the IL-1 family consist of

A

The pro-inflammatory cytokines IL-1a, IL-1B, IL-18, IL-33, IL-36a, IL-36B and IL-36y as well as IL-37 and IL-38

63
Q

What do the IL-1 family of cytokines possess

A

N-terminal prodomains of variable length

64
Q

What can the activity state of the IL-1 cytokines be enhanced through

A

Restricted proteolysis within their N-terminal domains

65
Q

What is unusual about most of the IL-1 family members

A

they exhibit little or no detectable biological activity as full length proteins at physiological concentrations

66
Q

In their active forms, IL-1 family cytokines act as….

A

Potent but differential activators of diverse cell types

67
Q

What can all IL-1 family members promote

A

The release of a diverse array of pro-inflammatory and wound healing factors form many cell types promoting the hallmarks of inflammation

68
Q

What can IL-1 cytokines do to the adaptive immune system

A

Polarise the adaptive immune response to specific types of T cells

69
Q

What have IL-18 and IL-33 been implicated in

A

The activation of local Tregs to induce wound healing responses in the lung and heart

70
Q

What do IL-1 family members signal via

A

Heterodimeric plasma membrane receptors through a common signalling chain

71
Q

What is the common signalling chain of the IL-1 family

A

IL-1RAcP

72
Q

When is IL-1RAcP recruited

A

Upon ligand binding to the receptor

73
Q

What is the motif in the IL-1 receptor family

A

TIR

74
Q

What do IL-1alpha and B signal through

A

IL-R1

75
Q

What does IL-18 signal through

A

IL-18R

76
Q

What does IL-33 signal via

A

IL-33R (ST2)

77
Q

What do the IL-36 cytokines signal through

A

IL-36R/IL-1R2

78
Q

What may IL-37 signal through

A

It might act as an antagonist for the IL-18R but maybe via the orphan IL-1 family receptor SIGIRR

79
Q

Why do IL-1 family cytokines require proteolytic processing for activation

A

IL-1 family cytokines may serve as activity recognition receptors for aberrant protease activity

80
Q

What do the N-terminal prodomains serves as

A

Inhibitory regions to suppress the protease activity

81
Q

What can the N-terminal pro-domains of IL-1 family members be cleaved by

A

By diverse proteases that are not normally present in the intracellular or extracellular spaces

82
Q

What are the three sources of protease activity that have emerged as effectors of IL-1 family cytokine processing

A
  1. Intracellular proteases
  2. Extracellular proteases
  3. Non-self proteases
83
Q

Discuss intracellular proteases

A

These are caspases and calpains, which are activated as a consequence of injury initiated necrosis, or pathogen-driven inflammasome activation that typically results in programmed necrosis (pyroptosis)

84
Q

Discuss extracellular proteases

A

These include elastase, cathepsin H, mast cell chymase, cathepsin S or thrombin that are secreted by first responder cells of the immune system in response to tissue damage or pathogen detection

85
Q

Discuss non-self proteases

A

These include Streptococcal protease SpeB, the Pseudomonas protease LasB, or the house dust mite protease Der p1, that are associated with infectious agents or allergens

86
Q

Why do IL-1 family cytokines require proteolytic processing for activation

A
  • The requirement for an activation step is simply an additional level of regulation that is imposed upon these cytokines to ensure that they are only deployed under the appropriate circumstances (maybe not the most likely)
  • Cytokines have evolved specifically for the purpose of sensing abberant protease activity that is frequently associated with infectious agents or liberated cells of the immune system
87
Q

What may IL-1 family cytokines serve as

A

Activity recognition receptors for molecular activity that betrays a severe deviation form tissue homeostasis and serves as a proxy for the detection of infection or tissue necrosis

88
Q

What has been suggested about protease activity and helminths

A

Since helminths do not have strong PAMPs that readily permit their detection by PRRs, the protease activity may serve as a proxy for the detection of the worms by the immune system

89
Q

In addition to the detection of conserved non-self molecular patterns (PAMPs), what has the immune system co-evolved to do

A

It has co-evolved a system to detec abberant molecular activities that perturb normal tissue and cellular homeostasis as a proxy for the detection of pathogen activity or a severe departure from tissue integrity

90
Q

Why do proteases represent good proxies for infection or tissue damage

A
  1. All infectious agents contain multiple proteases that are often implicated as virulence factors
  2. Multiple proteases are activated upon tissue injury in the context of the coagulation and complement cascade
  3. Proteases are activated intracellularly or released extracellularly in the context of programmed as well as non-programmed necrosis
91
Q

What are proteases associated with

A

Infection, injury, the detection of pathogens and pathogen responses

92
Q

What did the Ruvkan lab suggest

A

Perturbation of key cellular machinery can also trigger pathogen responses

93
Q

What has the IL-1 family cytokines evolved as

A

Sensors for protease activity associated with infectious agents and tissue injury that couple the detection of aberrant protease activity to the rapid initiation of inflammatory responses that coordinate wound healing as well as pathogen clearance

94
Q

What further supports the idea that the IL-1 family cytkines are major initiators of inflammation

A

The family also contains several receptor antagonists or non-signaling decoy receptors

95
Q

What can the loss of function of the IL-1R and IL-36RA lead to

A

Spontaneous autoinflammatory diseases that can be fatal and exacerbated through inducing tissue injury

96
Q

How can inflammation be limited via the actions of the IL-1 family

A

Preventing the release of DAMPs through apoptosis rather than necrosis

97
Q

What are some mechanisms that prevent necrosis occuring involving IL-1 DAMPs

A
  • IL-33 are inactivated through caspase dependent proteolysis in apoptotic cells
  • The pro-domain of IL-1alpha has been found to contain a nuclear localisation signal that tethers the protein within the nuclei of apoptotic cells preventing its escape
98
Q

What therefore is the primary reason for apoptosis

A

To limit the escape of DAMPS during regulated cell death through facilitating the early removal of the cells, destroying their associated DAMPs within the phagolysosomes of the engulfing cell

99
Q

What does processing and activation of IL-1 family cytokines occur by

A

Inflammasome mediated activation of caspase-1

100
Q

What are inflammasomes assembled in response to

A

Noxious detection of intracellular PAMPs

101
Q

Describe the NLRP3 inflammasome

A
  1. The inflammasome is activated by noxius stimuli promoting necrosis.
  2. This leads to potassium efflux which permits assembly and activation of the inflammasome
  3. This liberates the pro forms of IL-1B and IL-18
  4. Caspase-1 activation on inflammasomes enables the latter protease to process and activate IL-1B and IL-18 into their active forms
102
Q

What do neutrophils release as part of the granule

A

Elastase, cathepsin G and proteinase 3

103
Q

What are neutrophil proteases efficient activators of

A

Multiple IL-1 family cytokines

104
Q
A

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