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BIOL3013- Molecular recognition > Cytokines > Flashcards

Cytokines Flashcards

1
Q

how many known types of cytokines are there?

A

50

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2
Q

how big are cytokines?

A

5-20kDa

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3
Q

where are cytokines released and what to they affect? where are they especially important?

A

released by cells to affect other cells. they are especially important for cells of the immune system.

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4
Q

what are the 4 distinct structural families of cytokines?

A

-TNF (tumour necrosis factor)
-Interferon
-Chemokines
-Hematopoeitin

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5
Q

what about TNF structure is different to the other structural families?

A

exists as a trimer that interacts with 3 TNF2 receptors.

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6
Q

EPO is an example of what sort of cytokine?

A

hematopoeitin

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7
Q

what does the cytokine response depend on?

A

expression of a cognate receptor and the cells type and development.

cell type differentiates what sort of receptors it has on its surface and developmental regulation of receptor expression.

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8
Q

in normal oxygen conditions what occurs to HIf1a?

A

prolyl hydroxylase hydroxylates Hif1a and marks it for ubiquitination/destruction

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9
Q

what occurs in hypoxic conditions to Hif1a?

A

asparagin hydroxylase hydroxylates Hif1a and its activation results in target gene expression

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10
Q

what does EPO stand for?

A

erytropoietin

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11
Q

what does EPO do?

A

stimulates RBC maturation and activates erythroid progenitor cells

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12
Q

what is a CFU-E

A

colony forming unit erytroid

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13
Q

if a CFU-E doesnt interact with EPO what occurs?

A

Apoptosis.

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14
Q

as the erythoroid progenitors differentiate what happens to their EPO receptor number?

A

they dilute. less receptors with each differentiation.

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15
Q

Not all receptors need to be bound with ligand gain physiological response? T/F

A

True. 50% physiological response is gained with approx 18% of receptors being occupied.

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16
Q

what is the Hematocrit?

A

percentage of red blood cells in your blood.

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17
Q

what are some conditions that are causes for low Hematocrit?

A

can tend to be caused by cancers that increase production of other types of blood cells.

lymphoma: increased B/T lymphocyte WBC

Hodgkins lymphoma: increased lymphocyte WBC

leukaemia: increased immature WBC

MULTIPLE MYELOMA: increased myeloma cells (malignant plasma cells in bone marrow) reduces production of several blood producing stem cells on the expense of RBC production.

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18
Q

what is EPO uses for in the treatment of disease?

A

treating anemia in conditions like:
chronic kidney disease,

infalmmatory bowel disease (Crohn’s and ulcer colitis),

myelodysplasia (resulting from exposure to chemicals like benzene and treatment of cancers using radio and chemotherapy)

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19
Q

what is JAK?

A

a kinases that senses the downstream signal from EPO->EPO-R -> JAK

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20
Q

where does JAK bind to the EPO-R?

A

bound at the tail of the receptor. each receptor can bind to a JAK kinase.

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21
Q

on the EPO-R where is the transmembrane alpha helix bound?

A

at the surface of the cell.

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22
Q

Upon binding of ligand what happens to the receptor and the JAK kinase?

A

cytokine binding causes the dimerisation of the cytokine receptor.

phosphorylation of the associated JAK kinase also occurs leading to its activation.

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23
Q

What about the dimerisation leads to the phosphorylation of the JAK?

A

dimerisation brings the JAK kinases closer together allowing them to phosphorylate eachother.

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24
Q

what occurs with the phosphorylation of the JAK’s?

A

further phosphorylation of additional residues. (hyperphosphorylation)

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25
Q

upon hyperphosporylation of the EPO-R what occurs that leads to a signal cascade?

A

It is recognised by a inactive monomeric transcription factor STAT. it recognises the phosphorylated tails of the receptors and in doing so leads to the phosporylation of STAT.

26
Q

what occurs after STAT is activated by phosphorylation?

A

it gets released from the receptor and dimerises with another STAT revealing its ‘nuclear localisation signal’ allowing for its entry into the nucleus to bind to DNA and activate transcription.

27
Q

In SH2 domains what residue gets phosphorylated?

A

Tyrosine.

28
Q

what is the short term adaptation to regulate cytokine action in the case of the JAK STAT pathway?

A

SHP1. has a phosphatase domian that nibbles off the phosphate at the lip domian of the JAK. Also has a SH2 domain that binds to the following phosphate on the tail.

29
Q

what about SHP1 structure allows for its selective activity?

A

is folded in a way that it is inactive in the cell and only gets activated upon binding to inactive kinases when needed.

30
Q

What is the long term adaptation to regulate the cytokine response in the JAK STAT pathway?

A

SOCS. bind to each individual phosphate. has a SH2 domain and SOCS box each. the SOCS box is very attractive to E3 (ubiquitin ligase) that binds to SOCS signalling it for destruction.

31
Q

What other pathways other than JAK STAT does EPO signal?

A

GRB/Shc: regulates the Ras/MAP kinase pathway

Phospholipase Cgamma: regulate Ca2+ levels

PI-3 kinase: activate the protein kinase B pathway

32
Q

in the JAK STAT pathways which STAT regulates what cytokines?

A

STAT-1: INFgamma
STAT-1, -2: IFNalpha/beta
STAT-5: EPO

33
Q

what does STAT stand for?

A

signal transduction and activation of transcription

34
Q

Describe the conformation of the IFNy Interferon

A

Alpha helical dimeric ligand. has 2 receptors.

35
Q

In normal oxygen levels what do prolyl hyroxylases do to HIF1a?

A

they hydroxylate HIF1a and mark it for ubiqutination/destruction

36
Q

In hypoxic conditions what occurs to HIF1a?

A

gets hydroxylated by Asparagin hydroxylase. leads to its activation and results in target gene expression.

37
Q

What does EPO do and what is it?

A

Erytropoietin stimulates RBC maturation. it activates erythroid progenitor cells and is a cytokine.

38
Q

What are the steps in the JAK-STAT signalling cascade

A
  1. cytokine binding
  2. Receptor dimerisation
  3. JAK activation
  4. STAT binding
  5. STAT phosphorylation
  6. STAT dimerisation and translocation
  7. Gene expression
39
Q

What is the SH2 domain and its involvement in the JAK STAT pathway?

A

A conserved protein domain of around 100 amino acids in length that is found in a variety of intracellular signaling proteins. It binds specifically to phosphorylated tyrosine residues on target proteins and is an important component of the JAK/STAT signaling pathway.

40
Q

What is the role of JAK in the JAK-STAT signaling cascade?

A

JAK (Janus kinase) proteins are activated by cytokine or growth factor binding to cell surface receptors and phosphorylate tyrosine residues on the receptors’ cytoplasmic tail, creating docking sites for STAT proteins.

41
Q

What is the role of STAT in the JAK-STAT signaling cascade?

A

STAT (Signal Transducers and Activators of Transcription) proteins bind to the phosphorylated docking sites on receptors and are themselves phosphorylated by JAKs. Phosphorylated STATs then form homo- or hetero-dimers and translocate to the nucleus to act as transcription factors for target genes.

42
Q

What is the role of C-terminal phosphorylation in the JAK-STAT signaling cascade?

A

C-terminal phosphorylation of STAT proteins by JAK is crucial for their activation and dimerization. Once the STAT proteins are phosphorylated, the phosphate tail of one monomer binds to the SH2 domain of the other monomer, forming a dimeric transcription factor that can translocate to the nucleus and regulate gene expression.

43
Q

What is SHP1?

A

SHP1 (Src homology 2 domain-containing phosphatase 1) is a protein tyrosine phosphatase that can directly dephosphorylate tyrosine residues on receptors and signaling molecules in the JAK-STAT pathway, thereby inhibiting downstream signaling.

44
Q

What is the function of SHP1?

A

SHP1 plays a role in regulating immune cell activation and differentiation by acting as a negative regulator of cytokine signaling. It acts as a short-term adaptation to cytokine signaling, rapidly dampening the response to cytokine stimulation.

45
Q

What are SOCS proteins?

A

SOCS (Suppressor of Cytokine Signaling) proteins are a family of intracellular proteins that act as negative feedback regulators of cytokine signaling by inhibiting JAK-STAT activation.

made up of a SOCS box (has a E3 ubiquitin ligase system) and SH2 domain (binds to the phosphate)

46
Q

How do SOCS proteins work?

A

SOCS proteins bind to phosphorylated tyrosine residues on receptors and JAKs, preventing the recruitment and activation of downstream signaling molecules. In addition, SOCS proteins can also target activated receptors for degradation. SOCS acts as a long-term adaptation to cytokine signaling, preventing chronic activation and maintaining homeostasis.

47
Q

What is the role of SOCS in the immune system?

A

SOCS plays an important role in controlling the intensity and duration of immune responses to maintain proper immune function and prevent overactivation or self-damage. Dysfunction or dysregulation of SOCS can contribute to the development of various immune disorders and diseases.

48
Q

What does STAT stand for?

A

SINGAL TRANSDUCTION and ACTIVATION of TRANSCRIPTION

49
Q

What is IFN-y

A

interferon gamma. is a cytokine that is produced by immune cells such as T cells and NK cells.

plays a critical role in the immune response to infections and tumours. It can activate immune cells to kill infected or cancerous cells. Is able to regulate inflammation and promote the growth and differentiation of certain cells.

50
Q

how does INFy orchestrate viral defence?

A

Signals through the JKA-STAT pathway. it stimulates the production of > 300 genes including cytokines that can have autocrine and paracrine action.

Autocrine: can move towards infected cell and inhibit virus replication and lead to apoptosis.

paracrine: move towards direct neighbours and can upregulate MHC-1 and NK cell activation

T cells and NK cells produce INFy.

51
Q

What are interferons?

A

Interferons are proteins that play a critical role in the body’s immune response to viral infections.

52
Q

What is IFNα/β?

A

IFNα/β is a type of interferon produced by dendritic cells and fibroblasts in response to viral infections.

53
Q

What is the signaling pathway for IFNα/β?

A

IFNα/β signals through the Jak1/Tyk2 pathway and STAT1/2 heterodimers.

54
Q

What are the functions of IFNα/β?

A

IFNα/β activates the transcription of genes that stimulate the immune response, promote the destruction of infected cells, and inhibit viral replication.

55
Q

What is the signaling pathway for IFNγ?

A

IFNγ signals through the Jak1/Jak2 pathway and STAT1 homodimers.

56
Q

What is the difference between IFNα/β and IFNγ?

A

IFNα/β is produced by dendritic cells and fibroblasts, signals through STAT1/2 heterodimers, and activates antiviral proteins.

IFNγ is produced by T-cells and NK cells, signals through STAT1 homodimers, and activates genes that promote the immune response and inhibit viral replication.

57
Q

what is the signalling pathway for EPO?

A

via JAK2 and STAT5 homodimers.

58
Q

What are the stages of wound healing?

A

The stages of wound healing include the early phase (recruitment of inflammatory cells), the proliferative phase (production of growth factors, cytokines, and chemokines), and the resolution of inflammation.

59
Q

What happens during the early phase of wound healing?

A

During the early phase of wound healing, inflammatory cells such as neutrophils and macrophages are recruited to the wound site by chemo-attractants such as CXCL8 and PDGF. These cells work to clear infections and debris from the wound.

60
Q

What happens during the proliferative phase of wound healing?

A

During the proliferative phase of wound healing, growth factors such as PDGF stimulate the growth of new tissue. Cytokines and chemokines are also produced to coordinate the activities of the cells involved in wound healing.

61
Q

What is the role of platelet activation in wound healing?

A

Platelet activation releases growth factors such as PDGF, which help to attract more cells to the wound site and stimulate the growth of new tissue.

62
Q

Why is the resolution of inflammation important in wound healing?

A

While inflammation is important for clearing infections and promoting healing, it can also be damaging if it persists for too long. Therefore, the transition to an anti-inflammatory response is important for allowing healing to occur.

BIOL3013- Molecular recognition (7 decks)

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