48-Cytokines Flashcards
What is a cytokine?
proteins released by cells that participate in the immune response
How is cytokine expressed?
released extracellularly or expressed on surface of the cell
How are cytokines recognized?
unique receptors in surface of immune cells. activation of receptor results in changes in the function
what are the functions of cytokines in the immune response?
hematopoiesis chemotaxis inflammation antiviral response (interferons) immune cell activation suppression
how do cytokines act?
autocrine, paracrine, endocrine
what is pleiotropy?
a single cytokine has more than 1 function depending on the cell it targets
B cell-activation, proliferation, differentiation
thymocyte-proliferation
mast cell-proliferation
what is redundancy?
cytokines have the same action
IL2, 4, 5 do proliferation
what is synergy?
cytokines act together for a response IL4 and 5 induce class switch to IgE
what is antagonism?
cytokines inhibit one another Il4 and IFNy block class switch to IgE
How is a cell fate decided?
cells integrate signals from many cytokines
what are the phases of sepsis?
cytokine storm and immune suppression?
what is the cytokine storm?
1st phase in sepsis, driven by release of inflammatory cytokines
what is the immune suppression in sepsis?
2nd phase, days to weeks after onset, immunosuppressive cytokines released. this phase is resolved with elimination of infection or death
cytokine treatments for sepsis
most have failed. have not shown and increase in survival and have worsened death
what are the 7 cytokine families
growth factory family TGF-B IL-1 TNF IL-17 chemokine classical
how are the cytokine families delineated
by their receptor which have distinct signaling pathway. signaling pathway defines the treatment for cytokine
Growth factor family receptor
tyrosine kinase domains
growth factor family action
increased tyrosine phosphorylation signaling, immune cell differentiation
TGF-B receptor
serine/threonine kinase domains, tetramerization of 2 type 1 and 2 type 2 for phosphorylation of SMAD proteins
TGF-B action
inhibit immune cell function, t cell differentiation, antibody production, promote tissue repair
IL-1 Family receptor
TIR domain, binding of MyD88
IL-1 family action
MyD88 induces downstream signaling to activation NF-kB for inflammation
What does IL-1Ra do?
inhibit IL-1
TNF family receptor
TRAF and TRADD
TNF family action
TRAF is inflammatory
TRADD does apoptosis
What does TNF alpha and TNFR1 (receptor) do?
part of TNF family that can be inflammatory or do apoptosis
IL-17 Family receptor
TLR and TNF
IL-17 family action
dimerization and bind ACT1 which interacts with TRAF for inflammation
Chemokine family receptor
7 transmembrane g protein coupled receptor
chemokine family action
activation of small molecular weight g proteins, chemotaxis (migration of immune cells)
what are the functions of chemokine receptors
inflammatory: movement towards infection
homeostatic: movement before an infection during homeostasis
atypical: silent and act as negative regulators
viral: allow pathogens to modulate immune responses
Classical cytokine family receptor
JAK/STAT, heterodimeric or trimeric
Classical cytokine family action
activation of JAK kinases to phosphorylate STAT, lots of functions
Type I Cytokine
Hemopoietin, conserved structural elements
Conserved cysteines, conserved WSXWS, conserved y, conserved B, conserved gp130
differentiation, homeostasis, activation, suppression
Type II Cytokine
Interferon
conserved cysteines, use distinct pools of JAK and STAT
antiviral responses
Three main classes of drugs targeting cytokine function
actual cytokine: EPO
antibody inhibitors of cytokines (anti-TNF)
small molecule drugs (anti-JAK kinase)
How do recombinant cytokines work
15 recombinations
enhance immune function (interferon a, b, y, epo, il-2, il-11, G-CSF, GM-CSF)
what is the exception to recombinant cytokines?
anakinra
how does anakinra work?
IL-1Ra which inhibits IL-1
what is the problem with recombinant cytokines
very powerful and substantial side effects
how do antibodies targeting cytokines work?
treat rheumatic disease, target IL-6, Blys, TNF-a, interferon-a
what is the problem is antibody cytokine drugs?
increased infection, expensive, not as dangerous because of redundancy and low level activation
how do small molecule inhibitors work?
inhibit JAK/STAT
what are the problems with small molecule inhibitors?
increased infection, cancer, thrombocytopenia
