Lecture 15: Cytokine Signals

Question 1

Cytokine signaling function

Answer 1

-macrogphages to induce cell migration
-B cell development for Igs
-blood differentiation
-T cell activation
-cell proliferation
-wound healing

Question 2

Expression of cytokines and receptors

Answer 2

-highly regulated
-control pro and anti inflammatory response

Question 3

Macrophage release of chemokines induces

Answer 3

neutrophil migration

Question 4

Neutrophil migration

Answer 4

-innate immunity
-infection activates macrophage to release chemokines that recruit cells
-IL-1B, TNF-a, IL-6, CXCL8, IL-12
-all lead to inflammation

Question 5

Cytokines released from macrophages

Answer 5

-IL-1B
-TNF-a
-IL-6
-CXCL8
-IL-12

Question 6

IL-1B and TNF-a

Answer 6

-increase blood vessel permeability
-allow cells and fluid to enter infected tissue

Question 7

IL-6

Answer 7

-induces fat and muscle metabolism
-raise temp in tissue

Question 8

CXCL8

Answer 8

-recruits neutrophils from blood and guides them to tissue

Question 9

IL-12

Answer 9

-recruits/activates NK cells that secrete cytokines that strengthen macrophage response

Question 10

Neutrophil in absence of infection

Answer 10

-circulate in blood
-rolling adhesion on selectin

Question 11

selectin

Answer 11

-glycoproteins that weakly bind to sialyl-Lewis X carbs on neutrophills in blood stream
=rolling adhesion

Question 12

Neutrophil recruitment

Answer 12

1. Rolling adhesion
2. Tight binding
3. Diapedesis
4. Migration

Question 13

ICAM-1

Answer 13

-cell-adhesion molecule
-induced by TNFa
-binds LFA-1 on neutrophils

Question 14

Tight binding

Answer 14

-ICAM-1 initiates binding to LFA-1 integrin on neutrophils

Question 15

Diapedesis

Answer 15

-after binding LFA-1, neutrophils can cross endothelium

Question 16

Migration

Answer 16

-CXCL8 secreted by macrophages directs neutrophils across endothelium and to the tissue
-moves along gradient of CXCL8

Question 17

monocytes (premacrophage)

Answer 17

-similar process to neutrophils
-recruited by CCL2

Question 18

CXCL8 is a chemokine because

Answer 18

it promotes movement of various immune cells in a certain direction

Question 19

Cytokine Receptor families (excluding chemokine/GPCR)

Answer 19

-TNF
-Type I and II cytokine receptors
-IL-1
-IL-17

Question 20

TNF receptor family

Answer 20

-trimeric cysteine
-TNF-a
-fibronectin domain

Question 21

Type I and II families

Answer 21

-both have JAK/STAT pathways
-IL-6
-cysteine

Question 22

IL-1 receptor family

Answer 22

Ig like

Question 23

IL-17 family

Answer 23

-IL-17 ligand

Question 24

fibronectin domain

Question 25

TNFa

Answer 25

-membrane anchored or soluble forms -released by lymphocytes and monocytes during infection -target TNFR1 and 2 -fever, apoptosis, inflammation

Question 26

TNFa release

Answer 26

-from lymphocytes and monocytes -along with IL-1, IL-6, interfeon y

Question 27

TNFa receptors

Answer 27

-cys rich domains -TNFR1 and TNFR2

Question 28

TNFR1

Answer 28

-constitutively expressed on most cell types -PRO inflammatory -apoptotic

Question 29

TNFR2

Answer 29

-restricted to endothelial, epithelial, some immune cells -ANTI inflammatory -cell proliferation

Question 30

TNFa signaling pathway

Answer 30

-TNFa binding leads to receptor oligomerization -generates active complex of multiple proteins -activates NF-kB or MAPK pathway -effects often conflict

Question 31

TNFa dysregulation

Answer 31

-alzheimers, depression, IBD

Question 32

Tasonermin

Answer 32

-TNFa itself -immunostimulant to treat some cancers

Question 33

Etanercept

Answer 33

-treat rheumatoid arthritis and psoriarisis -prevent ligand binding to receptor -fusion protein made by recombinant DNA -extracellular TNFR2 fused to Fc region of IgG1 antibody

Question 34

Type I receptors

Answer 34

-common chain for different subfamilies = redundancy -IL-15 and IL-4 y chain -GM-CSF and IL-5 B chain -IL-6 and IL-11 gp130 chain

Question 35

common chain type I

Answer 35

-cytokine binds to a subunit -complex associates with B subunit (cross-react) -signal transduced through B subunit (redundancy)

Question 36

IL-6 and receptor common gp130 and signaling pathways

Question 37

IL-6

Answer 37

-PRO inflammatory -secreted by T cells -important for differentiation of T and B cells

Question 38

IL-6 receptor signaling

Answer 38

-forms heterohexameric complex : (IL-6, gp130, IL-6Ra) x2 -common gp130 chain response activates PI3K, JAK, MAPK -stimulates accute phase protein synthesis, survival, production of neutrophils, regulates inflammation

Question 39

Heterohexameric complex

Answer 39

-association of IL-6 with IL-6Ra -then with gp130 = trimer -trimer dimerizes

Question 40

JAK/STAT pathway

Answer 40

-type I and II receptors 1. JAK kinase w/ receptor 2. cytokine binding dimerizes receptor = pair of JAK kinases 3. JAK activated, phosphorylzes receptor 4. STAT docks and is phosphorylated 5. pSTAT dissociates and pSTAT dimerizes 6. pSTAT dimer goes to nucleus and mediates transcription of target gene

Question 41

Redundancy from

Answer 41

-common chain -all stimulate B cell proliferation -all trigger JAK/STAT pathway

Question 42

IL-6 dysregulation

Answer 42

-rheumatoid arthritis, sclerosis, lupus, prostate cancer, myeloma

Question 43

IL-6 in cancer

Answer 43

-chronic inflammation -regulation of tumor microenvironments and metastisis

Question 44

Enterovirus 71

Answer 44

-contagious -mild illness -hand/foot/mouth disease -LEADS to ENCEPHALITIS which IL-6 contributes to

Question 45

Drugs against IL-6

Answer 45

-siltuximab -tocilizumab and sailumab

Question 46

siltuximab

Answer 46

-antibody against IL-6 -binds ligand so it cannot get to receptor -treats castleman disease

Question 47

tocilizumab and sarilumab

Answer 47

-Igs against soluble and membrane bound IL-6R -treat rheumatoid arthritis -bind to receptor

Question 48

IL-17

Answer 48

-homodimer and heterodimer of IL-17 A and F -secreted by T cells -thought to be heterotrimer with C

Question 49

IL-17 targets

Answer 49

-macrophages -T cells -endothelial cells -fibroblasts

Question 50

IL-17 signaling pathway

Answer 50

-ACT 1 association with receptor and kinases -increase expression of PRO inflammatory cytokines

Question 51

IL-17 effects

Answer 51

-PRO inflammatory -good vs bacteria and fungus

Question 52

IL-17 overexpression

Answer 52

-asthma -COPD -dampens anti-tumor immunity

Question 53

Secukinumab

Answer 53

Ig against IL-17A -treat psoriaisis