Lecture 15: Cytokine Signals Flashcards
Cytokine signaling function
-macrogphages to induce cell migration
-B cell development for Igs
-blood differentiation
-T cell activation
-cell proliferation
-wound healing
Expression of cytokines and receptors
-highly regulated
-control pro and anti inflammatory response
Macrophage release of chemokines induces
neutrophil migration
Neutrophil migration
-innate immunity
-infection activates macrophage to release chemokines that recruit cells
-IL-1B, TNF-a, IL-6, CXCL8, IL-12
-all lead to inflammation
Cytokines released from macrophages
-IL-1B
-TNF-a
-IL-6
-CXCL8
-IL-12
IL-1B and TNF-a
-increase blood vessel permeability
-allow cells and fluid to enter infected tissue
IL-6
-induces fat and muscle metabolism
-raise temp in tissue
CXCL8
-recruits neutrophils from blood and guides them to tissue
IL-12
-recruits/activates NK cells that secrete cytokines that strengthen macrophage response
Neutrophil in absence of infection
-circulate in blood
-rolling adhesion on selectin
selectin
-glycoproteins that weakly bind to sialyl-Lewis X carbs on neutrophills in blood stream
=rolling adhesion
Neutrophil recruitment
- Rolling adhesion
- Tight binding
- Diapedesis
- Migration
ICAM-1
-cell-adhesion molecule
-induced by TNFa
-binds LFA-1 on neutrophils
Tight binding
-ICAM-1 initiates binding to LFA-1 integrin on neutrophils
Diapedesis
-after binding LFA-1, neutrophils can cross endothelium
Migration
-CXCL8 secreted by macrophages directs neutrophils across endothelium and to the tissue
-moves along gradient of CXCL8
monocytes (premacrophage)
-similar process to neutrophils
-recruited by CCL2
CXCL8 is a chemokine because
it promotes movement of various immune cells in a certain direction
Cytokine Receptor families (excluding chemokine/GPCR)
-TNF
-Type I and II cytokine receptors
-IL-1
-IL-17
TNF receptor family
-trimeric cysteine
-TNF-a
-fibronectin domain
Type I and II families
-both have JAK/STAT pathways
-IL-6
-cysteine
IL-1 receptor family
Ig like
IL-17 family
-IL-17 ligand
fibronectin domain
TNFa
-membrane anchored or soluble forms
-released by lymphocytes and monocytes during infection
-target TNFR1 and 2
-fever, apoptosis, inflammation
TNFa release
-from lymphocytes and monocytes
-along with IL-1, IL-6, interfeon y
TNFa receptors
-cys rich domains
-TNFR1 and TNFR2
TNFR1
-constitutively expressed on most cell types
-PRO inflammatory
-apoptotic
TNFR2
-restricted to endothelial, epithelial, some immune cells
-ANTI inflammatory
-cell proliferation
TNFa signaling pathway
-TNFa binding leads to receptor oligomerization
-generates active complex of multiple proteins
-activates NF-kB or MAPK pathway
-effects often conflict
TNFa dysregulation
-alzheimers, depression, IBD
Tasonermin
-TNFa itself
-immunostimulant to treat some cancers
Etanercept
-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
Type I receptors
-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
common chain type I
-cytokine binds to a subunit
-complex associates with B subunit (cross-react)
-signal transduced through B subunit (redundancy)
IL-6 and receptor common gp130 and signaling pathways
IL-6
-PRO inflammatory
-secreted by T cells
-important for differentiation of T and B cells
IL-6 receptor signaling
-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
Heterohexameric complex
-association of IL-6 with IL-6Ra
-then with gp130 = trimer
-trimer dimerizes
JAK/STAT pathway
-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
Redundancy from
-common chain
-all stimulate B cell proliferation
-all trigger JAK/STAT pathway
IL-6 dysregulation
-rheumatoid arthritis, sclerosis, lupus, prostate cancer, myeloma
IL-6 in cancer
-chronic inflammation
-regulation of tumor microenvironments and metastisis
Enterovirus 71
-contagious
-mild illness
-hand/foot/mouth disease
-LEADS to ENCEPHALITIS which IL-6 contributes to
Drugs against IL-6
-siltuximab
-tocilizumab and sailumab
siltuximab
-antibody against IL-6
-binds ligand so it cannot get to receptor
-treats castleman disease
tocilizumab and sarilumab
-Igs against soluble and membrane bound IL-6R
-treat rheumatoid arthritis
-bind to receptor
IL-17
-homodimer and heterodimer of IL-17 A and F
-secreted by T cells
-thought to be heterotrimer with C
IL-17 targets
-macrophages
-T cells
-endothelial cells
-fibroblasts
IL-17 signaling pathway
-ACT 1 association with receptor and kinases
-increase expression of PRO inflammatory cytokines
IL-17 effects
-PRO inflammatory
-good vs bacteria and fungus
IL-17 overexpression
-asthma
-COPD
-dampens anti-tumor immunity
Secukinumab
Ig against IL-17A
-treat psoriaisis
